Causes of Infertility

Backed by the expertise of our fertility specialists, we guide you through the medication options available. We understand that each individual's path to parenthood is different, and our goal is to provide clarity and support every step of the way.

Gain valuable insights into the complexities that may impact fertility, from hormonal imbalances to lifestyle considerations. Empower yourself with knowledge as you navigate the comprehensive provided, shedding light on the potential causes of infertility.

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Causes of Infertility

Adenmyosis and Infertility
Adenmyosis and Infertility
Options
Adhesions and Infertility
Adhesions and Infertility
Options
Aging and Infertility
Aging and Infertility
Options
Anti-Thyroid Antibodies
Anti-Thyroid Antibodies
Options
Caffeine and Infertility
Caffeine and Infertility
Options
Chlamydia and Infertility
Chlamydia and Infertility
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Covid-19 & Infertility
Covid-19 & Infertility
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Defective Uterine Lining
Defective Uterine Lining
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Diet and Ovulation
Diet and Ovulation
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Endometriosis and Infertility
Endometriosis and Infertility
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Female Athlete Triad and Infertility
Female Athlete Triad and Infertility
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Fibroids and Infertility
Fibroids and Infertility
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Hydrosalpinx, Infertility, And IVF
Hydrosalpinx, Infertility, And IVF
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Hypothyroidism Infertility And Pregnancy
Hypothyroidism Infertility And Pregnancy
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Insulin Resistance and Ovulation
Insulin Resistance and Ovulation
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Male Infertility
Male Infertility
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Obesity and Infertility
Obesity and Infertility
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PCOS
PCOS
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Premature Ovarian Failure
Premature Ovarian Failure
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Prolactin And Infertility
Prolactin And Infertility
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Smoking and Infertility
Smoking and Infertility
Options
Stress and Infertility
Stress and Infertility
Options
Thin Uterine Lining
Thin Uterine Lining
Options

Adenomyosis and Infertility

Anatomy of the uterus

To understand adenomyosis, it is necessary to understand that the uterus has different layers. The innermost layer, which lines the uterine cavity, is called the endometrium. An embryo implants in the cells of the endometrium. The endometrium is what is shed each month when a woman has a period. Moving outward, the next layer is composed of mostly muscle and is called the myometrium. The myometrium can be further divided into an inner layer which is also called the junctional zone (JZ) and an outer layer. The outermost layer of the uterus is a very thin covering called the serosa.

In normal women, the “dividing line” between the endometrium and the junctional zone (JZ) is clear and distinct. The JZ is thin.

Normal uterine layers

Adenomyosis

Adenomyosis is a poorly understood condition. Scientists and physicians are not certain what causes it to develop or the best way to treat it. Women with adenomyosis will sometimes have symptoms such as pelvic pain, pain with periods, irregular bleeding or heavy periods but sometimes they do not. It is uncertain whether women with adenomyosis are more likely to have infertility . More on that below.

Even describing adenomyosis is difficult. In milder cases, the only abnormality may be a thickened junctional zone. This thickening can be spread out all over the uterus (diffuse) or located in one spot (focal). In more advanced cases, there are areas where the endometrium has crossed the dividing line which normally separates it from the junctional zone. In the most severe cases, there are “islands of endometrial tissue in the muscle layer which form cysts in the uterus.

Previously, adenomyosis was only diagnosed after a woman had her uterus removed (hysterectomy) and inspected under a microscope. Today, there are two techniques that be used to help identify women with adenomyosis: transvaginal ultrasound  and magnetic resonance imaging (MRI). Even with these excellent new tools, the diagnosis of adenomyosis remains difficult.

Criteria used to make a diagnosis of adenomyosis on transvaginal ultrasound are as follows:

  • A globular or bulky uterus
  • Poor definition of the dividing line between the  endometrium and the muscle portion of the uterus (myometrium)
  • Thickening of the muscle portion of the uterus (myometrium) especially if it is
  • thicker on one side compared to another (asymmetry)
  • the junctional zone can be measured and is thicker than 10 or 12 mm
  • Cysts in the muscle portion of the uterus (myometrium)
  • Different appearance of the texture of the muscle portion of the uterus (myometrium)
  • Increased blood flow in the junctional zone
Ultrasound features of adenomyosis
Adenomyosis on ultrasound
Image credits: Michelle L. Stalnaker, MD, and Andrew M. Kaunitz, MD OBG Manag. 2014;26(6)

Adenomyosis and infertility

It is uncertain whether adenomyosis is a cause for infertility in women. There are few studies on the topic and even fewer good studies. One of the reasons why it has been difficult to determine whether adenomyosis is a cause for infertility is due to the fact that many women with adenomyosis also have another problem called endometriosis which is well known to cause infertility. Studies have estimated that of women with endometriosis, anywhere from 27% to 70% of those women may also have adenomyosis. The large range is due to differences in how adenomyosis is diagnosed (ultrasound vs MRI versus surgical removal of the uterus) and the criteria used to make the diagnosis.  

There are several reasons to suspect that adenomyosis could be a cause for infertility. The first has to do with uterine contractions. Some uterine contractions are good. There are uterus and fallopian tube contractions that help sperm to reach the egg in the fallopian tube. It seems that adenomyosis disrupts these good contraction. Later, at the time of embryo implantation, too many uterine contractions are bad. Adenomyosis may actually increase these bad contractions. The final reason is very complex. Whatever factors are responsible for the development of adenomyosis may simply make the uterus less able to allow embryos to implant.  

In vitro fertilization is one of the best treatments for infertility that we have. Several studies have been performed to try to determine whether adenomyosis affects in vitro fertilization pregnancy rates. In 2013, an analysis in which all of these studies were combined suggested that adenomyosis reduces the chance for pregnancy and increases the risk for miscarriage. Of particular interest was a study that looked at women using egg donation  instead of their own eggs. Using donated eggs ensures that all the women had good egg quality. Any difference in the pregnancy rate is more likely to be due to problems with the uterus. This study found that women with adenomyosis had double the risk of miscarriage. Remember, that the quality of these studies and their ability to rule out other causes of infertility (like endometriosis) are poor.

Treatment of adenomyosis to improve fertility

If we are not even sure that adenomyosis causes infertility then how can we be sure that treatment of adenomyosis will improve fertility. The answer is – we aren’t sure. Until better studies are performed, the treatment of adenomyosis to treat infertility should be considered experimental.

Surgery for adenomyosis and infertility

This is certainly the most invasive and the riskiest option. Some cases in which portions of the uterus with focal or nodular adenomyosis are removed and then resulted in pregnancy have been reported. These are difficult surgeries to perform because adenomyosis does not have distinct borders that distinguish normal uterus from the adenomyosis some precise removal is challenging. This is obviously not an option for diffuse adenomyosis.

Medications for adenomyosis and infertility

GnRH agonists (Lupron) which are commonly used to treatment endometriosis by lowering estrogen levels have been used to treat adenomyosis as well with some reported pregnancies. Aromatase inhibitors such as Letrozole also lower estrogen levels and have also been reported in the treatment of adenomyosis. Some scientists have identified that the junctional zone in women with adenomyosis may grow blood vessels more readily that other women. This is called angiogenesis. Angiogenesis is complex but one factor which drives the growth of new blood vessels is a hormone called VEGF. Therefore, a possible treatment to improve fertility in adenomyosis could be to reduce the action of VEGF in the uterus. One medication that does this is called cabergoline.  Fertility doctors are very familiar with the use of cabergoline since it is more commonly used to treat women with high prolactin levels. Another medication that may block the action of VEGF is called pentoxiphylline which is commonly used to improve blood flow in in patients with circulation problems. Pentoxiphylline has been studied as a treatment for endometriosis but so far has failed to be of proven benefit.

Adhesions and Infertility

Pelvic adhesions are also commonly referred to as scar tissue. Adhesions are areas of fibrous tissue that form as a result of the healing process which remain after the original inflammation or trauma has healed. Adhesions can cause different organs in the abdomen or pelvis to become stuck together. As a result, adhesions can distort the normal pelvic anatomy or cause decreased mobility and function. Therefore, pelvic adhesions can be a cause of infertility.

Adhesions can result from a number of different causes. Common causes of adhesions are infections, previous surgery, abdominal trauma, endometriosis , and appendicitis. Essentially, anything that causes inflammation in the abdomen can cause adhesions. In some cases, women are found to have adhesions even without a history of any of the above conditions. In some of these women, adhesions might have resulted from a previous pelvic infection. Since not all pelvic infections in women may have noticeable symptoms, the woman might not have realized that she had the infection. Nonetheless, adhesions may have formed as her body worked to get rid of the infection.

Tube and Ovary Interaction

Normally, the ovaries and fallopian tubes are mobile and can easily interact with each other. At the time of ovulation, the developing egg starts to bulge outward causing a bump on the surface of the ovary called the “stigma”. The ends of the fallopian tubes have fine fingers or “fimbriae” which can capture the egg. At the time of egg release, the stigma becomes sticky. The fallopian tube, which normally can sweep the fimbriae over the surface of the ovary, will stick to the area of the stigma so that the egg is released directly into the fallopian tube.

Adhesions may affect the chances for a woman to get pregnant if it becomes more difficult for the egg to enter the fallopian tube at the time of ovulation. Adhesions will sometimes form a barrier between the ovary and the fallopian tube. Think of a sheet with the ovary on one side and the tube on the other. When the egg is release from the ovary, the tube cannot get to it. Other types of adhesions may pull the tube and ovary apart so that the fimbriae cannot reach the egg at ovulation.

There are cases in which a woman may have adhesions in her abdomen or pelvis that don’t affect the tubes or ovaries. These adhesions may cause pain or other health problems but they will not impair her ability to become pregnant.

Tubal Blockage Versus Adhesions

It is important to distinguish between fallopian tubes that are “blocked” from those that are “open” but affected by adhesions. Blocked fallopian tubes occur when there is an actual obstruction within the fallopian tube. The tube itself may have normal mobility. A blocked fallopian tube can be diagnosed using a hysterosalpingogram . Pelvic adhesions can only be diagnosed with surgery to look inside the abdomen.

Categories of Pelvic Adhesions

Over the years, physicians have tried classifying adhesions so that more uniform descriptions can be given for adhesions. This allows for more easy comparisons between patients and allows fertility doctors to more easily assess the potential benefits of treatments to remove or prevent adhesions.

Filmy adhesions are very thin and can usually be broken apart easily with gentle pressure or tugging. Thick adhesions often are vascular (contain blood vessels) and require disruption via mechanical mean or with energy (such as electrical or laser) to be removed. Band adhesions may connect two structures by forming a “band” or string-like structure between them. Flat adhesions result when two structures are “stuck” together.

Treatment of Adhesions to Improve Fertility

Surgery is the only effective treatment for pelvic adhesions. Fertility doctors will use the term “lysis of adhesions” to describe the surgical procedure to cut away adhesions and restore the normal pelvic anatomy. As a general rule, the less adhesions that are present, the more it is likely that surgery will be effective at producing a pregnancy. Why aren’t all surgeries to remove adhesions successful? One reason is that adhesions can recur after a surgery. In addition, new adhesions may form after a surgery is performed, even if the purpose of the surgery was to remove adhesions.

Fertility doctors will try to use many techniques to prevent adhesions from returning or to prevent new adhesions from forming. Often, this involves putting absorbable “barriers” in the pelvis to prevent different structures from getting stuck together. Another method is to place various types of fluid in the abdomen after the surgery.

Be Aware of False Treatments

On the internet, there have been heavily advertised websites promoting the use of various types of abdominal massages to improve the fertility of women with pelvic adhesions. By mixing in a little bit of science and preying on the hopes of couples with infertility, people have been successful at separating couples from thousands of dollars of their hard earned money for “treatments” that lack any proven benefit.

The pelvis is protected on all sides by several bones. The very top of the pelvis is below the pubic hair. Massaging someone’s abdomen does not even come close to manipulating the pelvic organs. Do not fall prey to these false treatments.

Aging and Reproduction

The largest number of births ever in the United States occurred in the post World War II “baby boom” between 1947 and 1965. Women born during this time period have reached the age of 35 starting in 1982 and will continue until the end of the century. During this time period, there is an unprecedented number of women in their late child bearing years.

In addition, many women have decided for various reasons to delay childbearing. This is a significant change from the patterns of our parents’ generation, and means that more couples will be seeking pregnancy after the age of 35. Furthermore, these couples also have a desire to complete their families in a shorter period of time.

Decline of Fertility with Age

Fertility experts now all agree that fertility decreases with age. There are several pieces of evidence that point to this fact. Some of the most interesting studies involve a religious group known as the Hutterites. The Hutterites migrated to the U.S. from Switzerland in the 1870s and now live in the Dakotas, Montana, and parts of Canada. They are believers in large families and condemn the use of any form of contraception. They also marry only within their own group and since they live in a set geographic area, are relatively easy to investigate. For these reasons, they make ideal candidates to study the effects of aging on reproduction. It was thus found that the fertility rate (the number of women achieving a pregnancy per 100 women) is much higher in younger women (twenties) than in older women (forties). After a pregnancy is delivered, it is the Hutterites’ practice to immediately attempt to achieve pregnancy again. However, it was noted that the time between pregnancies became increasingly longer with increasing age of the women studied. The average age at the time of the last pregnancy was 40.9.

Other data also supports the notion that fertility decreases with age. Compared with younger women, women over the age of 35 seek evaluation for infertility twice as often. Some investigators have suggested that this decline is due to a decreased frequency of intercourse in “older couples”. For this reason, investigators in France studied the fertility rate amongst women who were attempting to become pregnant in a donor insemination program because their own partners had no sperm. In this way, the frequency of intercourse did not interfere with calculations of fertility. As expected, the fertility rate dropped significantly after the age of 30 and again after the age of 35. Another similar study suggested that the probability of having a baby decreased 3.5% per year after the age of 30.

Increased risk of Miscarriage with age

In addition to the lower chance of becoming pregnant, as women age they also have a higher chance of losing the pregnancy (miscarriage ). What are the reasons for this? To explain, it is necessary to discuss some aspects of genetics.

We basically all start out when our father’s sperm fertilizes our mother’s egg. We therefore have the characteristics of both our parents. These characteristics are coded in a special way and are found in the structures known as chromosomes. In fact, the information found on these chromosomes contains all the information about every part of us. The sperm and egg each contain 1/2 of the chromosomes necessary to make a complete human being. In fact, to describe it in lay terms, the process of making sperm and eggs is nothing more than the packaging of different combinations of chromosomes so that they can be “mixed” together with another egg or sperm to make different varieties of humans.

Women are born with all the eggs that they will ever have in their lives (with the chromosomes inside). Men, on the other hand, make fresh sperm continuously throughout their whole lives. It takes approximately 90 days for a sperm to be made and to reach maturity. This is an extremely important difference between the sexes because, for example, if a 35 year old man and a 35 year old women attempt to achieve a pregnancy, they are basically trying to combine a 35 year old egg with a 3 month old sperm.

The longer an egg sits around in the ovary, however, the more likely it is to develop abnormalities in its chromosomes. If an egg with abnormal chromosomes is fertilized, then the chances are greater that the resulting pregnancy will end in miscarriage. In fact, chromosomal abnormality is the single most common cause of miscarriage. From many studies, we know that at least 2/3 of all miscarriages are due to abnormal chromosomes.

A young women (in her 20s), therefore, has only a 12-15% chance of having a miscarriage each time she becomes pregnant. A women in her 40s has, however, a 50% risk of miscarriage.

Down’s Syndrome and other Chromosomal problems

Aneuploidy rate according to age

Not every pregnancy in which the embryo has abnormal chromosomes will end in a miscarriage. Some will continue to develop and even result in the birth of a live baby. These babies, however, can have varying problems, including birth defects and mental retardation. Down’s syndrome is the most common problem of this type but there are others. The table lists the risk of a baby with Down’s Syndrome (Trisomy 21) or with other chromosomal abnormalities depending on the age of the mother at the time of delivery. As can be seen, there is a progressive increase in the risk as age increases. This is all as a result of aging of the eggs.

Why does Fertility Decrease? The Debate Between the Eggs and the Uterus

Up until recently, it was not known why fertility decreases with age. One thing was known for sure and that was that the age of the male partner didn’t seem to matter much. Even men in their 70s still seemed to be able to produce pregnancies. The Bible carries stories of men in their 90s fathering children. Some recent data has suggested that there may be a decrease in fertility as male age however, it is a very mild effect and doesn’t seem to have an absolute upper limit. In women however, the likelihood a pregnancy after age 45 is an extremely rare event.

The next question to answer was, why? Research has focused on two areas: aging of the uterus versus aging of the eggs. Until recently there was no way to separate these factors out. However, the technology of egg donation has enabled to look at these factors separately. Egg donation is the process whereby eggs from a young woman can be fertilized and placed into the uterus of an older woman. If fertility decreases because an older woman’s uterus is less capable of carrying a pregnancy, then using younger eggs shouldn’t produce very many pregnancies in older women. What we found, of course, was exactly the opposite. If you use younger eggs, the rate of achieving pregnancies in older women is very high. In fact, egg donation gives the highest rate of pregnancy that is achievable with any type of fertility treatment!

Aging and Reproduction

This graph shows that women in their forties, fifties, and even sixties can all achieve very high pregnancy rates with egg donation. On the other hand, women who attempt IVF with their own eggs see a steady decline the chances for a live birth. This is excellent proof that fertility decreases with age due to aging of the eggs and chromosomes. Studies that have removed eggs from the ovaries of older women have shown that a large percentage of them have abnormal chromosomes. So there is probably a continuum of possible outcomes in chromosomally abnormal eggs. Most probably won’t fertilize, of those that due many will be lost to miscarriage, the few that remain will end up as a Down’s Syndrome or a related problem.

But I had a friend who had a normal baby when she was 46 years old!

Every human being is different. Not all women will develop abnormalities in their egg’s chromosomes at the same age. And if course, even if a women has a majority of her eggs that contain abnormal chromosomes, it only takes one to achieve that “normal pregnancy”. The great majority of women will not be able to become pregnant at age 46. On the other hand, some younger women can have a more rapid decline in the ability of their eggs to produce a pregnancy.

AMH and Ovarian Reserve

AMH or anti-mullerian hormone is a hormone produced by the viable follicles (which contain eggs) that remain in the ovary. It is an excellent indicator of ovarian reserve. Young women with large numbers of healthy eggs tend to have high AMH levels whereas older women or women with a low number of healthy eggs will have lower levels of AMH.

AMH levels do not fluctuate very much and are no impacted by the levels of other hormones such as estrogen or progesterone.

Abnormal AMH levels are usually determined by comparing a woman’s own AMH level with that of a large group of women her own age who do not have infertility. For example, an AMH of 1.4 would be considered very low for a fertile 18 year old but would be considered average for a 36 year old.

FSH (Follicle Stimulating Hormone) and Ovarian Reserve

Another important test used by physician’s to determine a woman’s “ovarian reserve“, that is, the capability of her eggs being able to produce a pregnancy, is a blood test called FSH. FSH stands for Follicle Stimulating Hormone. FSH is made in a gland near the brain gland called the pituitary. It is the KEY hormone responsible for the cyclic development of eggs every month. As a woman’s eggs become less capable of producing a pregnancy, the levels of FSH begin to rise. Therefore, as you might expect, FSH generally increases in women as they get older. Women who have gone through menopause have very high levels of FSH (and are incapable of becoming pregnant with their own eggs). However, young women who have had an accelerated decline in the quantity or quality of their eggs can also have high FSH levels.

In order to determine a woman’s FSH levels for the purpose of predicting fertility, the blood should be drawn on the third day of the menstrual cycle. At the IVF1 Laboratory, a normal level for FSH on day 3 is less than 10 IU. Women with levels between 10 and 15 are considered elevated but have been able to achieve pregnancies with us. Women with levels consistently over 15 have an extremely poor chance for pregnancy.

Now to add little more complexity. Day 3 FSH levels can vary from month to month and can be affected by such things as estrogen levels. In other words, a high FSH level one month doesn’t necessarily mean it will be elevated every month. This makes the determination of a woman’s ovarian reserve more difficult since the measurement on a given month may appear to be normal. Unfortunately, women who have FSH levels that fluctuate seem to have as poor a chance for a live birth as women who have persistently elevated FSH levels.

Other measure of ovarian reserve that have emerged in recent years include the clomid challenge test , blood levels of AMH , and ultrasound measurements of ovarian volume and antral follicle counts.

Fertility Treatment for Older Women

Unfortunately, there are no treatments available which can “turn back the clock” on a woman’s ovaries. Many physician’s use fertility medications to try to increase the chance of pregnancy. For this indication, the idea behind using fertility medications is to increase the number of eggs that develop in a given month, thus enhancing the chance that at least one of them might be able to be fertilized and develop into a viable pregnancy. This seems to result in some improvement in results, but the pregnancy rates are not as good as in younger women. Also, many women don’t respond well to fertility medications as they get older. Others have advocated In vitro Fertilization – IVF as a means to achieve pregnancy in such cases. Unfortunately, the pregnancy rates with In vitro Fertilization – IVF in women over the age 40 are very low.

Currently, the only consistently successful method to improve pregnancy rates in women with age related infertility is egg donation (also called oocyte donation). As compared to pregnancy rates of less than 10% per cycle for women over the age of forty, egg donation results in pregnancy rates of over 65% per cycle. In addition, the risks of miscarriage and Down’s Syndrome are dramatically reduced. Thus the likelihood of “taking home a baby” are very much higher.

Fertility decreases with age. This decrease is most likely due to aging of the eggs and the chromosomes inside them. The risk of miscarriage and chromosomal abnormalities in babies also increase with age. The most successful method for achieving a pregnancy and taking home a baby at advanced female age is with the use of egg donation.

Anti-Thyroid Antibodies

The most common cause of hypothyroidism is the presence of elevated levels of antibodies directed to the thyroid gland (this used to be known as Hashimoto’s thyroiditis). It is possible, however, to have elevated levels of anti-thyroid antibodies and still have a normally functioning thyroid gland. In this case, it is important to monitor the thyroid hormones on a regular basis since these women are at greater risk for hypothyroidism in the future. They must also be checked in pregnancy and after delivery since these are times when a woman may be more prone to thyroid malfunction.

Anti-Thyroid Antibodies and Miscarriage

Women with anti-thyroid antibodies and a normally functioning thyroid gland may be at greater risk for miscarriage. Some studies looked at women with recurrent miscarriage and found that they have higher levels of anti-thyroid antibodies compared to women without recurrent miscarriage. Some studies did not find an association. One publication combined the results of 18 studies on this topic (meta-analysis) and concluded that there is an ASSOCIATION between the presence of elevated anti-thyroid antibodies and miscarriage. One of the most recent studies on the topic, which has also been one of the largest, again showed a correlation between thyroid antibodies and miscarriage. There are several explanations for why there may be an association between anti-thyroid antibodies and miscarriage.

Link to Other Autoimmune Problems

It is possible that women with elevated levels of anti-thyroid antibodies may have other immune problems and these other problems may be responsible for miscarriage. It is well accepted, for example, that another type of immune problem involving anti-phospholipid antibodies can cause miscarriage. Some of the studies did try to control for this problem by excluding women who had abnormal levels of other known antibodies but there still may be immune issues that they did not control for.

Direct Involvement of the Antibodies

A commonly asked question is why antibodies against the thyroid gland would cause a problem elsewhere. It may be possible that the anti-thyroid antibodies may “get confused” or “cross react” and therefore also attack placental or fetal tissues. If this hypothesis were true, we should see a “dose-response relationship” That is, we would expect higher levels of anti-thyroid antibodies in women who actually miscarried compared to those who had a full term delivery. Most studies did not look at this. Two studies did not find a dose response relationship and one did.

Effect of Age

In most of the studies analyzed, women with elevated levels tended to be older as a group compared to those women with normal antibody levels. Since the miscarriage risk for women increases with age, this could be an explanation.

Sub-Clinical Hypothyroidism

Women with anti-thyroid antibodies are at higher risk for developing clinical hypothyroidism. They also have a higher rate of sub-clinical hypothyroidism. Some studies show that even when thyroid function is in the normal range that women with antibodies may have a slightly higher TSH level than women without antibodies.

Treatment of Anti-Thyroid Antibody Related Miscarriage

Selenium

Very well designed trials indicate that selenium supplementation may reduce the levels of some types of anti-thyroid antibodies. It is possible that if the levels of the antibodies can be reduced, then the risk of miscarriage may also be reduced The effects of selenium in pregnancy were recently evaluated in a study performed in Italy. Approximately 150 pregnant with with elevated levels of one group of thyroid antibodies were split into two equal groups. One group received 200 micrograms of selenium and the other group received placebo. During pregnancy and post-partum, more women who took the placebo were more likely to show evidence of thyroid malfunction and need thyroid hormone supplementation.

Additional information about selenium

Thyroid Hormone Supplementation

One very small study found that low dose supplementation of thyroid hormone reduced the miscarriage risk when compared to another common immune therapy. Another larger study did not find a benefit. In this study, women who were positive for anti-thyroid antibodies were randomly assigned to receive either thyroid hormone or placebo. These two groups were compared to a third group who were negative for anti-thyroid antibodies. All the patients in the study underwent IVF to achieve pregnancy.

The study findings were as follows :

  • The pregnancy rate with IVF was similar in all groups. In other words, the presence of anti-thyroid antibodies did not influence the chances for success and using thyroid hormone did not improve the chances for success.
  • The miscarriage rate with IVF was higher in women who had anti-thyroid antibodies. Using thyroid hormone for treatment did not reduce the risk for miscarriage.

The largest study to date involved over 1000 women. Women with elevated thyroid antibody levels were compared to women with normal levels. Those women with thyroid antibody elevations were divided into two groups. One group received thyroid hormone, the other did not.   The results of the three groups were then compared.  The women who did not have thyroid antibody elevations and the women who received thyroid hormone had lower miscarriage rates. The group with thyroid antibodies that did not receive thyroid hormones had a much higher risk for miscarriage. Statistical analysis showed that these results were unlikely to be due to chance.  

At this point, therefore it does seem reasonable to use selenium and thyroid hormone as a means to reduce miscarriage risk in women with thyroid antibodies.    

Caffeine and Infertility

Caffeine and Fertility for Women

Caffeine use is associated with a decreased potential to produce a pregnancy. Studies show link between caffeine and infertility .

In a 1999 study of 100 women who abstained consumed less than one cup of coffee or its equivalent per day conceived 26.9 pregnancies per 100 menstrual cycles compared with 10.5 per 100 menstrual cycles among those who consumed more than one cup of coffee per day.

In another study from 1989, 104 healthy women who had been attempting to become pregnant for three months were interviewed about their use of caffeinated beverages. In their subsequent cycles, women who consumed more than the equivalent of one cup of coffee per day were half as likely to become pregnant, per cycle, as women who drank less. The more a woman drank, the lower her chances for becoming pregnant.

The effects of caffeine intake from different sources on fertility were assessed in a national survey of 423 Danish couples. Couples were recruited to the study in 1992-95 through a mailing to 52,255 female trade union members seeking women who were 20-35 years old, lived with a partner, had no previous pregnancies, and intended to discontinue contraception in order to become pregnant. Compared with women with a very small caffeine intake, those with a moderate intake of caffeine had a lower chance for conception while those with a higher consumption had a much lower chance for pregnancy. The relationship held up after adjustments for weight, alcohol intake, diseases of the female reproductive organs, semen quality, and duration of the menstrual cycle.

In early 2005, a study published in the journal Diabetes Care demonstrated that caffeine makes it more difficult for insulin to control blood sugar. This problem, known as insulin resistance , can play an important role in women. Insulin resistance can cause a woman not to ovulate. Women who already have insulin resistance include those who are obese and those with PCOS.

Caffeine and Fertility for Men

Much confusion has arisen over caffeine use in males. When sperm are treated under laboratory conditions with caffeine there is a short increase in the percent of motile sperm. However, over the longer term, the percent of moving sperm declines more quickly.

When men drink caffeine, most studies show a decrease in their ability to produce a pregnancy. The same Danish study that found a decrease in fertility from caffeine in women also found a similar decrease when men were the ones consuming caffeine.

Chlamydia and Infertility

Chlamydia is a common sexually transmitted infection (STI) caused by the bacterium, Chlamydia trachomatis. Chlamydia infection is extremely common. Chlamydia is the most common sexually transmitted infection in the United States. The Center for Disease Control estimated that 2.8 million Americans are infected with chlamydia each year.

Chlamydia can be transmitted during vaginal, anal, or oral sex. Chlamydia can also be passed from an infected mother to her baby during childbirth. Any sexually active person can be infected with chlamydia. The greater the number of sex partners, the greater the risk of infection.

About 75% of infected women and about 50% of infected men have no symptoms of chlamydia infection. If symptoms do occur, they usually appear within 1 to 3 weeks after exposure. Women who do have symptoms might have an abnormal vaginal discharge or a burning sensation when urinating. If the infection spreads from the cervix to the fallopian tubes some women still have no signs or symptoms; others have lower abdominal pain, low back pain, nausea, fever, pain during intercourse, or bleeding between menstrual periods.

Chlamydia Can Cause Infertility

In women, untreated infection can spread into the fallopian tubes and cause the tubes to become blocked at the very ends. This is known as hydrosalpinx. They can also develop scar tissue around the fallopian tubes that makes it more difficult for the tube to “pick up” the egg at the time of ovulation. The problems can lead to infertility and an increased risk for ectopic (tubal) pregnancy.

Distal tubal obstruction can be detected by performing a hysterosalpingogram. Pelvic adhesions , however, can only be detected by undergoing a surgical procedure to look inside of the abdominal cavity. This is usually done using a technique called laparoscopy where a fiber optic telescope is inserted through the belly button under general anesthesia. Since laparoscopy is a much more invasive procedure, it is desirable to avoid it whenever possible.

Blood Tests To Detect Tubal Damage From Chlamydia

The most common test to detect chlamydia infection in women involves taking a swab from the cervix during a speculum exam in the doctor’s office. The swab is tested for chlamydia DNA. The problem with this test is that it does not tell the physician how long the infection has been present, how severe the infection is and whether the woman with the infection has sustained tubal damage. The swab test can also miss an infection that has moved up into the uterus or tubes and is no longer in the cervix.

Blood tests can also be performed to detect the antibodies the body makes when exposed to the chlamydia bacteria. These blood test are fairly predictive for finding women with tubal damage during laparoscopy. A recent study found that the presence of the chlamydia antibody predicted the presence of tubal damage (blockage or adhesions) correctly 62% of the time. Conversely, the absence of the chlamydia antibody predicted the absence of tubal damage 90% of the time.

It is important to note that the presence of elevated levels of chlamydia antibody does not necessarily mean that a woman has an active chlamydia infection. It simply indicates that she was exposed to the bacteria. In fact, it is estimated that, if left untreated, about 45% of infected women without symptoms will clear the bacteria from their bodies. In women who clear an infection rapidly, the risk of tubal damage may be low. On the other hand, persistent exposure may result in chronic inflammation and may increase the risk of tubal damage.

Another blood test that may be useful is called the C reactive protein (CRP). For many years, CRP was known as a highly sensitive but non-specific marker for acute inflammation. It is produced in the liver and rises to very high levels within 4-6 hours following acute injurious conditions such as trauma, surgery, or infection. More recently, researchers have developed a more sensitive test called hsCRP (highly sensitive CRP). with this new test, it is now possible to measure conditions indicative of chronic, low grade inflammation.

A recent study has found that combining the chlamydia antibody test and the hsCRP increased the chance of finding tubal disease to almost 90%.

Treatment of Chlamydia For Infertility

Chlamydia can be easily treated and cured with antibiotics. Her partner should be tested and treated. The couple should abstain from sexual intercourse until they have completed treatment, to prevent reinfection. Having multiple infections increases a woman’s risk of infertility.

Commentary

Laparoscopy is not a benign procedure. It is a surgery that requires general anesthesia and carries the same risks as any surgical procedure. It is very desirable to have a way to predict ahead of time which women are likely to benefit from laparoscopy and which women are unlikely to benefit. It appears from the results of this recent study that we can predict accurately about 90% of the time.

Women who have elevated levels of the chlamydia antibody and hsCRP should be given the option of having a laparoscopy as part of their infertility evaluation.

Covid-19 & Infertility

This information is current as of August 1st 2021.

Can Covid-19 Be Transmitted From Mother to Fetus During Pregnancy?

There is currently SOME evidence that women can infect their babies with Covid-19 while pregnant or through giving birth to them.

In a large study from the UK, of the babies born to infected women, 5% tested positive for SARS-CoV-2. Half of those positive tests were taken immediately after birth suggesting infection occurred during pregnancy.

So far it seems that the risk to a fetus during a pregnancy in which the mother is infected in the 3rd trimester is small*

Can Covid-19 Cause Infertility?

Not many studies have not been done to see if having COVID-19 could make it harder to get pregnant. Studies performed here at IVF1 did not show lower pregnancy rates in women undergoing IVF embryo transfer in women with a previous Covid infection compared to women who were not infected.

Can Covid-19 Cause Male Infertility?

Currently, there is limited EVIDENCE that Covid-19 infection leads to male fertility problems.

Some studies have found evidence of inflammation in the testicles of men who died from Covid 19. One study compared 14 men with mild symptoms of COVID-19, 4 with moderate symptoms, and 14 healthy control men. They found lower sperm numbers and lower sperm movement in the men with Covid compared to healthy men

Another study of 23 men examined their semen about a month after they tested positive for Covid-19 and did not find any impact on sperm numbers, movement or appearance.

In a 3rd study of 12 men with Covid, 11 had moderate symptoms. A semen analysis done about 2 and a half months later was normal in 8 out of the 12. Hormone changes in men were found. Finally, a fourth study of 30 men showed that Covid infected men had a higher percentage of abnormal appearing sperm.

If I Contract Covid-19 While I Am Pregnant, Would My Illness Be More Severe?

There is good evidence, that pregnant women who contract Covid-19 are at risk for becoming more ill than others.

A recent data analysis from the Centers for Disease Control and Prevention (CDC) COVID-19 surveillance identified over 400,000 women with Covid-19 during the first wave. The findings showed that compared to non-pregnant women, pregnant women have

  • A 3 fold increased risk of ICU admission (10.5 per 1000 of pregnant vs 3.9 per 1000 non-pregnant women)
  • A 3 fold increased risk for needing mechanical intubation (2.9 versus 1.1 per 1,000 cases)
  • A 70% higher chance of dying (1.5 versus 1.2 per 1,000 cases)
  • Irrespective of pregnancy status, ICU admissions, receipt of invasive ventilation, and death occurred more often among women aged 35–44 years than among those aged 15–24 years
  • Black and Hispanic women were more likely to be affected

The Delta variant appears to be more infectious and cause more severe disease than earlier Covid variants. In a large study from the U.K., the percentage of pregnant women who were admitted to the hospital and developed moderate or severe Covid illness was

  • 24% in the first wave
  • 36% in the second wave
  • 45% in the third wave

Does Infection With Covid-19 Increase My Risk For Miscarriage?

A small study did NOT find that 1st trimester miscarriage was more common in women who were infected with SAR-CoV-2. The study was performed in Italy. Researchers identified 100 women who miscarried in the first trimester and compared them to a similar group of 125 women who did not have a miscarriage. The percentage of women who tested positive for Covid was the same in each group. Although this was a small study, these initial results are reassuring

Does Infection With Covid-19 Increase My Risk For Other Pregnancy Complications?

Preterm delivery appears to be more common when the mother is diagnosed with Covid-19 during the 2nd or 3rd trimester. A CDC study of 3,912 live births with known gestational age, 12.9% were preterm (<37 weeks), higher than the reported 10.2% among the general U.S. population in 2019.

More recent studies have found the the likelihood for developing pre-eclampsia, eclampsia or HELLP syndrome was was higher in pregnant women with Covid, even if their disease was mild. Other respiratory viral infections during pregnancy, such as influenza, have been associated with adverse outcomes, including low birth weight and preterm birth.

Defective Uterine Lining

The uterine lining is called the endometrium. The endometrium has two important parts. The basal layer is the bottom layer closest to the muscle of the uterus. The basal layer always remains in the uterus even after a woman has her period every month. The basal layer does not grow or change in response to hormones. Most importantly, the basal layer contains many of the stem cells which are necessary to regenerate the uterine lining every month.

The functional layer is located on top of the basal layer. This layer grows and changes in response to hormones. These changes are mandatory in order to allow an embryo to implant. In the absence of pregnancy, it is the functional layer that is shed every month when a woman has her period.

Decidualization

After ovulation, the ovary produces progesterone. Progesterone (along with a slew of other molecules and growth factors) changes the uterine lining so that an embryo is able to implant. In the first several days after ovulation, the changes in the uterine lining are called secretory changes. After several days, there are further changes which are called decidual changes. The entire process is known as decidualization.

Much has been learned about the process of decidualization in the last few years. It is now believed that defects in the process of decidualization may cause infertility, miscarriage and other complications of pregnancy.

Important Cells For Decidualization

Once group of cells found in the functional layer of the endometrium are called endometrial stromal cells (EnDC). Progesterone (and other factors) change the EnDC into decidual cells (DC). However, not all of the EnDC cells will become decidual cells. Some may instead develop into a different cell type that doesn’t allow for healthy embryo implantation. These “bad” cells are acute senescent decidual cells (sometimes referred to as SASP). Senescent cells do not respond to progesterone and are responsible for the shedding of the lining each month.

How Does The Uterine Lining Become “Healthy”?

In seems that healthy decidualization starts with the uterine lining regenerating itself normally after a woman has her period. The EnDC must be replenished and, after ovulation, they must be converted to decidual cells (DC) instead of senescent cells.

Cells in the basal layer called Endometrial Mesenchymal Stem-Like Progenitor Cells (eMSC) are primarily responsible for replenishing the EnDC. However, recent evidence has now pointed to another important source of stem cells to help replenish the uterine lining. These cells come from the bone marrow!

The Important Role of Bone Marrow

Inside of your bones are stem cells that are important for replenishing many different kinds of cells. Most people are aware that the bone marrow is the source of blood cells. Some of the bone marrow stem cells also make other types of cells (not blood cells). The cells are called bone marrow derived cells (BMDC). It now appears that BMDC are important for forming and maintaining a uterine lining that has healthy decidualization.

How Does The Uterus Communicate With The Bone Marrow?

Estrogen from the ovaries causes the uterine lining to thicken and causes the production of a growth factor called SDF-1. SDF-1 causes the bone marrow to release BMDC and draws those BMDC to the basal layer of the endometrium.While there, the BMDC change into eMSC which replenish the EnDC and promote the formation of decidual cells instead of senescent cells.

How Can This Help Me Have a Baby?

Doctors may be able to manipulate this system with medications to help women gain a healthier uterine lining and improve decidualization.

For example, studies have found that women with recurrent miscarriage have low levels of eMSC in the basal layer and have an excessive amount of senescent cells compared to decidual cells after ovulation.

One recent study used a diabetes medication called sitagliptin in women with recurrent miscarriage and found that it increased the amount of eMSC and improved the ratio of healthy decidual cells compared to senescent cells. It also appeared to reduce the risk of miscarriage.

Role Of Diet In Ovulation Problems


It is estimated that about one in six couples will be faced with the problem of infertility at some point during their reproductive lifetime. Of those couples, problems with ovulation (making and releasing an egg in a regular fashion) can be identified in 18-30% of cases. Several factors have been found in medical studies to affect the likelihood of ovulation. Most commonly, extremes of body weight (both obese and underweight) have been associated with ovulation problems. Recently, evidence has begun to emerge that the type of diet a woman consumes may influence her risk for ovulation problems.

In a recent study, researchers used data from a large group of nurses known as the Nurses Health Study II. The Nurses’ Health Study II was started in 1989 when more than 116,000 female registered nurses aged 25–42 years completed a mailed baseline questionnaire. Participants have been followed every two years since then with mailed questionnaires. Finding women who were trying to get pregnant With each questionnaire, participants were asked if they had tried to become pregnant for more than 1 year without success since the previous questionnaire. They were also asked to identify whether they believed their inability to conceive was caused by blockage of their fallopian tubes, a problem with ovulation, endometriosis, cervical mucus factor, male factor, or was not found, was not investigated, or was due to another reason.

In order to determine how accurately, these nurses reported their actual diagnosis, the researchers conducted a “validation study” in which they reviewed the medical records of a small portion of the larger group. The researchers found that a diagnosis of an ovulation problem was correctly reported by the nurses 95% of the time.

Women were also asked if they became pregnant during the preceding 2-year period, including pregnancies resulting in miscarriages or induced abortions. Only married women without a history of infertility and with available information on diet, physical activity, height, and weight were eligible to enter the analysis.

In total, the researchers identified 17,544 women without a history of infertility who tried to become pregnant or became pregnant during the study period – which lasted eight years. 25,217 pregnancies and pregnancy attempts were estimated among this group. 3,209 nurses reported difficulty in becoming pregnant. Of these, 2,032 actually sought medical care for the diagnosis of infertility. Only 416 of the infertile women reported an ovulation problem as one of the reasons for their infertility.

Assessing the diet of these women In the mailed questionnaires, the nurses were also asked to report how often, on average, they consumed each of the foods, beverages, and supplements included in a “food frequency” diary during the previous year. The researchers were interested in several components of diet. Specifically, the categories were:

  • The amount of trans fats compared to “monounsaturated” fats
  • The amount of protein from animal sources (meat) compared to vegetable sources (beans)
  • The amount of carbohydrates from refined sources (white bread)
  • The use of multivitamins and specifically the amount of iron intake
  • The amount of “high fat” dairy products versus “low fat dairy products”


Within each category, a “fertility score” was given based on perceived benefit or harm. For example, a large amount of trans fats in the diet was thought to be bad and so this would be given a low score. Conversely, a high percentage of protein that came from vegetable sources was thought to be good and so was given a high score.

Fertility Diet Score

Results

The results of this study showed that diet plays a role in causing ovulation problems. The higher a woman’s fertility score, the less likely she was to have an ovulation problem. Looked at in another way, if each category was considered a dietary habit, the more “good” dietary habits a woman had, the less likely she was to have problems with ovulation. It should be noted that these relationships still held up when the researchers compared women under age 35 to women over age 35 or for those who had pregnancies previously compared to those who didn’t  and for women who were normal weight or overweight.

Lowest to Highest Likelihood of having ovulation problems
1 Baseline
2 32% less likely compared to group 1
3 35% less likely compared to group 1
4 47% less likely compared to group 1
5 66% less likely compared to group 1


The study also confirmed what many other studies found: that extremes of weight are also associated with ovulation problems. The impact of weight was identified by using a calculated number (body mass index) which takes into account a woman’s height and weight. A normal body mass index is between 20 and 24.99. A number below 20 is considered underweight. A number of 25 or over is considered overweight. A number of 30 or over is considered obese.

  BMI Likelihood of having ovulation problems
Less than 20 38% more likely compared to normal weight
20-24.99 Baseline
25-29.99 32% more likely compared to normal weight
30 or more 35% more likely compared to normal weight

Recommendations

The results of this study should be interpreted with caution. First of all, the numbers are very small. From a group of over 100,000 nurses in the original group, only 416 were found to have ovulatory infertility. If is from these few hundred women that all the conclusions are based.

Furthermore, these recommendations only apply for women who have a problem with ovulation. The current study does not indicate associations with these diet parameters and other types of infertility. For example, this study did not address women with unexplained infertility. There is no evidence from this study to indicate that other causes of infertility are related to diet.

This study also did not attempt an experiment where the type of diet was changed to see if ovulation improved in women who previously had a problem. Although it might seem logical to assume that the changes in dietary habits from “bad” to “good” should result in lowering the rate of ovulation problems, this study did not attempt to prove that. There may be other factors related to diet that could be of importance. For example, the authors noted differences in the rates of alcohol use, caffeine use and smoking when comparing women with high fertility diet scores to women with low scores. These other factors may be important confounding factors.

On the other hand, with one exception, the type of diet that the authors claim is related to a lower risk of ovulation problems is generally considered to be a healthier diet overall. For example, much data points to the adverse effects of trans fats in the diet. The one exception is that increasing amounts of “high-fat” dairy items seems to be associated with less ovulation problems than “low-fat” dairy items for unknown reasons.

So keeping all this in mind, here are some general recommendations for women with ovulatory infertility:

1. Maintain a healthy weight (a body mass index of between 20 and 24.99).

Lose weight, if you’re overweight or obese and try to gain weight if you are underweight. Exercise may help with losing weight but, by itself, may not help improve the chances for ovulation.

2. Avoid trans fats completely.

Trans fat is typically found in stick margarine, fried foods, and yes, Girl Scout cookies. Foods in the United States are required to list their trans fat content on the package. If trans fat is not listed, look at the ingredients and avoid foods that contained “partially hydrogenated” oils.

Computer models of the nurses’ diet patterns indicated that eating a modest amount of trans fat (2 percent of calories) in place of other, more healthful nutrients like polyunsaturated fat, monounsaturated fat or carbohydrate would dramatically increase the risk of infertility. To put this into perspective, for someone who eats 2,000 calories a day, 2 percent of calories translates into about four grams of trans fat. That’s the amount in two tablespoons of stick margarine, one medium order of fast-food french fries or one doughnut.

The total amount of fat in the diet wasn’t connected with ovulatory infertility once weight, exercise, smoking and other factors that can influence reproduction had been accounted for. The same was true for cholesterol, saturated fat and monounsaturated fat—none were linked with fertility or infertility.

3. Stop eating excessive sugar and refined carbohydrates like white bread.

Not that long ago, carbohydrates such as bread, pasta, rice, and potatoes made up more than half of our calories. Then came the no-carb diet craze. Like all diet fad, the no-carb craze lost its luster and faded from prominence. However, it did result in studies being performed which allowed us a greater understanding of the role of carbohydrates in our diets.

Women should try to avoid easily digested carbohydrates such as sugary breakfast cereals, white bread, white rice, potatoes and sugar containing sodas. A better choice are the slowly digested carbohydrates that are rich in fiber such as brown rice, pasta, whole grains, beans, vegetables, whole fruits and dark bread.

A very important point to remember is that this study found that the total amount of carbohydrate in the diet wasn’t connected with ovulation problems. Women in the low-carb and high-carb groups were equally likely to have had ovulation problems.

4. Consume more protein from vegetables rather than from animals.

This means decreasing the amount of meat in your diet. Good sources of vegetable protein include beans (all types) and lentils.

Using computer models of the data from the study, the researchers found that when total calories were kept constant, adding one serving a day of red meat, chicken or turkey predicted nearly a one-third increase in the risk of ovulatory infertility. And while adding one serving a day of fish or eggs didn’t influence ovulatory infertility, adding one serving a day of beans, peas, tofu or soybeans, peanuts or other nuts predicted modest protection against ovulatory infertility.

Swapping 25 grams of plant protein for 25 grams of carbohydrates shrank the risk of ovulation problems by 43 percent. Replacing 25 grams of animal protein with 25 grams of plant protein was related to a 50 percent lower risk of ovulatory infertility.

5. Consume more than 54 mg of iron daily.

Of course, animal protein is typically high in iron but the previous recommendation is to limit meat. Therefore, you need to try to get your iron from other sources. Prenatal vitamins contain iron but different brands contain different amounts ranging from 27 to 90 milligrams per tablet. Higher iron content may cause you to have stomach upset or constipation. Other non-animal sources of iron are listed here:

List of Grains Rich in Iron Iron (mg.)
Brown rice, 1 cup cooked 0.8
Whole wheat bread, 1 slice 0.9
Wheat germ, 2 tablespoons 1.1
English Muffin, 1 plain 1.4
Oatmeal, 1 cup cooked 1.6
Total cereal, 1 ounce 18.0
Cream of Wheat, 1 cup 10.0
Pita, whole wheat, 1 slice/piece, 6 ½ inch 1.9
Spaghetti, enriched, 1 cup, cooked 2.0
Raisin bran cereal, 1 cup 6.3
  
List of Iron Rich Legumes, Seeds, and Soy:     
Sunflower seeds, 1 ounce 1.4
Soy milk, 1 cup 1.4
Kidney beans, ½ cup canned 1.6
Chickpeas, ½ cup, canned 1.6
Tofu, firm, ½ cup 1.8
Soy burger, 1 average 1.8 to 3.9*
  
List of Vegetables Rich in Iron:   
Broccoli, ½ cup, boiled 0.7
Green beans, ½ cup, boiled 0.8
Lima beans, baby, frozen, ½ cup, boiled 1.8
Beets, 1 cup 1.8
Peas, ½ cup frozen, boiled 1.3
Potato, fresh baked, cooked w/skin on 4.0
Vegetables, green leafy, ½ cup 2.0
Watermelon, 6 inch x ½ inch slice 3.0

6. Consider starting a prenatal multivitamin.

Ask your doctor for a prescription prenatal versus one that you get over the counter. This does not have to do with ovulation problems; instead, the prescription prenatal vitamins have higher amounts of folic acid which have been found to reduce the risk of certain types of birth defects. Also, many prescription prenatal vitamins now contain an “unsaturated” fatty acid called DHA. DHA has been found to improve fetal brain development and has numerous health benefits for the women taking them regularly.

7. Consume one daily serving of full-fat dairy.

For example, 1 cup whole milk, full-fat yogurt, or 1-2 ounces cheese. In a previous study, the researchers found that women eating a half cup of ice cream two or more times a week had a 38% lower risk of ovulation problems than women consuming ice cream less than once a week. But, of course, ice cream contains refined sugar and calories!

In addition, whole milk has nearly double the calories of skim milk. If you are drinking three glasses of milk a day, trading skim milk for whole means an extra 189 calories a day. That could translate into a weight gain of 15 to 20 pounds over a year if you don’t cut back somewhere else. Remember that being overweight can reduce fertility and might therefore negate the potential benefits of the whole fat dairy in the first place.

Once you are pregnant, you can cut back to the low fat dairy again.

Endometriosis and Infertility

Endometriosis is the name give to a disease in which the tissue which normally grows in the uterus (endometrium) grows outside of the uterus. It is commonly associated with pelvic pain and infertility. The most common symptoms of endometriosis are pain with periods, pelvic pain at times other than during the period, pain with intercourse, bowel symptoms (diarrhea, cramping, constipation, pain with defecation), urinary symptoms (painful bladder, pain with urination) and infertility.

endometriosis and infertility

How Common is Endometriosis?

Endometriosis has been found in about 6-10% of reproductive aged women. In women with fertility problems it is much more common (21-47% of women). Those women with chronic pelvic pain have the highest prevalence (71-87%). The average age at the time of diagnosis is 28 years old.

Is Endometriosis a Genetic Disease?

Endometriosis is a complex disease that has a definite genetic component. First of all, it does run in families. If a sister or mother has endometriosis, the risk for a woman to have endometriosis is 7-10 times higher. Genetic studies have (so far) identified seven genetic areas that increase the risk of endometriosis. The more abnormal genetic areas a woman has, the more severe the degree of endometriosis.

How Does Endometriosis Cause Infertility?

The more severe forms of endometriosis is associated with scar tissue in the abdomen which causes distortion of the pelvic anatomy which makes it harder for an egg to get into the fallopian tube at the time of ovulation. It is uncertain about how milder endometriosis may cause infertility.

One theory suggests that a woman’s eggs might be directly affected. For example, a study looking at the use of donated eggs found no difference in pregnancy rates between women with endometriosis and those without. This would suggest an egg problem. However, another study looked at the practice of splitting the eggs from one egg donor into two women (one with and one without endometriosis) and found lower pregnancy rates in the endometriosis group. This would suggest a uterine problem.

How is Endometriosis Diagnosed?

The gold standard for diagnosing endometriosis is still surgery with biopsy of suspected areas and subsequent confirmation under the microscope. Much effort has gone into trying to find a blood test that could accurately identify endometriosis but to date such a marker remains elusive.

How is Endometriosis Treated?

First, the goals of treatment must be determined. At the present time, there is no “cure” for endometriosis.

Treatment to Control Pain

Treatment to alleviate pain is different than treatment to improve fertility. For the control of pain, the main objective is the suppression of hormones that cause endometriosis to develop. A number of medications can accomplish this.

endometriosis surgery

The medications in birth control pills (synthetic estrogen and progesterone) have been shown to work better than a placebo. This is true when combined or even when synthetic progesterone is used alone. The most well studied synthetic progesterone is called norethindrone.

Gonadotropin releasing hormone agonists (GnRHa) such as Lupron have also been shown to work better than placebo and are as effective as synthetic progesterone. However, this therapy is associated with short term side effects which result from the lowering of estrogen levels (hot flashes, vaginal dryness etc) and long term reductions in estrogen will decrease bone density and raise the risk for fractures. As a result, GnRHa are limited to 6 months of use. However, combining GnRHa with other medications may allow longer term use.

Surgery can also be used to control pain symptoms. Studies show that laparoscopy to eradicate endometriosis decreased pain better than a “diagnostic” only surgery. There is a problem with pain recurrence, however. Many studies have found that the recurrence risk can be reduced by using medical suppression after surgery.

Treatment to Improve Fertility

For the improvement of fertility, studies have found that surgery for milder stages of endometriosis has a beneficial effect. However, the impact is relatively small. You would have to do surgery and eradicate endometriosis on 11 patients in order to get one extra pregnancy. For more severe stages of endometriosis, there is more uncertainty about whether surgery helps. And there is some risk. Women with endometriosis involving the ovaries are more likely to have decreased ovarian reserve. Surgery to remove ovarian endometriosis will further decrease this reserve.

IVF does improve the chance for pregnancy in women with endometriosis. It is unclear whether endometriosis still has some impact, however. One study, looking at the U.S. IVF registry (SART) found that women with endometriosis only (no other infertility diagnoses) had a similar to slightly higher pregnancy rate in IVF compared to other diagnoses.

Medical suppression of endometriosis such as described above for pain, do not increase fertility and, in fact, results in less pregnancies per time because pregnancy cannot be attempted during the time of suppression. It is unclear whether suppression with GnRHa for 2-6 months prior to IVF will improve the chances for IVF to produce pregnancy.

Endometriosis and IVF

A number of studies have attempted to determine whether the presence of endometriosis is associated with a decrease in in vitro fertilization pregnancy rates. Some of these studies showed an impact but other studies have not. A very interesting study was performed which looked at women who were attempting pregnancy using donated eggs. Eggs from the same women were split into two groups of recipients. One group had endometriosis but the other did not. There was no difference found in the pregnancy rate, miscarriage rate or live birth rate.

Endometrioma and IVF

Some physicians think that if a patient has severe endometriosis with endometriomas, then she will have a worse chance for achieving a pregnancy with in vitro fertilization. However, several studies have not been able to demonstrate this. In fact, in one study doctors compared eggs that were retrieved after inadvertently exposing the eggs to the endometrioma fluid during egg retrieval to eggs from the same patient that were not exposed. No difference was found in either the fertilization rate or the percent of embryos judged to be of good quality.

More recently a study found that surgery to remove endometriomas resulted in IVF patients having less follicles and less eggs retrieved.

Cyst removal resulted in less good quality embryos for transfer in IVF cycles.

Female Athlete Triad

In 1972, Title IX of the Educational Amendment Act, took effect. What followed was an explosion of female participation in athletics. This law has profoundly affected student participation, especially female participation, in athletics from middle school through college. For example, since 1972 male participation in high school athletics has increased by 22%. Female participation has increased by nearly 1000%. While there is a myriad of benefits for girls and women participating in athletics, there are some unique risks that boys and men do not face. In 1992, an association was found between disordered eating, amenorrhea (lack of menstrual cycles) and osteoporosis (low bone density leading to fractures) and athletic activity – especially those types that emphasized e lean physique such as running or dancing. This became known as the Female Athlete Triad.

How Are These Problems Linked?

In order to have normal reproductive function, women must consume an adequate amount of food energy. The amount of energy is measured in calories. Any situation which disrupts the balance between the amount of calories that a woman eats and the number of calories she burns through her activities can interfere with her normal reproductive function.

Female Athlete Triad

Inadequate Energy Availability: The First Part Of The Female Athlete Triad

Inadequate Calorie Intake

There are four instances that may result in a woman failing to eat enough to support her body functions. The first is unintentional. A woman may simply not realize that she is failing to eat enough to account for all of her activities. This may be due to a lack of nutrition education, errors in calculating her needs or the lack of time or resources to keep up with her training. For some athletes, there is an intentional reduction in the amount that they eat. There is an unfortunate, pervasive but mistaken belief among athletes that increasing calorie intake will REDUCE athletic performance. This is especially common in runners and ballet dancers.

Still other women may have developed abnormal eating behaviors that fail to rise to the level of an eating disorder but are important nevertheless. These includes restrictive eating,   binge-eating and or purging, fasting, frequently skipped meals, use of diet pills, laxatives, or diuretics and use of enemas.

Finally, some women have a full blown eating disorder which is characterized by abnormal eating behaviors, an irrational fear of gaining weight, and false beliefs about eating, weight, and shape. Several studies have found that eating disorders are much more common in athletes than in in other women.

Excessive Calories Being Burned

Even if a woman consumes what would ordinarily be considered to be an adequate amount of calories, an increase in her physical activity may simply outpace her consumption. For example, an average 18 year old woman who is not very active may need only 1800 calories a day whereas she may need 3000 or 4000 calories a day if she participates in daily practice for a high school sport.

Stable Weight: Don’t Be Fooled

Some women incorrectly believe that as long as they are not losing weight, then they must be eating enough calories. When energy availability is too low, the body will first reduce the amount of energy that is used for cellular maintenance, temperature regulation, growth, and reproduction. This compensation will maintain weight at the expense of these other body functions. A good rule of thumb is that weight loss is always a sign of low energy availability but low energy availability does not always cause weight loss.

Energy And The Brain

There are parts of the brain that are responsible for producing electrical signals which control the reproductive system. The signals, which occur in periodic pulses are necessary for proper hormone production which in turn is what allows ovulation to occur in its normal monthly pattern. These areas of the brain are very sensitive to the amount of energy available in the body. If a woman decreases the amount of calories she eats or increases the amount of exercise she performs, these brain areas will shut down their electric pulses and cause a cascade of effects which result in the failure to ovulate and therefore the failure to have periods.

Lack Of Menstrual Periods – The Second Part Of The Female Athlete Triad

When the ovaries are working correctly, and ovulation is occurring, the ovaries are also producing hormones; estrogen before ovulation and both estrogen and progesterone after ovulation. These two hormones are responsible for thickening the uterine lining and then preparing it for a possible pregnancy. In the absence of a pregnancy, the hormone levels drop and this triggers the period. So it turns out that the lack of a regular period can be a sensitive indicator of low energy availability causing interference with the reproductive system.

Depending on their age, women with low energy availability may fail to ever start having periods (called primary amenorrhea) or may cause the periods to stop coming after they have begun (secondary amenorrhea). These problems are far more common in athletes. For example, less than 1% of all women have primary amenorrhea but it happens in 10% of ballet dancers and 20% of gymnasts. Secondary amenorrhea occurs in 2-5% of all women but in 65% of distance runners and almost 70% of dancers.

Infertility And The Female Athlete Triad

Failure to ovulate is a common cause for infertility. Women who are no longer in school may not think of themselves as athletes but many participate in athletic activities such as running, biking, swimming and dancing. These women have the same risks for developing the Triad as school age girls and women. As such, they may need to assess their calories balance and energy availability if they are not showing evidence for ovulation and/or having infrequent or absent periods.

Bone Health – The third part of the Female Athlete Triad

So what does it matter if women get their periods? Not many high school students are trying to get pregnant after all. While the periods themselves (the actual bleeding) are not important, the hormone production which causes the periods is very important for developing and maintaining the strength of bones. Estrogen production from the ovaries is critically important for building bone strength. Athletes who are not ovulating are at greater risk for developing stress fractures which may prevent her from being able to participate in athletics. Since 90% of the mass of bones in women occurs before the age of 20, those women who don’t reach their peak bone strength will be at greater risk for developing osteoporosis and bone fractures later in life – a major source disability and even death in older women.

Cardiovascular Health – The Fourth Part Of The Female Athlete Triad

We normally think of athletes as having a low risk for cardiovascular disease. For the most part this is true. However, female athletes who are not getting their periods regularly are at higher risk for problems with their arteries. These problems result in abnormal blood vessel constriction and the development of blockages in the blood vessels which can lead to heart attacks and strokes in otherwise young healthy women.

How is Female Athlete Triad Treated?

The treatment of Female Athlete Triad is to restore energy availability by either reducing the amount or intensity of exercise or by increasing the amount of calories that a woman consumes. This is not an easy prescription. Athletes, especially competitive athletes do not want to cut back on their training. There are many roadblocks to getting women to increase their calorie intake. Women with eating disorders should be treated appropriately by a qualified mental health professional.

It will take time to see a return to a healthy system. Whereas recovery of energy availability can occur in days to weeks, recovery of ovulation and periods may take months. Improved bone health may take years.

The wrong thing to do is to cover up the problem by using birth control pills, patches or contraceptive rings. It will not prevent the underlying and health issues and will give a woman a false sense of security by causing her to get periods.

Fibroids and Infertility

Fibroids are benign (that is, non-cancerous) tumors of the uterus. They are also called uterine leiomyomas, or simply myomas. They grow from the muscle cells of the uterus and may protrude from the inside or outside surface of the uterus or they may be contained within the muscular wall.

  • Submucous fibroid
  • A fibroid which grows just under the uterine lining.
  • Intracavitary fibroid
  • A fibroid which grows inside the uterine cavity.
  • Intramural fibroid
  • A fibroid which grows in the muscular wall of the uterus.
  • Subserosal fibroid
  • A fibroid which grows just mainly on the outer surface of the uterus.
  • Pedunculated fibroid
  • A fibroid which is attached to the uterus by a thin “stalk”.

Fibroids are very common. About 25 percent of women in their childbearing years will have signs of fibroids that can be detected by a pelvic examination, although not all will experience symptoms.

Cause of Fibroids

Although the exact cause is unknown, the growth of fibroids seems to be related to a gene that controls cell growth. When this gene functions normally, cells grow normally. When the gene is not functioning, cells grow and divide at an accelerated rate. In this way, one cell becomes two, two becomes four etc until finally a mass of these cells or fibroid is detected. Fibroid growth is affected by the reproductive hormones estrogen and progesterone. When these hormone levels decrease at menopause, many of the symptoms of fibroids begin to resolve. However, it is not clear that the hormones actually cause the fibroids to occur. For example, women who have had high levels of both of these hormones as a result of pregnancy or birth control pills have a lower incidence of fibroids later in life.

Abnormalities in the blood vessels around the uterus may play a role in development of fibroids. Changes in chemicals in the body that cause tissue to grow may also be involved.

Fibroid Risk Factors

A number of factors influence the risk of developing fibroids. These include:

  • Number of pregnancies Women with one or more pregnancies that extended beyond 5 months have a decreased risk of fibroid formation.
  • Use of birth control pills — Use of birth control pills can generally protects against fibroids, but use of the pill at an early age (between age 13 and 16) may be associated with an increased risk.
  • SmokingWomen who smoke appear to have a decreased risk of having fibroids. This may be due to the estrogen lowering effect if smoking.
  • DietEating large amounts of red meats is associated with an increased risk, and consumption of green vegetables decreases risk. However, no study has shown that changes in diet lead directly to changes in the incidence or symptoms of fibroids.
  • Ethnic backgroundFibroids are 2 to 3 times more common in African American women than in Caucasians. Among women undergoing hysterectomy (removal of the uterus), black women are significantly more likely to have fibroids, to be younger at the time of diagnosis and hysterectomy, and to have more severe problems associated with fibroids than their white counterparts.

Fibroid Symptoms

The majority of fibroids are small and do not cause any symptoms at all. But many women have significant problems that interfere with some aspect of their lives and want to be treated. The symptoms are related to the number, size, and location of the fibroids, and fall into four main groups:

  • Increased uterine bleedingFibroids may cause the menstrual bleeding to be heavier, or increase in the duration of bleeding or may cause bleeding in between periods. Some women may have a combination of bleeding symptoms. The presence and degree of uterine bleeding is determined mainly by the location of the fibroid. Women with fibroids that protrude into the uterus are more likely to have significant increases in bleeding.
  • Pelvic pressure and painFibroids can range in size from microscopic to the size of a basketball or even larger. Larger fibroids may cause a sense of pressure and fullness in the abdomen, similar to that caused by pregnancy. Fibroids of variable sizes can cause other symptoms depending on where they are located. For example, if the fibroid is pressing on the bladder, frequent urination can occur. A fibroid that pushes on the rectum can cause constipation, and one that puts pressure on the cervix can result in painful intercourse.
  • Infertility and miscarriageFibroids may cause infertility in a number of different ways. A fibroid may cause compression on the fallopian tubes resulting in a blockage of the passage of sperm or eggs. A large fibroid may distort the pelvic anatomy sufficiently to make it difficult for the fallopian tube to capture an egg at the time of ovulation. If a fibroid protrudes into the uterine cavity or causes distortion of the uterine cavity, it may present a mechanical barrier to implantation. Some studies have suggested that fibroids in the muscle portion of the uterus may cause an alteration or reduction of blood flow to the uterine lining making it more difficult for an implanted embryo to grow and develop. Another theory suggests that even small fibroids that grow inside of the uterine cavity may act as a foreign body and result in an inflammatory reaction that makes the uterine environment hostile for an embryo to implant.Some of these same possibilities may also increase the risk of an embryo to miscarry. Another possible cause for miscarriage is “running out of space” as the fetus grows.
  • Pregnancy complicationsSome studies have suggested a slightly increased risk of certain problems during pregnancy in women with very large fibroids, including difficulties with labor, breech presentation of the fetus, premature rupture of the “bag of waters”, and abruptio placenta (a condition in which the placenta separates from the uterine wall during the pregnancy). These problems are more likely if the placenta is implanted over the area of the large fibroid. However, many women with fibroids have completely normal pregnancies and deliver healthy babies with no complications.

Fibroid Diagnosis

Larger fibroids, especially those that protrude on the outside of the uterus may be felt during a routine pelvic exam. However, in an infertility center, most fibroids will be detected by ultrasound. Ultrasound allows the detection of much smaller fibroids than can be appreciated by a pelvic exam. This is especially true if a woman is overweight. One limitation of ultrasound is the inability in many cases to determine whether there are small fibroids in the uterine cavity or whether fibroids in the muscular wall of the uterus protrude into or distort the uterine cavity.

  • Hysterosonogram – This is an excellent test for determining the relationship of fibroids to the uterine cavity. First, saline (salt water) is gently instilled into the uterine cavity. This separates the walls of the uterine cavity just enough to allow an ultrasound to detect abnormalities inside the cavity. A fibroid shows as an area where the saline must flow around. Hysterosonogram also allows for the measurement of the distance of a fibroid from the uterine cavity.
  • Hysterosalpingogram – Similar to a hysterosonogram, the hysterosalpingogram uses clear dye that shows up on x-ray film to separate the walls of the uterine cavity. The hysterosalpingogram has an additional advantage of being able to determine whether the fallopian tubes are blocked.
  • Hysteroscopy – Insertion of a fiber optic telescope through the vagina and cervix and into the uterus can detect fibroids that are within the uterine cavity or causing significant distortion of the cavity. Hysteroscopy cannot detect fibroids in the muscular wall of the uterus unless they cause distortion of the cavity. It is also unable to identify even large fibroids that are located outside the wall of the uterus.
  • MRI – Magnetic resonance imaging uses high powered magnets to determine the difference between different types of tissue. It is very good for determining the difference between fibroid tissue and normal uterine tissue. It is also helpful for distinguishing the difference between fibroids and another less common problem of the uterus known as adenomyosis.
  • Surgery – Occasionally fibroids are identified during an abdominal surgery such as a laparoscopy . This is useful for fibroids that cause distortion of the outer contour of the uterus or those that are only attached to the uterus by a thin stalk.

Fibroid Treatment

If there are no symptoms, treatment is usually not required. In women with significant symptoms, treatment may be medical or surgical.

Medical Treatment

  • Gonadotropin-releasing hormone (GnRH) analogs (Lupron) – are commonly used in the medical treatment of fibroids. They are usually only given as a temporary measure, such as during the time a woman is preparing for surgery to remove the fibroids. GnRH analogs cause a reduction in estrogen levels. Most women taking these medicines have a cessation of the menstrual period. The lack of periods can help women with anemia from fibroid related heavy or prolonged menstrual bleeding to build their blood counts up before surgery. In some cases, GnRH analogs can cause shrinkage of fibroids which may allow them to be removed through a smaller incision. The fibroids rapidly enlarge again after the medication is discontinued. Since there are adverse effects from prolonged low estrogen levels, GnRH analogs are only a temporary measure.
  • Aromatase inhibitors (Letrozole) – work by reducing estrogen levels and causing shrinkage of the fibroid.
  • Progesterone antagonists (mifepristone)

Surgical Treatment

The type of surgery needed is dependent upon the size, number and location of fibroids. In addition, the underlying problem is important. Obviously, a woman with infertility who wants to keep her uterus would be treated differently than a peri-menopausal woman who is done with her childbearing. Procedures that are performed for women to maintain the capability for childbearing or to improve fertility include:

  • Abdominal myomectomyMyomectomy means removal of a fibroid. In an abdominal myomectomy, an incision is made through the abdomen to expose the uterus, and the fibroids are excised from the uterine muscle. This approach is most appropriate in women who want to maintain childbearing, and who have multiple fibroids or very large fibroids.
  • Laparoscopic myomectomyIn this procedure, the fibroids are removed through laparoscopy . With laparoscopy, a fiber optic telescope inserted through a tiny incision in or below the belly button, through which the surgeon can visualize the uterus. Additional tiny incisions are used to introduce long thin operating instruments which can be manipulated to remove the fibroids and repair the uterus afterward. Laparoscopy is most appropriate for women with one or two small to moderate sized fibroids that are located on the outer surface of the uterus.
  • Hysteroscopic myomectomyAs in the case of diagnosing fibroids, hysteroscopy involves placing a fiber optic telescope through the vagina and cervix and into the uterine cavity. Long thin surgical instruments can be introduced into the uterus using an operative channel in the hysteroscope. Saline is used to keep the walls of the uterus separated. This procedure can only be done on fibroids that mostly located within the uterine cavity.
  • Surgical Complications — Serious complications are uncommon but can include bleeding, infection, damage to other body structures, anesthesia problems or even death. Some fear that if damage to the uterus is extensive that a hysterectomy might be required. This would be a very rare complication.

About 11 to 26 percent of women who have had myomectomy will require a second surgery. In addition, abdominal and laparoscopic myomectomy carry varying degrees of risk for uterine rupture during pregnancy or labor. Due to this risk, the surgeon may recommend a cesarean section for delivery.

Other Types of Treatment

  • Uterine artery embolization (UAE or UFE) – is performed by a radiologist. Using x-ray, a catheter is threaded through blood vessels toward the uterus. Tiny spheres are injected into the blood vessels that feed a fibroid causing the blood supply to be blocked. Without a blood supply, the fibroid will begin to breakdown. There is very little data on the potential risks it may cause for a woman who subsequently becomes pregnant. A Dutch study looked at the effect of uterine artery embolization on ovarian function. Doctors in the study measured a hormone (anti-Mullerian hormone or AMH) which is correlated with ovarian reserve. Women who had UAE had a much more rapid decline in AMH than would have been expected. This suggests that uterine artery embolization may cause damage to the ovaries and deplete the number of eggs remaining in the ovaries.In 2008, results were published from the Fibroid Registry for Outcomes Data (FIBROID) for Uterine Embolization. The FIBROID study was a 3-year followup of over 2000 women who had uterine artery embolization. This study showed that almost one-third of the women who underwent this procedure stopped having period entirely – presumably due to lack of; blood supply to the ovaries.Some studies have identified an increase in some complications of pregnancy after UAE. For example, low birth weight, miscarriage and prematurity have been associated with UAE.
  • MRI Guided Highly focused ultrasound is also performed by a radiologist. The patient is placed in an MRI machine. The radiologist uses the MRI to guide high intensity sound waves to directly to the fibroid tissue. The sound waves heat and destroy small areas of fibroid tissue until most or all of the fibroid is destroyed. As with uterine artery embolization, there isn’t very much information about whether this treatment will improve fertility or have any adverse effects on a pregnancy. Successful live deliveries have been reported. This treatment is limited to a few centers that have the equipment necessary to perform the procedures.
  • Sonata System The Sonata Treatment uses an intrauterine ultrasound handpiece to locate and target the individual fibroids. Radiofrequency energy is delivered by needles inside the fibroid which heat and destroy the fibroid tissue. This shrinks the fibroid and reduce symptoms. Like the other non surgical fibroid treatments above, the Sonata system has been studied mostly in women who have not been attempting pregnancy. Women have achieved pregnancy after Sonata ablation of fibroids.

Infertility Controversy

There is much disagreement amongst physicians about when a myomectomy for infertility should be performed. Most would agree that fibroids that are within the uterine cavity or causing significant distortion of the cavity should be removed. However, what about a single small fibroid that is located within the muscular wall of the uterus but does not protrude into or distort the cavity? What if there were two such fibroids? What about a very large fibroid that is only attached to the uterus by a thin stalk? The controversy exists because it is very difficult to do studies that prove the effect of myomectomy. Much of the data that is published in the medical literature compares the number of pregnancies in a group of patients before and after a procedure. However, this doesn’t prove that a myomectomy was responsible for an improvement in fertility just because the pregnancy occurred after the surgery.

The best type of study looks at a larger group of women with identical fibroids. One half of the group would have a myomectomy and the other group would have a “sham” surgery where no fibroid was removed. Obviously, this type of study could never be done so the controversy is likely to continue for some time.

Hydrosalpinx, Infertility, And IVF

A hydrosalpinx is a blockage of the far end of a woman’s fallopian tube which results in the accumulation of fluid within the tube. The condition can affect one or both fallopian tubes. Often the affected area can become substantially swollen and grow even as big as a few centimeters in diameter.

Usually, there are few symptoms noticed by patients although some women may suffer from abdominal or pelvic pain. The most common mean by which a woman becomes aware that she has this problem is the development of infertility. Women, who are not trying to get pregnant and have no pain, may go undiagnosed.

Hydrosalpinx Impact On Fertility In General

As mentioned previously, the main presentation of a hydrosalpinx is infertility. The fallopian tube plays a crucial role in establishing a pregnancy. As sperm enter the vagina, they travel through the opening of the uterus (cervix), through the uterus, and into the fallopian tubes. If intercourse happens at the time of ovulation, then an egg may be present in one of the fallopian tubes. A sperm can fertilize the egg forming an embryo. Afterwards, the embryo migrates down the fallopian tube into the uterus. If the embryo implants into the uterus, a pregnancy has been established.

However, if this tube is blocked, the egg cannot be captured by the fallopian tube and the egg and sperm are prevented from meeting. Thus fertilization cannot occur and pregnancy is prevented.

In addition, studies have shown that even when women have one tube which is open, their chances for pregnancy are reduced if they have a hydrosalpinx on the other tube.

Possible Reasons For Less Success

There are various theories that try and explain why the success rates in these patients are so much lower. One suggests that the flow of fluid into the uterus could interfere with and hinder implantation of an embryo. This fluid could contain lower levels of proteins, various amounts of debris, and other toxic substances found in the body that are harmful to the embryo itself or possibly the lining of the uterus. Another theory states that the fluid is a mechanical flush for the uterus, sweeping away the embryo. It is not known whether these effects would be worse if both fallopian tubes are affected, although that is thought to be the case.

Hydrosalpinx Impacts The Success Of IVF

In vitro fertilization bypasses fallopian tube blockage by extracting the eggs directly from the ovary and fertilizing them in the laboratory. The embryos are then placed directly into the uterus. Thus, the fallopian tubes are completely bypassed. With the growing success of IVF and other fertility treatments in the past years, many women suffering from a hydrosalpinx are turning to these treatments to enhance their chances of pregnancy. However, there is substantial evidence to suggest that the success of in vitro fertilization is significantly lower for women with hydrosalpinx compared to other causes of infertility.

Study On Hydrosalpinx And IVF

Investigators recently compiled the results from 14 different studies to try and see what the IVF success rates are in women with this condition. The analysis compared two groups of women. Of a total of 5592 patients, 1004 of them had one or both tubes blocked by a hydrosalpinx and 4588 of them had tubal blockage but with out a hydrosalpinx. A total of 8703 IVF embryo transfers were performed with either fresh or frozen embryos.

There were four outcomes measured:

  1. The overall pregnancy rate was shown to decrease in the women with the hydrosalpinx. The women with no blockage had a pregnancy rate of 31.2% compared to the women with the hydrosalpinx at 19.67%.
  2. The implantation rate, which looks at how many transferred embryos were able to implant in the uterine wall, also decreased in the women with a hydrosalpinx. It went from 13.68% in women with out a hydrosalpinx to 8.53% in women with one.
  3. The delivery rate decreased drastically as well. Almost twice as many women delivered without a hydrosalpinx (23.4%) than with a hydrosalpinx (13.4%).
  4. The delivery rate was lower in part because less women became pregnant but also because more of the women miscarried. Early loss in pregnancy was seen more often in the women affected than not. The rate for affected women was 43.65% loss compared to 31.11% loss.

Conclusions

Other studies have come out with results similar to these. Generally, for a woman with hydrosalpinx trying IVF, the chances for pregnancy are greatly reduced compared to the average infertile woman. While the possibility for pregnancy still exists in these patients, these women should be counseled that their chances for live birth are significantly lower if they have a hydrosalpinx.

Treatment Options For Hydrosalpinx To Improve Fertility

Salpingectomy

The complete surgical removal of a fallopian tube is called a salpingectomy. The procedure can be done laparoscopically or with a standard surgery performed by making a horizontal incision in the abdomen just above the pubic hair line. Both procedures are performed under general anesthesia so that the patient is completely asleep.

Salpingectomy

Laparoscopy is a minimally invasive way of performing surgery. An small fiber optic telescope is inserted in a small incision just below the navel. This allows the reproductive surgeon to see into the abdomen and pelvis. Two additional incisions of about one centimeter each are made above the pubic hair line. Through these small incisions, instruments can be placed that allow the reproductive surgeon to detach the tube from the uterus and blood vessels and to remove it from the abdomen.

Laparoscopy is the preferred method for performing a salpingectomy since no overnight hospitalization is required and the smaller incisions are associated with a shorter recovery time.

Tubal Ligation

Tubal ligation is when the fallopian tubes are either severed or pinched shut, but not removed. It is often referred to as getting one’s “tubes tied.” This can also be done laparoscopically, abdominally, or even vaginally. The most common way to seal the tubes is by using a cauterizing clamp which when applied to the outside of the tube, will seal it shut. Other methods include placing strong, tight rings or rubber bands around the tube that pinch them closed.

Theoretically, by blocking the fluid from entering the uterine cavity, this may restore a normal chance for achieving pregnancy.

The most common use of tubal ligation is as a permanent form of birth control. It is generally not considered to be reversible.

Salpingectomy vs. Tubal Ligation: Which method is best for improving fertility?

Natural conception

If a woman has one fallopian tube blocked with a hydrosalpinx and the other tube is normal, the chances for pregnancy are reduced.

In a recent study, researchers looked at 25 women with one hydrosalpinx and one open fallopian tube. They attempted to determine whether treatment of the hydrosalpinx with either a salpingectomy or tubal ligation was more effective for improving pregnancy rates naturally without IVF. 18 underwent a salpingectomy and 7 had a tubal ligation of the abnormal tube. In the end, 22 (88%) women achieved pregnancy after the surgeries without the use of IVF. There were no ectopic pregnancies and no multiple births.

Both procedures seemed to improve the chances for becoming pregnant. Interestingly, the women who had a salpingectomy became pregnant more quickly compared to the women who had a tubal ligation.

This research seems to indicate although a one sided hydrosalpinx can cause infertility, it may be possible to reverse the effects of this condition. These women did not need further fertility treatment and their mean time to pregnancy was only 5.6 months after the procedures. For that reason, if a woman with one hydrosalpinx has been unable to achieve a pregnancy, treatment of the hydrosalpinx is a reasonable treatment option.

IVF

Obviously, if both fallopian tubes are blocked, than natural conception is impossible. Several studies have looked at whether treatment of hydrosalpinges is effective for improving the chances for pregnancy with IVF. Studies have looked at various alternatives such as salpingectomy and tubal ligation. Some studies even sought to determine whether draining the fluid from the hydrosalpinx (transvaginal aspiration) might be helpful.

Published guidelines from the American Society for Reproductive Medicine listed the following conclusions:

  1. Patients with hydrosalpinges undergoing IVF experience approximately one-half the pregnancy rate of patients who do not have hydrosalpinges.
  2. Salpingectomy performed for hydrosalpinx prior to IVF improves subsequent pregnancy, implantation, and live birth rates.
  3. Current data are insufficient to permit recommendation of other treatment alternatives such as transvaginal aspiration of hydrosalpinx fluid or proximal tubal ligation.

Hypothyroidism

Hypothyroidism occurs when the thyroid gland is not producing as much thyroid hormone as it should. Hypothyroidism is common in women of reproductive age.

Depending on its severity, hypothyroidism may cause a variety of symptoms and may affect all body functions. In mild cases, there may be no symptoms at all. In more severe cases, the body’s metabolism slows, causing mental and physical sluggishness and a variety of other symptoms. In women of reproductive age, hypothyroidism can be a cause for failure to ovulate or failure to ovulate regularly. This, in turn, causes a woman’s periods to occur less frequently (oligomenorrhea) or to stop completely (amenorrhea).

Thyroid gland

A common cause of hypothyroidism is the presence of elevated levels of anti-thyroid antibodies. Failure of the pituitary gland to secrete a hormone (TSH or thyroid stimulating hormone) to stimulate the thyroid gland (secondary hypothyroidism) is a less common cause of hypothyroidism. Other causes include congenital defects, surgical removal of the thyroid gland, irradiation of the gland, or inflammatory conditions. In an otherwise healthy woman, hypothyroidism can be easily detected by assessing the levels of TSH in the blood. A high TSH level indicates hypothyroidism. A slightly elevated level indicates a very mild case. A higher number indicates more severe disease and is often accompanied by a reduction in the level of T3 or T4 in the blood.

Sub-clinical hypothyroidism

An elevated TSH with a normal T3 and/or T4

Overt or clinical hypothyroidism

An elevated TSH and a low T4 and/or T3

Hypothyroidism and Ovulation Problems

Hypothyroidism can cause anovulation (failure to ovulate) directly or by causing elevation in another hormone called prolactin. Prolactin is the hormone used by the body to assist with lactation (milk production) after delivery. If a woman’s prolactin is elevated, she may experience milk discharge from her breasts (galactorrhea).

Treatment with oral thyroid hormone supplements (Synthroid, Levoxyl) will often correct the hypothyroidism and result in a return to normal ovulation and regular menstrual cycles. If prolactin levels were also elevated, then treatment usually results in a return of this hormone to normal levels with cessation of the breast discharge.

Once the thyroid is corrected, and ovulation is occurring, fertility is usually very good, unless there are other independent factors.

Hypothyroidism and Miscarriage

A 2002 study of women with both clinical and sub-clinical hypothyroidism in early pregnancy found that the miscarriage rate was higher in both groups and that treatment with thyroid hormone could reduce the miscarriage risk.

Miscarriage risk may also be higher in women with anti-thyroid antibodies.

Hypothyroidism in Pregnancy

It is extremely important to diagnose and treat clinical hypothyroidism in early pregnancy. The developing fetus cannot make its own thyroid hormone until about the 10th week of gestation. During this time, it relies on thyroid hormone production from the mom. Severe hypothyroidism is pregnant women, particularly in the 1st trimester, is associated with a host of pregnancy complications including pre-eclampsia (high blood pressure of pregnancy), placental abruption (separation of the placenta from the wall of the uterus), preterm birth, low birth weight and even fetal death. The babies can suffer from neurologic impairment, mental retardation, and intellectual impairment during childhood.

Fortunately, because women with hypothyroidism don’t usually get pregnant, clinical hypothyroidism in pregnancy is very rare, maybe occurring in 1 in 5000 pregnancies.

Sub-clinical hypothyroidism and IVF

A study presented in 2007 did not find any difference in the chances for IVF success if women had untreated sub-clinical hypothyroidism at the beginning of their IVF cycle.

Sub-clinical hypothyroidism in pregnancy

If a woman has only a mild elevation in her TSH and her T4 and T3 levels are normal, there is disagreement about whether these pregnancies are at any higher risk. Sub-clinical hypothyroidism is a bit more common, occurring in 2-5% of all pregnancies. Some studies have suggested that the children born may have lower IQ scores or impaired psychomotor development. These studies, which were small and often didn’t distinguish between clinical and sub-clinical hypothyroidism are difficult to interpret.

Very recently, researchers published results of the largest study to date of the effects of sub-clinical hypothyroidism on pregnancy. They screened 25,756 pregnant women and found 404 (2.3%) met the criteria for the diagnosis of sub-clinical hypothyroidism. The pregnancies in these women were 3 times more likely to be complicated by placental abruption and twice as likely to have preterm birth. The proportion of infants admitted to the neonatal intensive care unit, as well as those who developed respiratory distress syndrome (a common problem in premature infants) was doubled.

It is not yet known whether treatment of sub-clinical hypothyroidism will reduce these risks though it seems reasonable to think for now that it would.

Insulin Resistance And Ovulation

There are many reasons why a woman may not ovulate. Some women are resistant to the hormone insulin. Insulin is a hormone produced by the pancreas that helps keep blood sugar under control. Insulin is part of a complex system that keeps the blood sugar low. It is estimated that 25% to 50% of overweight adults have insulin resistance.

If blood sugar, also known as blood glucose levels, become too high, then a person is said to have diabetes. There are two main causes for diabetes: failure to make insulin (Type 1 Diabetes) and becoming resistant to the effects of insulin (Type 2 Diabetes).

In women, there are two common conditions that may result in insulin resistance: PCOS , also known as polycystic ovary syndrome , and obesity . Some women with PCOS are also obese. This can intensify the symptoms of PCOS. Women may also be obese and have insulin resistance without having PCOS. Women with PCOS or obesity or both problems will commonly have problems with ovulation.

Common signs that a woman may not be ovulating involve disruption of the normal pattern her menstrual cycles. Women who do not ovulate will often note absence of their periods, infrequent periods or irregular periods. Rarely, a woman with regular monthly periods may not be ovulating.

Diagnosis of Insulin Resistance

Diagnosis of insulin resistance can sometimes be challenging. This is due to wide variations in the levels of the hormones needed to assess for insulin resistance. When insulin resistance occurs, the body needs a higher level of insulin to keep the blood glucose under control. Therefore, high insulin levels are frequently seen in this condition. Other possible signs of insulin resistance include:

Blood Tests

  • High triglyceride levels
  • A low glucose to insulin ratio
  • High leptin levels
  • Low adiponectin levels
  • High fasting blood glucose
  • Abnormal oral glucose tolerance test

Physical Signs

  • Obesity
  • A large diameter of the waist
  • Acanthosis nigricans – a dark velvety appearance of the skin usually around the neck, under arms or groin

It is very important to note that in some women with insulin resistance, all of these signs and symptoms may be absent. There are more sensitive although complicated ways to test for insulin resistance. These are not usually done in clinical practice. There are typically performed when researchers are conducting studies.

Treating Insulin Resistance For Ovulation

If insulin resistance is the cause for a woman’s anovulation (not ovulating) then it stands to reason that improving the insulin resistance or lowering the insulin levels may be successful at causing ovulation to return. In fact this does seem to work…sometimes. Methods for lowering insulin resistance that have resulted in the resumption of ovulation include:

  • Weight loss
  • Exercise (even without weight loss)
  • Medications
  • Metformin   (Glucophage, Fortamet)
  • TZDs (Actos, Avandia)

A 5% to 10% loss in body weight has been shown to improve insulin levels and thereby reduce the risk of developing certain chronic diseases, such as type 2 diabetes mellitus and heart disease and improve the chance for ovulation in women.

There is no evidence that a low carbohydrate diet helps improve insulin resistance any better than any other type of diet. The key is weight loss.

Large, multi-center university studies have found that medication treatment of insulin resistance can work to achieve a live birth but is not as efficient as fertility treatments such as clomid.

Infertile women with anovulation and insulin resistance may consider treatment of insulin resistance as one alternative to improve their fertility. Women who are not interested in childbearing may also consider treatment of insulin resistance to help reduce the risk of developing diabetes.

Other Articles Involving Insulin Resistance:

Actos and Avandia for PCOS
Metformin for PCOS
Metformin in Pregnancy
Alternatives to metformin (Glucophage) for treating insulin resistance

Effects of Obesity on Fertility and Pregnancy

Obese women have more infertility and are less successful at conceiving than women of normal weight. Once pregnant, obese women are more likely to have complicated pregnancies and are less likely to have a live born baby because of a higher rate of miscarriage, ectopic pregnancy and stillbirth. The babies born to obese women are more likely to die in the first month of life.

It is clear that women who are obese are at increased risk for infertility and other reproductive problems. Numerous studies have demonstrated that women who are obese (body mass index over 30) are more likely to have ovulation problems that result in irregular or infrequent menstrual cycles and infertility. Women who are obese are also at increased risk for miscarriage though the reasons for this are as yet unclear. In the treatment of infertility, they are less successful. For example, in vitro fertilization (IVF) pregnancy rates are lower in obese women compared to those of normal weight. This may be due in part to the fact that obese women do not respond to fertility medications as well and have a higher percentage of immature eggs. Fertility surgery is also riskier in obese women compared to normal weight women.

In a recent study presented at the American Society for Reproductive Medicine meeting, overweight women were 50% more likely to have an ectopic pregnancy (a pregnancy outside of the uterus, usually in the fallopian tube).

Obesity is a significant risk factor in adverse pregnancy outcomes. A recent study from Sweden compared obese women (those with a body mass index of greater than 35) to normal weight women (those with a BMI less than 26). Even after controlling for other factors that are known to increase the risk for adverse outcomes, the obese women had a much greater likelihood of these problems.

  • Pre-eclampsia, a problem with elevated blood pressure in pregnancy, was four to five times more likely to occur in the pregnancies of obese women.
  • Stillbirth was two to three times more likely to occur in the pregnancies of obese women.
  • During labor and delivery, there is a serious problem called shoulder dystocia which occurs when the shoulder of the baby gets caught in the mother’s pelvis. It is considered a medical emergency and can result in death or injury to the baby. Shoulder dystocia occurs during the deliveries of obese women two to three times more often.

Babies experience distress during labor two to thee times more often in the pregnancies of obese women. As a result of the problems during delivery, obese women are delivered by cesarean section two to three times more often than women of normal weight.

Finally, the Swedish study found that death of the babies born to obese women are two to four times more likely to die in the first 28 days of life (neonatal death). Other studies have also identified a higher risk of gestational diabetes in the pregnancies of obese women.

Polycystic Ovary Syndrome – PCOS

In the entire field of reproduction and infertility, no topic has as many myths and misconceptions associated with it as polycystic ovary syndrome – PCOS. Even its name causes confusion. Is it PCO or polycystic ovary disease (PCOD) or polycystic ovary syndrome (PCOS)? Since the name includes the word “polycystic” does that mean that all women with this problem have cysts in their ovaries?

Syndrome: A group of signs and symptoms that occur together and characterize a particular abnormality.

Disease: A pathological condition of the body that presents a specific and consistent group of clinical signs, symptoms, and laboratory findings peculiar to it and setting the condition apart as an abnormal entity differing from other normal or pathological conditions.

The problem we are talking about then is not a disease. It is a syndrome. Not all women with polycystic ovary syndrome (PCOS) will present the same way or have the same symptoms or laboratory findings. Confused? For example, take the disease cystic fibrosis. All individuals with cystic fibrosis have the same underlying problem which is a mutation in the cystic fibrosis gene. In polycystic ovary syndrome (PCOS), on the other hand, there isn’t any one common factor that identifies all women as having polycystic ovary syndrome (PCOS).

According to the American college of Obstetrics and Gynecology (ACOG), there is no universally accepted definition of PCOS.

PCOS Signs and Symptoms

Ovulation problems

AnovulationNo ovulation at all
Oligo-ovulationInfrequent or irregular ovulation

Irregular Menstrual Cycles

AmenorrheaWomen does not get any periods at all
OligomenorrheaInfrequent periods
HypermenorrheaPeriods that occur too frequently
MenorrhagiaHeavy periods and/or those that last for many days or weeks
MetorrhagiaBleeding or spotting that occurs in between apparently normal periods

Insulin Resistance

The body does not respond to the hormone insulin as it normally should. Insulin’s primary function is to keep the levels of blood sugar under control. On laboratory tests, insulin resistance may not show up at all.

If it does, it may appear in one or more of the following ways:

High fasting insulin levels
Low glucose to insulin ratio
High triglyceride levels
Low levels of SHBG (Steroid Hormone Binding Globulin)

*Insulin resistance may lead to diabetes so laboratory findings consistent with diabetes can also be found in polycystic ovary syndrome (PCOS).

Hyperandrogenism

Androgens are what most people think of as “male” hormones. This is incorrect. All people have androgens. Males typically have levels that are much higher than women. However, women with polycystic ovary syndrome (PCOS)
have slightly elevated levels of androgens. Elevated androgen levels can result in the development of some signs and symptoms in women.

Hirsutism

Unwanted hair growth. Usually on the lip, cheeks, chin, neck,
in between the breasts,
beneath the umbilicus(belly button)
Acne

Alopecia

Male pattern hair thinning and loss.

On laboratory evaluation, hyperandrogenism may not show up at all. If it does, it may be seen in high levels in one of the following tests:

Total testosterone
Free testosterone
Dihydrotesterone (DHT)
3 alpha glucuronide (3AG)
Androstenedione
DHEAS (dehydroepiandosterone sulfate)

* There are numerous other androgen levels that may be elevated but these are not usually looked at in clinical medical practice)Androgen levels can be elevated in other types of problems besides polycystic ovary syndrome (PCOS). These other problems should be ruled out before someone is given a diagnosis of polycystic ovary syndrome (PCOS). The most common of these problems is called congenital adrenal hyperplasia (CAH).

Ultrasound Findings

Some women with polycystic ovary syndrome (PCOS) may have one or more of the following findings:

Enlarged ovaries
Large number (>10) of tiny follicles (cysts) just under the surface of the ovaries
The center of the ovaries is echogenic (highly reflective on ultrasound) and with very few follicles seen.

Ultrasound evidence of polycystic ovaries alone are a non-specific finding and are frequently found in women with normal menstrual cycles and regular ovulation. Ultrasound evidence of polycystic ovaries alone does not constitute a diagnose of PCOS. Women with ultrasound findings are said to have polycystic appearing ovaries (PAO).

IMPORTANT:

Not all women with polycystic ovary syndrome (PCOS) have polycystic appearing ovaries (PAO).
Not all women with polycystic appearing ovaries (PAO) have polycystic ovary syndrome (PCOS). In fact, many normal women with regular ovulation have polycystic appearing ovaries (PAO)

Miscellaneous laboratory findings: These laboratory findings can be found in some women with polycystic ovary syndrome (PCOS). Many women with these findings may not have polycystic ovary syndrome (PCOS).

Elevated prolactin levels
High levels of luteinizing hormone (LH)
High ratio of LH:FSH
High levels of inhibin-B
High levels of plasminogen activator inhibitor -1 (PAI-1)
High levels of AMH (anti-Mullerian hormone)

Causes of PCOS

Contrary to popular belief, obesity does not cause PCOS. In fact, 20% of women with PCOS are not obese. Obesity can, however, increase the signs and symptoms of PCOS. The genetic contribution to PCOS remains uncertain. there are currently no recommended genetic screening tests for PCOS. Also, there are no specific environmental substance that has been found to cause PCOS.

PCOS is not caused by eating a diet high in carbohydrates. Eating a low carbohydrate diet or a diet with a low glycemic index does not prevent or treat PCOS.

Health Risks Associated With PCOS

Women with polycystic ovary syndrome (PCOS) seem to have certain health problems more frequently than you would expect in the general population. It is thought that these problems are either caused by polycystic ovary syndrome (PCOS) or that they have the same underlying cause as polycystic ovary syndrome (PCOS). These include:

Hypertension
Type II Diabetes
Coronary artery disease
Endometrial cancer (cancer of the lining of the uterus) It is not specific to polycystic ovary syndrome (PCOS) however. Any problem which causes a woman not to ovulate is associated with a higher risk of endometrial cancer.

Pregnancy Risks Associated With PCOS

Gestational diabetes (diabetes that occurs during pregnancy)
Pregnancy induced hypertension (PIH)
Preeclampsia
Preterm birth
Babies from PCOS mothers have a higher rate of admission to the neonatal intensive care unit
Babies from PCOS mothers have a higher rate of perinatal death

The perinatal mortality rate is the combination of two separate death rates: antenatal mortality, which is defined as the death of a fetus after the 20th week of pregnancy but before delivery, plus neonatal mortality which is the death of a baby up to 28 days after birth.

Contrary to popular belief, a recent analysis has found that PCOS patients do not have a higher risk of miscarriage than non-PCOS infertility patients.

Treatment of PCOS

There isn’t one treatment for polycystic ovary syndrome (PCOS). The type of treatment is dependent on the symptoms that a woman has and her specific desires at that point in her life. Specific goals of treatment might include:

Promotion of fertility
Desire for regular menstrual cycles
Reduction of acne, unwanted hair growth or hair loss
Reduction of other health risks associated with polycystic ovary syndrome (PCOS)

Fertility Treatment

Treatment of insulin resistance

Can be accomplished by:

Use of fertility medications

Women with polycystic ovary syndrome (PCOS) do not respond to clomiphene citrate with the same success as other women. This has been called clomiphene resistance. There have been many methods attempted to reduce the chance for clomiphene resistance and include:

  • Increasing the dose of clomiphene citrate
  • Prolonging the duration of clomiphene administration
  • Adding insulin resistance medications
  • Adding dexamethasone
  • Adding naltrexone

Aromatase inhibitors

Aromatase inhibitors such as letrozole or anastrozole work in a similar fashion as clomiphene citrate. There is far less medical data that has looked at letrozole and its chances for success. Several small studies indicate that letrozole has a similar level of effectiveness to clomiphene citrate.

Gonadotropins

Women with polycystic ovary syndrome (PCOS) respond to these injectable fertility medications with a very high percentage of ovulation. However, polycystic ovary syndrome (PCOS) patients are more prone to the problems of gonadotropins such as ovarian hyperstimulation syndrome (OHSS) and multiple pregnancy.

Surgery

Ovulation problems in women with polycystic ovary syndrome (PCOS) can also be treated be destroying or removing portions of the ovaries. In the medical literature, there have been several methods described for doing this including:

Wedge resection
Multiple ovarian cystotomy (a.k.a. ovarian drilling)
Ovarian diathermy

The benefits of surgery include the avoidance of OHSS and multiple pregnancy. According to the American college of Obstetrics and Gynecology (ACOG), ovarian drilling and related procedures should be considered as a second line therapy for ovulation problems. The prime candidates are women who have failed clomiphene citrate.

Treatment of PCOS Without Concern For Fertility

Treatment of the other problems associated with polycystic ovary syndrome (PCOS) involve methods to restore normal menstrual cycle pattern and reduce the effect of high androgens. Hormonal contraceptives are commonly used for this purpose. More recently insulin resistance medications have been used. The combination of these two medications provides a potent one two punch for the treatment of polycystic ovary syndrome (PCOS).

Additional PCOS Information

Depression in PCOS patients may be due to obesity
PCOS Caused by Epilepsy Treatment?

Premature Ovarian Failure And Infertility

Premature Ovarian Failure is a disorder affecting the ability of a woman’s ovaries to function correctly. Premature ovarian failure (POF) affects approximately 1% of the female population. POF, also known as primary ovarian insufficiency, is characterized by absence of menstrual bleeding, low estrogen levels, and possible onset of autoimmune diseases in women younger than 40 years.

The word “failure” does not accurately reflect the true nature of this disease. The disorder is not permanent in all women. Remission of the disease is possible. In fact, up to 5% of women with POF may conceive without any specific fertility treatment. Thus, the preferred term now is ovarian insufficiency.

However, premature ovarian failure is a cause of infertility . Often, women with infertility and absence of menstrual cycles will be mistakenly diagnosed with an ovulation problem and referred to a fertility specialist for ovulation drugs. Ovulation drugs are ineffective in women with premature ovarian failure however.

Premature Ovarian Failure Is NOT Premature Menopause

Menopause is defined as the “permanent cessation of menses; termination of menstrual life.” It generally occurs around the age of 50. Premature ovarian failure is NOT premature menopause. Around 50% of women affected still experience unpredictable and intermittent ovarian function for many years. For this reason, some women can still become pregnant even after being diagnosed.

When treating POF, hormone therapy is essentially replacing the hormones the body would normally make on its own. When treating menopause, elevated ovarian hormone levels are extended, not replaced.

Understanding Premature Ovarian Failure

Primary ovarian insufficiency is when the ovary fails to respond to the hormone signals sent from other parts of the body like the hypothalamus and pituitary glands. This is the form that is commonly referred to as premature ovarian failure.

Secondary ovarian insufficiency is when the problem lies directly in the hypothalamus and pituitary glands. These parts of the central nervous system fail to stimulate the ovaries and subsequent ovarian function. Secondary ovarian insufficiency is not considered to be premature ovarian failure. Most fertility experts think of these as ovulatory problems.

Causes of Premature Ovarian Failure

Follicle Depletion Due To Chromosome Abnormality

All eggs in the ovaries are surrounded by supporting cells known as granulosae cells. As an egg begins to mature in the ovary, the granulosae cells produce a small amount of fluid. The term “follicle” refers to the small cyst that contains the egg, fluid and supporting cells. A woman has all of the follicles (and therefore eggs) she is ever going to have in her life before she is born. All during her life, the number of follicles is decreasing due to an ongoing process of degeneration.

Follicle depletion results in the lack of eggs in the ovary due to either an inadequate supply at birth or follicle atresia (degeneration). One example of follicle atresia occurs in fetuses with only a single X chromosome (normal females should have two X chromosomes). When these fetuses are born, they are referred to as having Turner’s Syndrome. Women with Turner’s Syndrome initially develop normal ovaries with a normal amount of immature eggs before birth, but accelerated follicle degeneration leads to ovarian insufficiency at an early age. Some women with Turner’s syndrome will never have periods. Others with a milder version may start to have periods as a teenager and then stop after a few months or years.

Follicle Dysfunction

Follicle dysfunction means that while apparently healthy eggs remain in the ovaries, they fail to function for properly.  The table below lists examples of causes of follicle dysfunction.

Signalling defects 
FSH receptor mutation FSH is a hormone that stimulates the growth of follicles. It acts though a receptor on the surface of the cells. A genetic defect can cause the receptor to be abnormal and therefore the follicles are incapable of responding to the hormone.  Very rare outside of Finland.
LH receptor mutation LH is a hormone that also stimulates the growth of follicles. Like FSH, it acts though a receptor on the surface of the cells. A genetic defect can cause the receptor to be abnormal and therefore the follicles are incapable of responding to the hormone.  Very rare.
G-protein mutation  
Enzyme deficiency 
Isolated 17,20-lyase deficiency One of the enzymes necessary for the normal production of hormones such as estrogen and progesterone. Rare.
Aromatase deficiency The enzyme that converts testosterone to estrogen. Results in inadequate estrogen production. Rare.
Autoimmunity 
Autoimmune lymphocytic oophoritis A type of white blood cell (immune cell) infiltrates into the area of the ovary that contains the immature follicles. Can result in ovaries with many follicles apparent on ultrasound. Immune problems can affect other organs such as the adrenal glands or thyroid gland.
Insufficient follicle number 
Luteinized graafian follicles Normally, after ovulation, the follicle which released the egg becomes luteinized and produces predominantly progesterone instead of estrogen. In some women with follicle dysfunction, more than 60% of the follicles are luteinized and thus don’t function properly.

Gene Mutation

It is suggested that approximately 6% of women with spontaneous POF have mutations in the FMR1 gene . This is the gene mutation responsible for fragile X syndrome -the most common cause of hereditary mental retardation. The risk of a woman having this mutation is higher if she has a family history of premature ovarian failure. Around 14% of women with a family history of POF will have an FMR1 mutation as compared with 2% of women who have no family history of POF. To prevent these genetic re-occurrences, it is important to research the family medical history.   There are other mutations that have been found in families with POF. There are likely others that have not been discovered. While each mutation individually is found in only a small percentage of POF patients, when taken together, they may be responsible for 25-30% of all cases of POF.

Problems With The Immune System

Autoimmune disease is a problem that occurs when the body fails to recognize its own parts as itself. Consequently, the body starts attacking its own cells and tissues.

Some of the diseases associated with autoimmune POF:

  • Thyroid dysfunction
  • Approximately 20% of women with POF develop autoimmune hypothyroidism.
  • Polyglandular failure I and II
  • Hypoparathyroidism
  • Rheumatoid arthritis
  • Idiopathic thrombocytopenia purpura (ITP)
  • Diabetes
  • Pernicious anemia
  • Adrenal insufficiency – It has been stated that around 4% of women with spontaneous POF are at risk for developing adrenal gland insufficiency, a potentially fatal disorder. The adrenal glands are located on the top of each kidney. Their normal function is to regulate the body’s stress hormone levels. It is very important to identify women with adrenal insufficiency before proceeding with egg donation fertility treatments such as egg donation. Untreated during pregnancy, adrenal insufficiency is associated with high rates of maternal and fetal complications including fetal death in the uterus. Symptoms of adrenal insufficiency include abdominal pain, anorexia, unexplained weakness, darkening of the skin, salt craving, and orthostatic hypotension – dizzy spell occurring when standing after being at rest for some time due to low blood pressure.
  • Vitiligo
  • Systemic lupus erythematosus -also called SLE or Lupus
  • Enzyme defects/Metabolic
  • Galactosemia
  • Blood disorders
  • Thalassemia major treated with multiple blood transfusions
  • Hemochromatosis
  • External Damage to the ovaries
  • Chemotherapy/Radiation therapy related
  • Surgical – removal of the ovaries
  • Viral infection

Symptoms of POF

Amenorrhea

Amenorrhea is the absence of a normal menstrual period

Estrogen Deficiency

Women with POF experience some symptoms of menopause including hot flashes, night sweats, sleep disturbance, and vaginal dryness. Other symptoms may include mood swings, energy loss, low sex drive, painful sex, and bladder control problems.

Women with low estrogen levels from POF appear also to be at an increased risk for developing osteoporosis (bone thinning which can lead to fracture) and heart disease.

Infertility

As mentioned before, women who have this disease have a significantly lower chance of getting pregnant compared to women without this disease. However, remissions and spontaneous pregnancies can occur.

Other symptoms

Other signs of POF should be taken into consideration as well. Another symptom present for some women is dry eye syndrome. POF patients have been shown to have an increased incidence of ocular surface disease as compared to normal women.

Treatment of Premature Ovarian Failure

Attempting pregnancy

Unfortunately, there has not been a treatment developed to improve ovarian function and increase the pregnancy rate in POF patients. Doctors and scientists have not developed a way to create new eggs or to make existing eggs work better. Yet, there are hormone replacement therapies available to treat the symptoms that results from low estrogen levels.

Spontaneous pregnancies can and do occur, although not commonly. There has been no medication, hormone or other treatment that results in pregnancy occurring more often than it does without any treatment at all. This is a very important point! Several well done studies have confirmed that treatment of women with POF does not result in a higher pregnancy rate than no treatment at all.

The only therapy that significantly improves the likelihood of a pregnancy in a woman with POF is egg donation. Egg donation is a form of in vitro fertilization in which eggs are removed from an “egg donor”, fertilized and then placed into the hormonally prepared uterus of the woman with POF. Since she is not using her own eggs, the chance for pregnancy using egg donation in a woman with POF is very high. The underlying cause of the POF does not impact on the very high success of this technique.

Estrogen Replacement

For estrogen replacement, most women do well using a transdermal patch. Oral estrogen therapy can be given to women who prefer this route. Typically, about twice as much estrogen is needed compared to post menopausal women to alleviate symptoms.

Oral contraceptives or birth control as hormone replacement therapy contain twice as much steroid hormone that is required to alleviate symptoms of POF. Nonetheless, many younger women prefer to use oral contraceptives since it does not carry the same “stigma” as other types of hormone replacement, which is usually used by older, menopausal women.

Some women have fears of about estrogen therapy; however, remaining deficient at such a young age most likely poses a greater health risk than replacing the hormones normally supplied by the body.

Because low estrogen levels causes a decrease in bone density possibly leading to osteoporosis, women should have 1200-1500 mg of calcium in their diet everyday. An adequate intake of Vitamin D is also important. Supplements should be taken if the need is not met.

To improve bone mass and muscle strength, POF patients are encouraged to perform weight-bearing exercise for 30 minutes at least 3 times a week. Participation in outdoor sports is recommended.

Conclusions

Despite the fact that this disease occurs only in roughly 1% of women, young women who develop Premature Ovarian Failure have unique needs that require special care. Egg donation is still considered the best option for infertility in women with POF. However, this disease can still result in spontaneous pregnancy. In this way, this condition is not early menopause and should not be treated as such. Women with POF/POI should be educated on the nature of their disease and the current research efforts. It is important to be aware of the condition and the options for future treatments.

Prolactin And Infertility

Prolactin is one of several hormones that is produced by the pituitary gland. Prolactin has many different roles throughout the body. Perhaps the most important role of prolactin is to stimulate milk production in women after the delivery of a baby. Prolactin levels increase during pregnancy causing the mammary glands in a woman’s breast to enlarge in preparation for breastfeeding. Prolactin also helps with the release of milk when the baby is nursing.

Prolactin Infertility

During the first several months that a woman is breastfeeding, the high prolactin levels also serve to inhibit ovulation. This is the reason why women who are breastfeeding do not get their periods and therefore do not often become pregnant. As time goes on however, the prolactin levels do not stay as high with breastfeeding and the woman may start to ovulate.

High prolactin levels may cause infertility . Another term for high prolactin levels is hyperprolactinemia. Women who are not pregnant and are not breastfeeding should have low levels of prolactin. If a non-pregnant woman has abnormally high levels of prolactin, it may cause her difficulty in becoming pregnant.

Prolactin may cause infertility in several different ways. First, prolactin may stop a woman from ovulating. If this occurs, a woman’s menstrual cycles will stop. In less severe cases, high prolactin levels may only disrupt ovulation once in a while. This would result in intermittent ovulation or ovulation that takes a long time to occur. Women in this category may experience infrequent or irregular periods. Women with the mildest cases involving high prolactin levels may ovulate regularly but not produce enough of the hormone progesterone after ovulation. This is known as a luteal phase defect. Deficiency in the amount of progesterone produced after ovulation may result in a uterine lining that is less able to have an embryo implant. some women with this problem may see their period come a short time after ovulation.

Symptoms of High Prolactin Levels

As noted above, some women with high prolactin levels may have no periods or have irregular periods. Another possible symptom of high prolactin levels is breast discharge. The discharge is the result of prolactin trying to stimulate the breast to produce milk. The occurrence of a milky discharge from the breast in a woman who has not recently been pregnant is called galactorrhea. Some women may see galactorrhea occur spontaneously. Others may see it only if they squeeze their nipples.

Measurement of Prolactin

Prolactin can be measured with a simple blood test drawn at the fertility doctor’s office. In order to get accurate results, prolactin should be drawn first thing in the morning. The woman should have had nothing to eat from the night before and should avoid any stimulation of the breast or nipples from the day before also.

One common mistake that doctors make is to draw a prolactin blood test immediately after a patient has had a breast exam in the office. these women will have high prolactin levels because of the exam and therefore do not have truly elevated levels.

Prolactin should also be drawn early in the menstrual cycle – before ovulation. This is because prolactin levels are naturally higher after ovulation.

There are different forms of prolactin known as isoforms or isotypes. Not all of the forms cause reproductive problems though all are measure together on a typical prolactin blood test. For this reasons, if a prolactin level comes back elevated, it should be repeated with a more detailed test that looks at the different isoforms individually.

Causes of High Prolactin Levels

Prolactinoma (Pituitary Adenoma)

In some people, a small group of cells may form a cyst in the pituitary gland which produces elevated levels of prolactin. these cysts are called prolactinomas or pituitary adenomas. It is unclear exactly how these cysts get started. The adenomas can be classified based on their size. The adenomas can be seen and measured using MRI (magnetic resonance imaging).

Small adenomas are known as microadenomas. They measure less than one centimeter in diameter. This is the most common type of adenoma found. Microadenomas can even be present in healthy people who do not have high prolactin levels. Microadenomas can be treated with medication. They do not grow large and do not need to be treated if hormone levels are normal.

Adenomas larger than 1 centimeter are called macroadenomas. If untreated, macroadenomas can grow larger and start to push on nearby structures. The closest structures are the optic nerves. If a macroadenoma causes compression of the optic nerves, partial blindness can result. for this reason, it is important to treat macroadenomas whether or not a woman is interested in getting pregnant. Medication can be used to treat them but if that fails, surgery may be necessary.

Hypothyroidism

If a woman has an underactive thyroid gland, a portion of the brain called the hypothalamus will secrete hormones to try to stimulate the thyroid gland. This same hormone may also cause excess prolactin to be produced from the pituitary. Treatment with thyroid hormone supplements will result in correction of both the thyroid and the high prolactin levels.

PCOS (Polycystic Ovary Syndrome)

PCOS is a common problem that can cause infertility by inhibiting ovulation. For unknown reasons, some women with PCOS may have slightly high prolactin levels.

Medications

Some medications can cause higher levels of prolactin to be produced. The most common medications that do this are known as anti-psychotic medications.  Other medications which may increase prolactin levels:

  • Some types of anti-depressants
  • Some types of sedatives
  • Estrogen
  • Oral contraceptives (birth control pills)
  • Some types of blood pressure medications (methyldopa, verapamil)
  • A medication for nausea (Reglan, metoclopramide)
  • Antacids (cimetidien)

Stress

A high prolactin level can sometimes be due to physical stress. Even drawing blood can by itself cause someone to produce to much prolactin.

Treatment of high prolactin levels

As noted above, prolactin levels can often be corrected by stopping or switching to a different medication. Correction of hypothyroidism is very effective also. If prolactin levels are persistently high, they can be effectively treated with a group of medications known as dopamine agonists.

Bromocriptine (Parlodel)

Parlodel is an effective and inexpensive medication for high prolactin levels.  Parlodel is usually taken at bedtime with a snack. This is because Parlodel will occasionally cause dizziness or stomach upset. so taking it before sleep and with food will reduce those side effects. generally with time, the side effects stop anyway.

The prolactin levels can be rechecked in about three weeks. If the levels are still elevated the dose can be increased or a different medication can be tried. The Parlodel can be stopped upon diagnosis of pregnancy. However, if a woman has a macroadenoma, Parlodel should be continue through pregnancy and delivery.

Due to the side effects, some women cannot tolerate Parlodel. For these women, they may try inserted the pills vaginally instead of taking them orally.

Cabergoline (Dostinex)

Because it is more expensive, cabergoline is not usually the first choice for treatment of high prolactin levels. It is usually used when Parlodel is ineffective or a woman cannot tolerate the side effects. Cabergoline is a longer acting medication. It is usually given twice a week instead of every day.

Smoking and Infertility

Smoking tobacco is associated with a decreased potential to produce a pregnancy.

According to the American Society for Reproductive Medicine virtually all scientific studies support the conclusion that smoking has an adverse impact on fertility. Compared to non-smokers, infertility is more common, and the time it takes to conceive is longer. This is true for passive cigarette smoke exposure as well as for active smokers.

A review of the effects of smoking on female fertility found that virtually every aspect of the reproductive process is affected by smoking. Smoking had a negative impact on

  • ovarian hormone production
  • egg production
  • egg maturation
  • ovulation
  • fertilization

Studies have even found that the fallopian tubes are less able to capture the egg at the time of ovulation,  less able to transport the embryo to the uterus and that the likelihood for an embryo to implant  is reduced.

Research also indicates that the degree of harm caused by cigarette smoking is dependent upon the amount and the period of time a woman smokes. Smoking appears to accelerate the loss of eggs and reproductive function and may advance the time of menopause by several years.

A 2015 study of almost 90,000 women found that compared to women who never smoked, those women who reported being active smokers at some point in their lives were 14% more likely to have infertility and 26% more likely to enter menopause early.

Even Secondhand Smoke Causes Infertility

Women who never smoked but were exposed to the most secondhand smoke were 18% more likely to have problems getting pregnant and to enter menopause at an early age, compared to women who never smoked and were exposed to the least amount of secondhand smoke.

Smoking Causes IVF failure

Nearly twice as many in vitro fertilization (IVF) attempts are required to conceive in smokers than in nonsmokers. Studies of IVF have reported that female smokers require higher doses of fertility drugs to stimulate their ovaries. Even when taking higher doses of fertility drugs, these women don’t produce as many eggs and have their IVF cycles canceled more often. They require more embryos to be transferred into the uterus to get as many pregnancies as in women who don’t smoke.

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Cigarette Smoking And Miscarriage

Smoking during pregnancy is the cause of several complications including low birthweight, placental abruption, and sudden infant death syndrome. However, 14% of pregnant women and 23% of women of reproductive age report being smokers. Secondhand smoke exposure is even more prevalent, with 37% of pregnant women being exposed. A recent review of 50 medical studies found that any active smoking was associated with a 23% increased risk of miscarriage. This risk was greater (32%) when smoking was during the pregnancy itself. The risk of miscarriage increased with the amount smoked. Secondhand smoke exposure during pregnancy increased the risk of miscarriage by 11%.

Cigarette Smoking And Infertility In Men

Men who smoke cigarettes have a lower sperm count and motility and increased abnormalities in sperm shape and function. Men can also be a significant source of passive smoke to women causing an indirect on their fertility as well.

Stress and Infertility

“You’re just trying too hard.  You’re too stressed out, relax and it will happen.”

If you are trying to get pregnant you have probably heard this advice from family or friends. But is is true? Read on, you might be surprised.

Can Stress Cause Infertility?

Probably not.  Infertility is very stressful, but there isn’t any GOOD proof that stress causes infertility. Researchers have looked at the effect stress may have on infertility treatments and the news is reassuring. A meta-analysis of 14 studies was recently published in the British Medical Journal.

Stress and infertility

These studies included 3,583 infertile women. The results support the view that emotional distress, for example feelings of tension, worry or nervousness caused by the infertility treatment or other life events are unlikely to affect fertility treatment outcomes.

What Can I Do To Decrease My Stress?

Talk to your partner. Take time to remember what you value about your relationship. Relationships have many positive aspects besides reproduction.  Consider your companionship, emotional support, making a home together, sharing leisure activities, and building a financial future.

  • Realize you’re not alone. Talk to other people who have infertility, through individual or couple counseling, or support groups.
  • Read books on infertility, which will show you that your feelings are normal and can help you deal with them.
  • Learn stress reduction techniques such as meditation, yoga, or acupuncture.
  • Avoid caffeine or other stimulants.
  • Exercise regularly to release physical and emotional tension.  
  • Have a medical treatment plan with which both you and your partner are comfortable.
  • Learn as much as you can about the cause of your infertility and the treatment options available.
  • Find out as much as you can about your insurance coverage and make financial plans regarding your fertility treatments.

When Should I Seek Professional Help?

It may be hard to know when emotional responses to the pain and frustration of infertility are within normal, expected range or are excessive and problematic.

If you are experiencing any of the following feelings, you may want to see an infertility counselor or therapist:

  • You have felt sad, depressed, or hopeless for longer than two weeks.
  • You have noticed changes in your appetite, either eating more or less than usual.
  • You are having trouble sleeping or are sleeping more than usual. You awaken not feeling rested.
  • You feel anxious, agitated, and worried much of the time.
  • You have panic attacks–particularly related to infertility situations or issues.
  • You feel lethargic or have lost interest in usually enjoyable activities.
  • You have trouble concentrating, are easily distracted, and/or have difficulty making decisions.
  • You have persistent feelings of worthlessness or guilt.
  • You feel easily irritated, angry, and frustrated.
  • You have thoughts of death or dying.
  • You have lost interest in sex and/or fail to have orgasms.
  • Relationships with friends and family are no longer rewarding and enjoyable and you prefer being alone.

Our infertility team can offer support and compassion. We know this is a difficult process.

References

American Society for Reproductive Medicine
Retrieved 4/15/2010 from:  http://www.asrm.org/topics/detail.aspx?id=1738

Burns, L.H. When to seek professional help
Retrieved 3/36/2010 from: http://familybuilding.resolve.org/site/DocServer/18_Professional_Help_for_Emotional_Aspects.pdf?docID=5707

Boivin, J. Griffiths, E. Emotional distress in infertile women and failure of assisted reproductive technologies: meta-analysis of prospective psychosocial studies, British Medical Journal, 2011;342:d223

Thin Uterine Lining

In in order for a pregnancy to occur, the embryo must implant into the uterine lining (also known as the endometrium). Two hormones produced from the ovaries thicken and prepare the uterine lining for implantation. Estrogen causes the thin uterine lining to thicken. Progesterone causes the thickened uterine lining to develop the characteristics needed for implantation.

Women who are attempting pregnancy using frozen embryos or with donor eggs will commonly receive estrogen and progesterone supplements in preparation for transfer of a thawed embryo into the uterine cavity.

Thin uterine lining

Numerous studies have found that if a woman has a persistently thin uterine lining despite receiving adequate amounts of estrogen, then the chance for pregnancy is reduced. For many women, the cause of a persistently thin uterine lining is unknown. Many different therapies have been used in an attempt to improve the thickness of the uterine lining during estrogen supplementation but none have shown consistent benefits in this group.

Possible Causes and Treatments For Thin Uterine Lining

In some women, a thin uterine lining may be the result of not getting a sufficient amount of estrogen. Estrogen levels can be checked with a blood test. Estrogen is most commonly given orally but if this fails, other alternatives include estrogen patches, estrogen injections or administering estrogen vaginally.

If the amount of estrogen is adequate, a thin uterine lining could be the result of damage to the uterine lining. For example, a previous uterine infection or surgery inside the uterine cavity could cause scar tissue to form which replaces the normal uterine lining. If this is the case, then surgery to remove scar tissue may be necessary.

Using ultrasound, doctors can measure blood flow to the uterus. Some studies indicate that failure of the uterine lining to thicken could be due to decreased blood flow. One study used high doses of Vitamin E and an amino acid called L-arginine to increase the thickness of the uterine lining. Unfortunately, this treatment only worked in about half of those women with poor blood flow which itself was not a common cause for thin uterine lining.

There have not been any studies to show that herbal supplements or “cleanses” will help thicken the uterine lining or improve fertility and should be avoided because of the possibility for adverse effects.

Acupuncture, massages, exercise, stress reduction has also failed to improve a thin uterine lining but there is no risks to these therapies.

New treatments for thin uterine lining

Since the cells of the uterine lining arise from stem cells at the bottom or base of the uterine lining. There have been recent studies looking at treatments to stimulate these stem cells to produce a healthier, thicker uterine lining.

Read more about clinical studies at IVF1 for women with persistently thin uterine lining.

Vagifem® (estradiol vaginal tablets)

What is Vagifem? (estradiol vaginal tablets)?

Occasionally, during infertility treatments, we may tell you that the uterine lining is thin based on ultrasound measurements. There is some evidence, though it is far from conclusive, that a thin lining may be associated with a lower chance for pregnancy in that month. We may, therefore, recommend using estrogen supplementation to improve the thickness. Since vaginal medications have a much better effect than those administered elsewhere, we use VAGIFEM? (estradiol vaginal tablets) for this purpose. Estradiol, is the bio-identical hormone to that that produced by the ovaries during development of the egg.

How Do I Use Vagifem? (estradiol vaginal tablets)?

Tear off a single applicator.

Separate the plastic wrap and remove the applicator from the plastic wrap.

First select the best position for vaginal insertion of VAGIFEM? (estradiol vaginal tablets) that is most comfortable for you.

One method is to recline on your back

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Another option is stand.

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The applicator should be held so that the finger of one hand can press the applicator plunger. The other hand should be used to guide the applicator gently and comfortably through the vaginal opening.If the tablet has come out of the applicator prior to insertion, do not attempt to replace it. Use a fresh tablet-filled applicator.

crinone

The applicator should be inserted (without forcing) as far as comfortably possible, or until half of the applicator is inside your vagina, whichever is less.

Once the tablet-filled applicator has been inserted, gently press the plunger until a click is heard and the plunger is fully depressed. This will eject the tablet inside your vagina where it will dissolve slowly over several hours.

After depressing the plunger, gently remove the applicator and dispose of it the same way you
would a plastic tampon applicator. The applicator is of no further use and should be discarded properly.

In most cases, our patients will be using vagifem twice daily. Insertion should be done upon waking in the morning and again in the evening before bed.

Treatment of Insulin Resistance in PCOS

Metformin

Metformin for the treatment of PCOS

Metformin is the generic name for a medication which reduces insulin resistance. It is also known as Glucophage, Riomet or Fortamet. Metformin is used as a fertility treatment to cause ovulation in women with insulin resistance or PCOS.

Read more…

Byetta is used to treat insulin resistance in PCOS patients
Byetta is used to treat insulin resistance in PCOS patients

Alternatives to metformin for treating insulin resistance in PCOS

Medications such as Byetta and Acarbose and minerals such as chromium have been studied in PCOS patients. Some may have benefit for patients with insulin resistance who do not ovulate.

Avandia treatment of insulin resistance
Avandia treatment of insulin resistance

Actos and Avandia for treating insulin resistance in PCOS

A class of medications called TZDs have been used in the past to induce ovulation in PCOS patient and others with insulin resistance. due to potential risks, this medication is rarely if ever used for this purpose any more.

Alternative PCOS treatments for insulin resistance

Table Of Contents

  • Alternatives to glucophage for treating insulin resistance in PCOS
  • Sitagliptin (Januvia)
  • Byetta (Exenatide for injection)
  • Glycosidase Inhibitors for PCOS Treatment
  • Precose (Acarbose)
  • Miglitol (Glyset)
  • Chromium treatment for PCOS
  • Exercise and PCOS
  • Green Teas for PCOS
  • Herbal Drugs and Chemicals
  • Cinnamon for PCOS
  • Vitex for PCOS

Alternatives to glucophage for treating insulin resistance in PCOS

For women with polycystic ovary syndrome – PCOS, insulin resistance is a common finding. In addition, many of these women do not respond to Clomid (Clomiphene Serophene) (Clomid resistance). For these reasons, many women are now treated with a diabetes medication known as glucophage (metformin) which works, in part, to reduce insulin resistance and improves the chances for ovulating spontaneously or with Clomid. However, many women will have side effects from glucophage such as bloating, cramping, diarrhea, flatulence and nausea. The most serious complication of glucophage is lactic acidosis which is a rare but potentially life threatening condition.

Sitagliptin (Januvia)

Incretins are naturally occurring hormones secreted from the intestines in response to food intake. In the pancreas, incretin hormones act to increase insulin secretion in response to rising sugar levels in the blood. This helps to ensure an appropriate insulin response following ingestion of a meal.

Sitagliptin prolongs the action of incretin hormones by prohibiting their degradation through inhibition of the dipeptidyl peptidase-4 enzyme (DPP4).

A 12 week study of obese women with PCOS who were unable to tolerate metformin were treated with sitagliptin. Sitagliptin was found to improve insulin resistance. another study found that the chance for ovulation was similar to metformin. sitagliptin, however, was tolerated much better than metformin was.

Sitagliptin has been rated by the FDA as belonging to pregnancy category B. Reproduction studies have been performed in rats and rabbits. Doses of sitagliptin up to 12 time the maximum recommended human dose did not impair fertility or harm the fetus. There are, however, no adequate and well-controlled studies in pregnant women. Sitagliptin administered to pregnant female rats and rabbits from gestation day 6 to 20 (organogenesis) did not produce birth defects at approximately 30- and 20-times the maximum recommended human dose. Higher doses increased the incidence of rib malformations in offspring at approximately 100 times human exposure at the MRHD.

Byetta (Exenatide for injection)

Byetta belongs to a class of medications known as incretin mimetics. The incretin hormone which scientists have studied the most is called glucagon-like peptide-1 (GLP-1). Byetta works by mimicking the effects of GLP-1. Studies show it increases insulin sensitivity.

Byetta is approved by the FDA for the treatment of diabetes – not PCOS yet. Two advantages of Byetta that have been shown in clinical studies include better control of blood sugar levels in diabetics and weight loss. Since Byetta improves insulin resistance, some scientists feel that PCOS patients may benefit from taking Byetta.

In a study of 60 overweight women with PCOS, Byetta improved the likelihood of women having regular menstrual cycles. The combination of Byetta with metformin was found to be better than either metformin or Byetta alone. Byetta alone showed improvement in several parameters such as weight, BMI, insulin resistance and androgen levels. Byetta in combination with metformin improved these parameters to a greater extent then Byetta alone.

It is clear, therefore, that Byetta exerts a positive impact on PCOS patients and that combining Byetta with metformin works better than either medication alone.

Byetta has been rated by the FDA as belonging to pregnancy category C. Byetta has been shown to cause reduced fetal and neonatal growth and skeletal effects in mice.  Byetta has also been shown to cause skeletal effects in rabbits. There are no adequate and well-controlled studies in pregnant women. Byetta should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

The most common adverse events associated with Byetta were nausea, vomiting, diarrhea, feeling jittery, dizziness, headache, and dyspepsia. In October of 2007, the FDA reported that it had received 30 reports of patients taking Byetta developing a serious condition known as pancreatitis. Five patients developed serious complications from the pancreatitis such as kidney failure. Although most patients improved after they stopped taking Byetta, eight out of the thirty patients did not improve.

Since those initial reports, there have been several studies trying to determine if there is a relationship between Byetta and pancreatitis. The results have been mixed, some studies showed an increased risk, some did not. Complicating the matter is the fact that type 2 diabetics have a higher rate of pancreatitis even without the use of Byetta. As of late 2011, there were no reports of PCOS patients taking Byetta developing pancreatitis.

At this time, Byetta cannot be recommended as a first-line treatment for PCOS. It may be considered as an alternative, however, with proper counseling.

Glycosidase Inhibitors for PCOS Treatment

Precose (Acarbose)

50-100 mg and are taken with meals

Miglitol (Glyset)

50-100 mg and are taken with meals

Acarbose is another medication used to treat diabetes. Acarbose is an alpha-Glycosidase inhibitor. It works by reducing the absorption of monosaccharides (simple sugars) through intestines and minimize the increase in blood sugar and insulin seen after meals. Serious side-effects of acarbose are rare and although it shares many of the gastrointestinal side effects as glucophage (abdominal distension, diarrhea and flatulence), lactic acidosis is not a problem with this drug. side effects may lessen over time.

Some studies have demonstrated that these medications are capable of lowering the androgen levels in women with PCOS.

In a recent study, researchers looked at 30 women with polycystic ovary syndrome – PCOS who did not previously respond to Clomid . The women were divided into two groups. One group received acarbose and Clomid. The other group received glucophage and clomid.

By the end of three months, the women taking acarbose lost more weight than the glucophage group. Both groups showed a similar improvement in the number of women who ovulated. There were 15 women in each in group and they were studies for three months so there was a possibility of 45 ovulatory cycles (15 x 3). The acarbose group had 20 ovulations and the glucophage group had 24 ovulations. The incidence of side effects was the same in both groups and there were no serious adverse effects in either group.

In summary, it seems that acarbose could provide a reasonable alternative to glucophage for treating insulin resistance in polycystic ovary syndrome – PCOS patients, though the expected benefits are minimal. This was a small study so there isn’t nearly as much data showing a positive effect as exists for glucophage at the moment. Acarbose did not have a better ovulation rate than glucophage so the main benefit comes down to a lower risk of lactic acidosis which is a very rare complication anyway.

I would think of acarbose as a second line drug for the time being. If first line drugs like glucophage were not tolerated or ineffective than trying something like acarbose might be reasonable.

Chromium treatment for PCOS

Chromium is a mineral required in small quantities by the body. It enables insulin to function normally and helps the body process (metabolize) carbohydrates and fats. Good sources of chromium include carrots, potatoes, broccoli, whole-grain products, and molasses. Picolinate, a by-product of the amino acid tryptophan, is paired with chromium in supplements because it is claimed to help the body absorb chromium more efficiently. Chromium deficiency is very rare in developed countries. Nonetheless, it has become a popular supplement.  Chromium picolinate has been suggested to promote weight loss, build muscle, reduce body fat, and enhance the function of insulin. It may lower levels of cholesterol and triglycerides.

Chromium picolinate is of possible interest in the treatment of PCOS patients due to its possible effects in improving insulin resistance. A few small studies have been performed in which women with PCOS were given chromium.

One such study, in women with polycystic ovary syndrome, found that chromium picolinate (200 μg/d) improved glucose tolerance compared with placebo but it did not improve ovulatory frequency or the abnormal hormonal parameters commonly found in women with PCOS. The authors of this study concluded that future studies in the polycystic ovary syndrome population should examine higher dosages or longer duration of treatment.

Another study examined the effects of chromium picolinate at a dose of 1000 ug per day. PCOS patients were given chromium but were instructed not to change their diet or exercise level. These PCOS patients experienced a  38% mean improvement in a measure of insulin resistance. These authors concluded that chromium picolinate, an over-the-counter dietary product, may be useful as an insulin sensitizer in the treatment of polycystic ovary syndrome.

Exercise and PCOS

Exercise may be the single most important lifestyle factor for both preventing and reversing insulin resistance. Exercise training results in a preferential loss of abdominal body fat and reverses the loss of muscle mass associated with insulin resistance, providing the single-most important intervention for changes in body composition.

Exercise improves insulin sensitivity in skeletal muscles and fat tissue, reducing both fasting blood sugar and insulin levels. Findings demonstrate that consistent exercise training, even without accompanying improvements in body composition, improve peripheral insulin activity in subjects with impaired glucose tolerance.

Even an exercise routine as simple as incorporating brisk walking four times weekly dramatically improves endurance fitness, decreases body fat stores, tends to reduce food consumption, and decreases insulin resistance.

To date, only a few controlled studies have examined the direct effects of physical exercise in PCOS women. In the first study, a 6-month exercise program significantly decreased plasma total homocysteine concentrations and waist-to-hip ratio, but had no effect on fasting insulin or androgen levels in young overweight and obese women with PCOS.

More recently, a 2005 study showed that insulin resistance was improved by up to 25% in sedentary women with PCOS and insulin resistance following a 5-month moderate-intensity exercise program without weight loss. In 2007, investigators determined that any improvements seen with exercise in PCOS patients were lost within 12 weeks if they stopped their exercise program.

Green Teas for PCOS

Many varieties of green tea have been created in China and other countries. these teas can differ substantially due to variable growing conditions, processing and harvesting time. Although many health benefits are supposed to result from drinking green teas, few if any of these claims have been proven in rigorously performed studies.

Herbal Drugs and Chemicals

Unfortunately, the internet has resulted in a huge increase in the use of herbal drugs and elixirs. In addition to being exempt from U.S. Food and Drug oversight, there is little evidence to support the use of these powerful chemical compounds. There are reported cases of adverse complications occurring in women taking these things to try to promote their fertility.

Cinnamon for PCOS

Cinnamon is a spice that comes from the bark of a small evergreen tree native to Sri Lanka and South India. The bark is widely used as a spice due to its distinct odor. In India it is also known as “Daalchini”.

Cinnamon is prepared by roughly pounding the bark, soaking it in sea-water, and then quickly distilling the result. Cinnamon contains a large amount of active chemicals including cinnamic aldehyde, ethyl cinnamate, eugenol, cinnamaldehyde, beta-caryophyllene, linalool and methyl chavicol.

Like other herbal remedies, there are many varieties of cinnamon which have distinct chemical components and may differ from each other substantially. It is therefore difficult to perform accurate scientific comparisons and draw valid conclusions.

In the summer of 2007, a very small pilot study was performed to determine whether cinnamon had any beneficial effects on women with PCOS. Fifteen women with polycystic ovary syndrome were randomized to daily oral cinnamon and placebo for 8 weeks. The results indicated a reduction in insulin resistance in the cinnamon group but not in the placebo group. Because the number of women studied was so small, a larger trial is needed to confirm the findings of this pilot study.

Vitex for PCOS

Vitex agnus-castus  (commonly called just Vitex, but also called Chaste Tree, Chasteberry, or Monk’s Pepper — is a plant which grows in the Mediterranean region. The leaves, stem, flowers and ripening seeds, have been used for medicinal purposes.

The berries have been used as an herbal drug for both the male and female reproductive systems. The leaves are believed to have the same effect but to a lesser degree. This plant is commonly called monk’s pepper because it was originally used as anti-libido medicine by monks to aid their attempts to remain celibate. It is believed to decrease sexual interest, hence the name chaste tree.

There is little if any clinical evidence of a benefit of Vitex for infertility or women with PCOS. Like other herbal drugs, many varieties of the plant are grown in various areas. The chemical composition is quite complex and varied from variety to variety.

One study has found that treatment with one variety of Chinese Vitex caused a slight reduction of a pituitary hormone known as prolactin in mice. There are no studies in human beings. There are no studies which have looked at the effects of Vitex in women with PCOS.

Actos and Avandia for PCOS

Background on Actos and Avandia

Actos (pioglitazone) and Avandia (rosiglitazone) belong to a class of medications known as thiazolidinidiones or TZDs. A third medication known as Rezulin (troglitazone) is no longer available in the United States. All three of these medications have been approved by the Food and Drug Administration for the treatment of diabetes. The use of Actos and Avandia for PCOS is considered an off label indication.

Because of the risks, TZDs such as Actos and Avandia are no longer recommended for the treatment of PCOS

Why diabetes drugs for PCOS?

There are many reasons why a woman may not ovulate regularly. It appears that some women are resistant to the hormone insulin. Insulin is normally thought of as a hormone that helps regulate blood sugar. Insulin is produced by cells that are located adjacent to the pancreas called the Islets of Langerhans. While this is true, insulin also has many other effects in the body. The ovary has receptors for insulin and thus insulin is capable of modifying hormone production from the ovaries.

The are several conditions that may result in a woman becoming resistant to the effects of insulin. Among these are PCOS (Polycystic Ovary Syndrome), genetics and obesity. When insulin resistance occurs, the body needs a higher level of insulin to accomplish the same tasks. High insulin levels are frequently seen in women with insulin resistance.

If insulin resistance is the cause for a woman’s anovulation (not ovulating) then it stands to reason that improving the insulin resistance or lowering the insulin levels may be successful at causing ovulation to return.

In fact some studies in women with PCOS demonstrated that thiazolidinidiones could be an effective treatment.

Rezulin in PCOS

Rezulin was the first TZD studied. Studies with Rezulin in PCOS patients demonstrated an improvement in some of the hormone abnormalities seen in PCOS.

In 2 other studies, Rezulin either alone or combined with clomiphene citrate induced ovulation in insulin and/or clomiphene-resistant patients with PCOS. Ovulation and pregnancy rate were 83% and 39% in 18 Clomid resistant patients, and in most of the patients, ovulation was achieved with Rezulin alone or in combination with low doses of CC.

Actos in PCOS

More recently, a well designed study using Actos in PCOS patients was published. The Actos study was a randomized, double-blind, controlled trial was to investigate whether Actos was capable of decreasing insulin resistance and the elevated levels of male hormones (androgens) that are common in women with PCOS. The Actos study also sought to determine whether the ovulation rate would improve in women with PCOS.

Forty pre-menopausal women with PCOS were assigned to treatment with either Actos (30 mg/d) or a placebo for three months. The results were very encouraging. The group which took Actos showed a decline in both fasting serum insulin levels and insulin response after giving them a high load of sugar.

This represented an increase in insulin sensitivity. In addition, Actos increased the levels of a protein called SHBG. SHBG binds up the male hormones in the circulation resulting in less “free” male hormones (androgens).

Treatment with Actos was also associated with higher ovulation rates.

Avandia in PCOS

A similar study using Avandia was published in March of 2005. The stated goal of this randomized, controlled, double-blind trial was to learn whether Avandia would improve the ovulation rate and androgen levels in non-obese women with polycystic ovary syndrome (PCOS). An interesting aspect of this study is that women were chosen based on the fact that all laboratory testing for insulin resistance was normal.

100 women with PCOS were enrolled in the study. The women received either 850 mg of Glucophage, 4 mg Avandia, a combination of both treatments, or a placebo twice a day for 6 months.

The results of this Avandia study are interesting. Women given Avandia gained an average of 1 kg (about 2.2 pounds). However, all treatment groups except the placebo group had a significant decline in their waist-to-hip ratio which implies a reduction in insulin resistance. Likewise, systolic blood pressure fell in all actively treated groups but not in those who received placebo.

Avandia and Glucophage treatment resulted in an increase in the number of times the PCOS patients ovulated. The highest rates of ovulation were found in the combined Avandia and Glucophage group and in the Glucophage only group.

The male hormone testosterone decreased significantly with active treatment.

Avandia dose for PCOS

Avandia 4 or 8 mg tablets. Maximum 8 mg daily

Actos dose for PCOS

Actos 15, 30 or 45 mg tablets. Maximum dose 45 mg daily.

Actos and Avandia side effects

Rezulin which is no longer available in the U.S. has been found to cause liver injury, jaundice and very rare cases of liver failure, liver transplants, and death. In early studies, Rezulin was noted to increase the levels of certain blood markers of liver injury (liver enzymes, AST, ALT). The other members of this class have not been found to cause similar problems. In fact, it is when Actos and Avandia were approved by the FDA that Rezulin was removed from the U.S. market. However, due to the close structural similarity of all these medications, it is strongly recommended that all patients undergo regular assessment of liver enzymes.

The incidence of other reported side effects in clinical trials of Actos and Avandia did not differ from that of placebo (sugar pills).

In a small percentage of people, Actos or Avandia may cause fluid retention. Others may notice swelling in the lower extremities during use.

Because of the possible risks, you should not take Actos or Avandia if:

1. You have known liver problems
2. You drink alcohol excessively
3. Heart disease

Patients who develop nausea, vomiting, abdominal pain, fatigue, loss of appetite, dark urine, light colored stools, or yellowing of the whites of the eyes should immediately report these symptoms to us.

Newly reported possible risks of Actos and Avandia

Takeda pharmaceuticals recently performed an analysis of its clinical trial database of Actos with a special focus on fractures, comparing patients treated with Actos or a comparator (either placebo or a different medication). The results suggest that Actos users are at higher risk for fractures. In the analysis, the maximum duration of Actos treatment was up to 3.5 years. There were more than 81 00 patients in the Actos-treated groups and over 7400 patients in the comparator-treated groups. The majority of fractures observed in female patients who received Actos were in the distal upper limb (forearm, hand and wrist) or distal lower limb (foot, ankle, fibula and tibia).

Based on their calculations, if 1000 women took Actos for one year, 19 fractures would be expected compared to 11 expected fractures in the comparison group. There was no increased risk of fracture identified in men.

Avandia was shown in a separate study published in the New England Journal of Medicine in May 2007 to possibly be associated with an increase in the risk for myocardial infarction (heart attack) and cardiovascular death. However, the study did not separate diabetics from PCOS patients and incldued both men and women. It is not clear at this time whether PCOS patients have a similar increase in risk.

Actos and Avandia: Effects on pregnancy

Rezulin and Avandia are considered pregnancy category B.

Animal studies in rats and rabbits at very high doses did not result in a higher than expected incidence of birth defects. At extremely high doses, body weights of fetuses were decreased. Postnatal development, attributed to decreased weight was delayed.

Actos is pregnancy category C. Delayed parturition and postnatal development and embryo toxicity (as evidenced by increased post-implantation losses, delayed development and reduced fetal weights) were observed in rats and/or rabbits when given very high doses.

There are no good, well-controlled studies in women. It is recommended that Actos or Avandia be stopped immediately upon the diagnosis of pregnancy.

Progesterone vaginal suppositories

Progesterone vaginal suppositories

Progesterone suppositories are relatively simple to use. Progesterone suppositories are compounded by the pharmacist and consist of natural progesterone suspended in a base similar to cocoa butter.

The suppositories will feel soft and "squishy" to the touch. Usually they are oblong or bullet shaped. Someitmes the suppositories will come with an applicator but an applicator is not necessary to use them.

The suppositories are intended to be used vaginally. First, the suppository must be removed form the wrapping or covering material. The suppository is then fitted onto the end of the applicator into the "cup". The applicator is inserted into the vagina. Once resistance is felt, stop advancing the applicator.

Press the plunger on the end of the applicator to release the suppository and then remove the applicator.

Alternatively, the suppository can be grasped between the fingers and inserted without an applicator.

Progesterone injections

What is Progesterone?


Progesterone, one of the reproductive hormones normally produced by the ovary after ovulation. It is needed to prepare the endometrium for implantation of an embryo and is used as part of an assisted reproductive technology (ART), ovulation induction or sometimes to induce a period in a woman who hasn’t ovulated.

Here are step-by-step instructions for administering Progesterone Injection injections:


Wash your hands thoroughly and make sure that the surface you work on is clean.

abdomen


Use an alcohol swab to cleanse the rubber stopper of the progesterone medication.

abdomen


Using the 3cc syringe with a 1.5 inch needle, pull back on the plunger to the 1cc mark.

Pierce the rubber stopper of the progesterone vial. Inject 1cc of air into the vial.

Turn the vial upside down, making sure the tip of the needle is below the fluid level. Withdraw the dosage ordered. Progesterone is an oil. It will pull into the syringe more slowly than sterile water does as when you use your other fertility medications.


Pull out the needle and replace the cap. Pull back on the plunger to clear the needle of any medication. Remove the needle from the syringe and replace with a new 1½ inch needle.

Flick the syringe with your finger

With the needle pointing toward the ceiling, flick the side of the syringe to disperse the air bubbles and the air pocket at the top of the syringe

Press the plunger on the syringe


Then gently push the plunger to eliminate any air until you expel one or two drops of liquid from the tip of the needle.

You are now ready to administer the progesterone by intramuscular injection.

Click here to learn how to give a intramuscular injection

IVF Progesterone supplementation

Progesterone is made from the ovaries after ovulation. During IVF cycles, progesterone is produced after the hCG trigger injection is taken. Using medications to prevent premature ovulation and performing an egg retrieval may cause the progesterone production to be inadequate. For this reason, we will supplement progesterone in women being treated with IVF.

Vaginal or IM Progesterone?

The most reliable way to get progesterone to the uterus is to administer it vaginally. Several studies have been performed comparing vaginal progesterone to intra-muscular injections. In the past, some studies have shown that vaginal progesterone is best whereas some studies showed that  intra-muscular progesterone is best. Today, it is almost universally agreed that there is no difference in the chance for pregnancy between the two.

Most women prefer to use vaginal progesterone. This is due to the fact that administration of intramuscular progesterone is painful and can result in welts at the injection site. some women also have allergic reaction to the oil base in the progesterone injections.

A few women seem to prefer progesterone injections because they do not like the vaginal discharge that can sometimes occur with the use of vaginal progesterone.

We like to use vaginal progesterone in the evening (either a natural progesterone cream called Crinone or a vaginal progesterone dissolving tablet called Endometrin ). Crinone comes in an applicator like medications that are used to treat yeast infections. One applicator of Crinone is given each morning and night starting on the night of the egg retrieval. Endometrin is used three times daily.

Safety of progesterone in IVF

Many couples worry whether treatment with progesterone is safe for the baby. The short answer is yes.

Progesterone supplements come in different varieties. Only a few of these types are safe to use in pregnancy. Progesterone that is chemically identical to the “natural” progesterone made in the ovaries is safe to use in pregnancy. In fact, two brands, Crinone and Endometrin, are natural progesterones that are approved by the U.S. FDA for use in fertility treatments. Some pharmacies can also make natural progesterone vaginal suppositories. Progesterone intramuscular injections also contain natural progesterone and may be used during pregnancy.

There are progesterone supplements that are synthetically derived and not chemically identical to the progesterone made in the ovaries. For example, the progesterones that are contained in birth control pills like norethindrone, drospirenone (and others) should not be used in pregnancy. A very commonly used type of synthetic progesterone called Provera should also not be used in pregnant women.

How long do you need to continue progesterone?

As noted above, there is concern about the ovaries ability to produce progesterone because of the use of medications and because of the egg retrieval. At about the 7th week of pregnancy, progesterone production begins to shift from the ovaries to the placenta. By about the 11th week, the shift is complete and all progesterone is being produced by the placenta. At this posint, progesterone supplementation is no longer needed.

Lupron (Leuprolide acetate)

What is Lupron (Leuprolide acetate)?

Lupron® is a gonadotropin-releasing hormone agonist. It inhibits the pituitary gland’s ability to control the ovary and, therefore, has been used to reduce the likelihood of unintended ovulation during assisted reproduction treatment cycles. In women with endometriosis, Lupron® provides pain relief and reduction in the size of endometriosis lesions.

How do I use Lupron (Leuprolide acetate)?

Here are step-by-step instructions for taking Lupron® (leuprolide acetate) injections: Lupron® is injected subcutaneously-or into the fatty tissue under your skin. The primary sites for injection are your abdomen – 2 inches on either side of the navel;- and your upper, outer-thigh where the skin is loose.
,

Lupron

Wash your hands thoroughly and make sure that the surface you work on is clean.

Use an alcohol swab to cleanse the rubber stopper of the vial.

Pull the plunger of the syringe back to the appropriate marking.

Pull off the cap of the needle, and pierce the rubber stopper of the Lupron® vial.

Push the plunger all the way in. Keeping the needle inside the bottle, turn the vial upside down. With the needle in the liquid, pull back the plunger, until the syringe fills to the proper mark. Remove the needle from the vial,

With the needle pointing toward the ceiling, flick the side of the syringe to disperse any air bubbles and the air pocket at the top of the syringe.

Gently push the plunger until one or two drops of liquid are expressed to make sure you have eliminated any air.

You are now ready to administer the lupron as a subcutaneous injection.
Click here to learn how to give a subcutaneous injection

Low Dose hCG

IMPORTANT: The low dose hCG should be premixed by the pharmacy. You should receive it on ice and it needs to be kept in the refrigerator. If you have not received your hCG in this way, please notify us immediately!

It is your responsibility to make sure you have received the correct medications. Do not wait until the last minute!

Do not attempt to use hCG for the trigger injection in place of low dose hCG!!!!

Why use Low Dose hCG?

hCG, or human chorionic gonadotropin, is very similar in structure to the pituitary hormone LH (luteinizing hormone). Many experts beleive that in order to optimally stimulate the ovaries for assisted reproduction technologies (ART), medications containing both FSH (follicle stimulating hormone) and LH are necessary.

Since most of the FSH medications used in ART are produced through recombinant DNA technology, they contain no LH activity. Supplementation with LH is problematic since LH is broken down very quickly in the body and therefore has very little effect.
hCG, however, lasts much longer and therefore has greater biologic activity. Very low dose hCG is used as a replacement for LH to help supplement the stimulation during ART cycles.

How do I use Low Dose hCG?

Here are step-by-step instructions for taking low dose hCG injections:
Low dose hCG is injected subcutaneously-or into the fatty tissue under your skin. The primary sites for injection are your abdomen – 2 inches on either side of the navel, and your upper, outer-thigh where the skin is loose. Wash your hands thoroughly and make sure that the surface you work on is clean.

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You should receive your low dose hCG premixed and on ice. Place it in the refigerator until ready for use. If your medication is not mixed by the pharmacy, you will need to bring it into our office to have the nurses mix it for you.

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The first time you use the low dose hCG vial, it will have a foil wrapper covering the top. Grasp the foil tab and pull the foil off the the low dose hCG vial.

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Wipe the top of the vial with an alcohol swab.

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Remove the syringe from its wrapper. The needle is already attached to the syringe. Remove the cap from the needle.

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Draw the plunger back on the syringe to the mark that you have been instructed.

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With the vial of premixed low dose hCG on a flat surface, insert the needle straight down through the marked center circle of the rubber stopper. Slowly inject the air into the vial by depressing the syringe plunger.

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With the needle still in the vial, invert the vial. Keep the tip of the needle below the surface of the fluid hCG mixture.

Pull the plunger back to the mark you have been instructed. Make sure that you keep the tip of the needle under the surface of the fluid while withdrawing the hCG mixture.

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Remove the needle from the vial. The syringe is now ready for you to administer the lose dose hCG injection subcutaneously. Remember to place the hCG vial back into the refigerator until its next use.

Click here to learn how to administer the subcutaneous injection of low dose hCG

Lovenox (enoxaparin) Injection Instructions

What is Lovenox™ (enoxaprin sodium)?

Lovenox™ is a medication used to help reduce the chances for blood clots (a.k.a thrombosis) from forming. At IVF1, we use Lovenox™ to prevent Deep Vein Thrombosis (DVT) from occurring during or shortly after surgery. We also use  Lovenox™ in women with recurrent miscarriage due to increased blood clotting.

How do I use Lovenox™?

Here are step-by-step instructions for taking Lovenox™ (enoxaparin) injections:

Lovenox™ is injected subcutaneously-or into the fatty tissue under your skin. The primary sites for injection are your abdomen – 2 inches on either side of the navel.

Wash your hands thoroughly before beginning.

Lovenox

Lovenox™

lovenox_step_1.jpg

Remove the needle cap by pulling it straight off the syringe and discard it in a sharps collector. Do not twist the cap. Do not push on the plunger when pulling off the cap.

lovenox_step_2.jpg

Hold the syringe like a pencil in your writing hand.

lovenox_step_3.jpg

With your other hand, pinch an inch of skin that you have cleaned with alcohol to make a fold in the skin. Next, insert the full length of the needle straight down – at a 90˚ angle – into the fold of skin.

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Press the plunger with your thumb until the syringe is empty.

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Then pull the needle straight out and release the skin fold.

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Point the needle down and away from yourself and others, and then push down on the plunger to activate the safety shield.

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Place the used syringe in the sharps collector.

Click here to learn how to give a subcutaneous injection

Letrozole (Femara) for Infertility Treatment

Background information

Letrozole is being used commonly as an infertility treatment. Letrozole is a recent addition to the drugs being used for fertility treatment. Fertility drugs are used often in infertility treatments. There are two situations in which fertility drugs may be useful. First, these drugs can be used to induce an egg to develop and be released in women who are not ovulating on their own. This is known as ovulation induction. Fertility drugs can also be used to increase the chances of pregnancy in women who are already ovulating. This is known as superovulation.

Letrozole for infertility
Letrozole for infertility

In many fertility centers, clomiphene citrate (Clomid, Serophene) has been the drug of first choice for either ovulation induction or superovulation for many years. In general, it has been a relatively effective medication. However, clomiphene citrate lasts for a long time in the body and may therefore have an adverse effect on the cervical mucus and uterine lining. Some groups of patients, such as women with PCOS – polycystic ovary syndrome, do not respond well to clomiphene citrate. The Pregnancy in Polycystic Ovary Syndrome (PPCOS I) study found that over 6 months time, 1 in 4 PCOS patients never had a single documented ovulation. The cumulative live birth rate was only 23% over the 6 months. One reason theorized for the lower pregnancy rate with clomid is an adverse effect on the uterine lining.

Another group of fertility drugs which are administered as injections are called gonadotropins (Gonal F, Follistim). The gonadotropins are very efficient at inducing ovulation and have higher pregnancy rates than clomiphene citrate. However, gonadotropins are much more expensive than clomiphene citrate and the injectable route is uncomfortable for patients to administer and inconvenient. The risk for multiple pregnancies is also much higher with gonadotropins.

Letrozole as a Fertility Treatment

Letrozole is a medication that has been widely used in women with breast cancer. It is sold under the trade name Femara. Letrozole belongs to a class of medications known as aromatase inhibitors. Aromatase is an enzyme that is responsible for the production of estrogen in the body. Letrozole works by inhibiting aromatase thereby suppressing estrogen production. Clomiphene citrate, on the other hand, blocks estrogen receptors. In both cases, the result is that the pituitary gland produces more of the hormones needed to stimulate the ovaries. These hormones, FSH and LH, can cause the development of ovulation in women who are anovulatory or increase the number of eggs developing in the ovaries of women who already ovulate. As a result, several studies have now been published using letrozole as a fertility drug.

One of the earliest studies using letrozole as a fertility drug looked at 12 women with inadequate response to clomiphene citrate. Ovulation on letrozole occurred in 9 of 12 cycles and 3 patients conceived. A later study by the same investigators compared the effects of letrozole to those of clomiphene citrate. This time 19 women were studied. Ten women received clomiphene citrate and nine women received letrozole. This study was unable to demonstrate any difference in the number of women who ovulated, the number of eggs that developed in each woman, or the thickness of the uterine lining during treatment. However, a more recent study by a different group of investigators found that compared with clomiphene citrate, letrozole is associated with a thicker uterine lining and a lower miscarriage rate.

At the 2013 meeting of the American Society for Reproductive Medicine (ASRM), the results of the PPCOS II study were first presented. In this study, which has now been published, 750 PCOS women were randomized to receive either letrozole or Clomid for up to 5 treatment cycles.

  • The findings convincingly showed that for women with PCOS:
  • The ovulation rate was superior with letrozole (61.7%) than with Clomid (48.3%)
  • The cumulative live birth rate was higher with letrozole (27.5%) the with Clomid (19.5%)
  • The live birth benefit was higher in obese women (BMI ≥ 35)
  • letrozole was equal or superior to Clomid at all BMI groups

There was no difference in:

  • the risk for pregnancy loss (letrozole 31.8% vs Clomid 28.2%)
  • Multiple pregnancy rates (all twins) (letrozole 3.2% vs Clomid 7.4%)
  • The number of serious adverse events

Use of letrozole in women without PCOS

The majority of studies looking at the use of letrozole compared to Clomid in women who do not have PCOS have concluded either there is no difference between the two or that clomid is superior for this group of patients.

Letrozole and birth defects

A study presented at ASRM in 2005, in which researchers analyzed births that occurred after treatment with letrozole found seven serious birth defects in 150 babies, which is about 4.7%. This was compared to a database of 36,050 normal deliveries. The incidence of birth defects in the control babies was 1.8% This means that birth defects were 3 times more likely to occur with letrozole.

This prompted the manufacturer (Novartis) to review their safety database and found 13 reports of already pregnant women receiving the drug worldwide. Of those 13 women, two had children with birth defects (15.4%).Novartis sent a letter to fertility physicians stating: “Femara (letrozole) is contraindicated in women with premenopausal endocrine status, in pregnancy, and/or lactation due to the potential for maternal and fetal toxicity and fetal malformations”.

In response, 5 Canadian fertility centers reviewed their birth outcomes and incidence of birth defects in women who conceived with letrozole and compared them to Clomid. The Canadian study involved 911 newborns. The major birth defect rate in the letrozole group was 1.2% (6/514) and in the Clomid group was 3.0% (12/397).

In the United States, the labeling of letrozole already warned that it had been associated with birth defects. Novartis has never sought FDA approval to market letrozole as a fertility medication and was clearly concerned about their liability if given in pregnancy.

Letrozole is a medication that is metabolized rapidly in the body. It is not thought to have significant levels in the blood or tissues for a prolonged period of time.

In the PPCOS II study, each baby born was closely studied for birth defects at the time of birth with additional screening within 1 month of birth by trained pediatric personnel. There was no difference in the rate of birth defects between letrozole and Clomid.

Letrozole side effects

Letrozole works based on its ability reduce estrogen levels. Low estrogen levels of any cause can cause a woman to have symptoms. The data on side effects comes from women who have been using letrozole for an extended period of time in order to treat breast cancer. The treatment duration for letrozole is only five days. In our experience, we have seen side effects that are similar to those seen with clomiphene citrate:

  • Hot flashes
  • Headaches
  • Breast tenderness

Letrozole and pregnancy

Studies conducted so far have shown either no increased risk of miscarriage or a decrease in miscarriage risk. Letrozole is considered pregnancy Category D. Letrozole should not be given to women who are already pregnant. Studies in rats and mice have shown that letrozole increases the risk of fetal death and malformations. Since there are no studies in human beings, it should be assumed that a similar effect is possible.

Letrozole Fertility Treatment Protocols

Monitoring with ovulation predictor kits and having intercourse only.

  1. Call the office on Day 1 of your period.
  2. Day 2 or 3 – Office visit- Blood test and ultrasound.
  3. Take the letrozole 2.5 mg tablet on days 5,6,7,8, and 9.
  4. Start testing urine on the morning of day 10 or 11.
  5. Look for the first definite color change. Do not continue to test after the color change.
  6. Have intercourse the same day you see the color change and the next day.
  7. Call the office when you see the color change. Schedule an appointment approximately one week later for a blood test to verify ovulation.

Monitoring with ovulation predictor kits and having an IUI – intrauterine insemination

  1. Call the office on Day 1 of your period.
  2. Day 2 or 3 – Office visit- Blood test and ultrasound.
  3. Take the letrozole 2.5 mg on days 5,6,7,8, and 9.
  4. Start testing urine on the morning of day 10 or 11.
  5. Look for the first definite color change. Do not continue to test after the color change.
  6. Call the office the same morning you see the color change. Have intercourse that night.
  7. Schedule the intrauterine insemination for the next day (The day after the color change)
  8. Schedule an appointment approximately one week later for a blood test to verify ovulation
  9. Schedule an appointment approximately two weeks later for a pregnancy test

Monitoring in the office with intrauterine insemination or intercourse

  1. Call the office on Day 1 of your period.
  2. Day 2 or 3 – Office visit- Blood test and ultrasound.
  3. Take the letrozole on days 5,6,7,8, and 9.
  4. Day 10 or 11 – Office visit – Blood test and ultrasound. You will receive instructions that afternoon when to return for the next visit.
  5. Only when instructed – Take the hCG trigger injection in the evening. Have intercourse that evening also.
  6. Schedule the insemination for 2 (two) days after the hCG trigger . If you are not doing intrauterine insemination, have intercourse again on this day
  7. 1 week after hCG trigger – Office visit – Blood test only (Progesterone level)
  8. 2 weeks after hCG trigger – Office visit – Blood test only (Pregnancy test)

hCG Trigger


What is the hCG Trigger?

The hCG trigger injection is a medication known as a human chorionic gonadotropin and is used after other fertility hormones, such as clomiphene citrate or menotropins, to induce ovulation (release of the egg from the ovary) or in women undergoing an assisted reproductive technology (ART), to induce final maturation of the eggs. The dose used for the trigger is dependent on the body mass index of the female.
There are several brand names for the hCG trigger and include:

Profasi

Pregnyl

Pregnyl

Novarel

Novarel

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Generic hCGDirections for mixing and giving the hCG trigger — 10,000 I.U.
Wash your hands thoroughly and make sure that the surface you work on is clean.

Clean vial with alcohol

Use an alcohol swab to cleanse the rubber stoppers of both vials.

Pull the plunger back

Using the 3cc syringe with a 1.5 inch needle, draw back on the plunger to the 1cc mark.

Pierce the rubber stopper of the diluent vial. Inject 1cc of air into the vial.

Turn the needle upside down, making sure the tip of the needle is kept below the fluid level. Withdraw 1cc of the liquid.

Remove the needle and pierce the vial containing the powder. Slowly inject 1cc of diluent into the vial of powder. Gently swirl the solution until the powder is dissolved.

Turn the vial upside down and withdraw all of the medication, making sure that the tip of the needle is kept below the fluid level.
Remove the needle from the vial and carefully replace the cap. Pull back on the plunger to clear the needle of any medication. Remove the needle from the syringe and replace with a new 1.5 inch needle for intramuscular injection or a new 0.5 inch needle for subcutaneous injection.

Flick the syringe

With the needle pointing toward the ceiling, flick the side of the syringe to disperse the air bubbles and the air pocket at the top of the syringe, then

Gently push the plunger until one or two drops of liquid are expressed to ensure you have eliminated any air.

Changes if you are giving 15,000 I.U.

You will need two bottles of hCG powder. Each bottle contains 10,000 I.U. Inject 2 cc of fluid into the first powder bottle. Once dissolved, draw the 2 cc of dissolved powder back into the same syringe. Inject the dissolved powder from the syringe into the 2nd bottle of powder. Once the second bottle is dissolved, draw only 1.5 cc back into the syringe. There will be 0.5 cc of medication that remains in the bottle.

Changes if you are giving 20,000 I.U.

You will need two bottles of hCG powder. Each bottle contains 10,000 I.U. Inject 1 cc of fluid into the first powder bottle. Once dissolved, draw the 1 cc of dissolved powder back into the same syringe. Inject the dissolved powder from the syringe into the 2nd bottle of powder. Once the second bottle is dissolved, draw all of the medication back into the syringe.

The hCG Trigger injection can be given as an intramuscular or a subcutaneous injection. Either way will work. The intramuscular injection will cause more bruising. The subcutaneous injection will cause the injection area to be red, swollen and itchy. It may stay this way for a few days. This is normal.

Click here to learn how to give a intramuscular injection

Click here to learn how to give a subcutaneous injection

Gonal F 450 Multidose Vials

Gonal F 450 Multidose Vials

What is Gonal-F??

Gonal-F? is a follicle stimulating hormone (FSH), one of the hormones that stimulates the ovary to make mature eggs. Gonal-F? is used to stimulate the development of multiple follicles in women undergoing assisted reproductive technology treatments(ART). This medication may also be used to induce ovulation in women for certain types of ovarian failure.

How Do I Use Gonal-F??

Here are step-by-step instructions for taking Gonal-F? (follitropin alfa) Multi-Dose injections:
Gonal-F? is injected subcutaneously-or into the fatty tissue under your skin. The primary sites for injection are your abdomen – 2 inches on either side of the navel, and your upper, outer-thigh where the skin is loose. Wash your hands thoroughly and make sure that the surface you work on is clean.

GonalFflipofflid

Using your thumb, flip off the plastic cap of the Gonal-F? Multi-Dose 450 IU vial.

GonalFwipeofflid

Wipe the top of the vial with an alcohol swab.

GonalFtwistoffcap

Carefully twist and pull off the rubber cap from the prefilled syringe
of Bacteriostatic Water. Do not touch the needle or allow the needle to
touch any surface.

GonalFinsertneedle

Position the needle of the syringe of water in a straight, upright
position over the marked center circle of the rubber stopper on the
vial of Gonal-F Multi-Dose powder. Keep the needle in a straight,
upright position as you insert it through the center circle. Slowly
inject the water into the vial by depressing the syringe plunger.

GonalFInjectdiluent

After all of the water has been injected into the vial, remove your
finger from the plunger, allowing the plunger to rise to its original
position. Withdraw the needle safely and dispose of it in a sharp
container.
Swirl the mixture gently until it becomes clear. Do not shake.

GonalFwipevial

Wipe the top of the vial with an alcohol swab.

Removewrapper

Remove the wrapper from the custom dosing injection syringe. Carefully
loosen and pull the plastic cap from the needle and avoid touching the
needle.

GonalFPushplunger

With the vial of reconstituted Gonal-f on a flat surface, insert the
needle straight down through the marked center circle of the rubber
stopper.

Invertvial

Without removing the needle from the vial, turn it upside down so that the needle points upward.

Pullplungerback

Slowly pull the plunger back until the syringe fills to slightly more
than the unit marking that corresponds to your prescribed dose. Keeping
the needle in the vial, slowly push the plunger to your prescribed
dose. This will clear any air bubbles.

GonalFrecap

Carefully
remove the syringe from the vial and recap the needle. The custom
dosing syringe is now filled with the prescribed dose of Gonal-f and is
ready for administration.

Click here to learn how to administer the subcutaneous injection of Gonal F

Gonal F 1200 Multidose Vials

What is Gonal-F?

Gonal-F is a follicle stimulating hormone (FSH) ,

one of the hormones that stimulates the ovary to make mature eggs. Gonal-F is used to stimulate the development of multiple follicles in women undergoing assisted reproductive technology treatments (ART). This medication may also be used to induce ovulation in women for certain types of ovarian failure.

How Do I Use Gonal-F?

Here are step-by-step instructions for taking Gonal-F (follitropin alfa) Multi-Dose injections:
Gonal-F is injected subcutaneously – or into the fatty tissue under your skin. The primary sites for injection are your abdomen – 2 inches on either side of the navel, and your upper, outer-thigh where the skin is loose. Wash your hands thoroughly and make sure that the surface you work on is clean.

Using your thumb, flip off the plastic cap of the Gonal-F Multi-Dose vial.

Wipe the top of the vial with an alcohol swab.

Carefully twist the needle cap off the syringe labeled "Bacteriostatic Water for Injection USP." Do not touch the needle or allow the needle to touch any surface.

Position the needle of the syringe of water in a straight, uprightposition over the marked center circle of the rubber stopper on thevial of Gonal-F Multi-Dose powder. Keep the needle in a straight,upright position as you insert it through the center circle.

Slowly inject the water into the vial by depressing the syringeplunger. When all the water has been injected into the vial, withdrawthe needle.Swirl the mixture gently until it becomes clear. Do not shake.

Remove the cap from a new syringe. Invert the vial and insert the needle. Depress the plunger all the way.

Withdraw the recommended dose of medication

With the needle pointing toward the ceiling, flick the side of thesyringe to disperse any air bubbles and the air pocket at the top ofthe syringe.

Gently push the plunger until one or two drops ofliquid are expressed to make sure you have eliminatedany air.

Click here to learn how to administer the subcutaneous injection of Gonal F

Gonal-F RFF 75 IU Vials


What is Gonal-F RFF?

Gonal-F? RFF (Revised Formulation Female) is a follicle stimulating hormone (FSH), one of the hormones that stimulates the ovary to make mature eggs. Gonal-F? RFF is used to stimulate the development of multiple follicles in women undergoing assisted reproductive technology treatments(ART). This medication may also be used to induce ovulation in women for certain types of ovulation problems.

How Do I Use Gonal-F RFF?

Here are step-by-step instructions for taking Gonal-F? RFF (follitropin alfa) injections:
Gonal-F? RFF is injected subcutaneously-or into the fatty tissue under your skin. The primary sites for injection are your abdomen – 2 inches on either side of the navel, and your upper, outer-thigh where the skin is loose. Wash your hands thoroughly and make sure that the surface you work on is clean.

GonalFflipofflid

Using your thumb, flip off the plastic cap of the Gonal-F? RFF vial

GonalFwipeofflid

Wipe the top of the vial with an alcohol swab.

GonalFtwistoffcap

Hold the barrel of the prefilled syringe of sterile water in one hand. firmly hold the plastic cap between the thumb and forefinger of the other hand and with a back and forth motion, gently snap and pull off the cap. If the grey cap remains, simply remove it.

GonalFinsertneedle

Remove the safety seal cover of the 18 G 1 1/2″ needle. Push the needle on the prefilled syringe until it is tightened. Holding the hub, or base, of the needle, secure the needle on the tip of the prefilled syringe and remove the needle cap.

GonalFInjectdiluent

With the vial of Gonal F RFF powder on a flat surface, insert the needle of the prefilled syringe straight down through the marked center circle of the rubber stopper. Slowly inject the water into the vial by depressing the syringe plunger. Swirl the mixture gently until it becomes clear. DO NOT shake.

GonalFwipevial

Invert the vial and pull back the 18 G 1 1/2″ needle as far as needed and withdraw the entire contents of the vial. Remove the syringe from the vial.

Removewrapper

If your dose requires more than one vial of GOnal F RFF 75 IU, use the mixture in the syringe to reconstitute the next vial of powder. Use the same 18 G 1 1/2 needle and syringe to reconstitute additional vials.

GonalFPushplunger

Gently pull the plunger back to allow a small air space. Recap the needle. Twist and pull off the needle from the syringe and discard in your sharps container.

Invertvial

Remove the safety seal cover of the 27 G 1/2″ needle for injection. Push the needle on the prefilled syringe until it is tightened. Holding the hub, or base, of the needle, secure the needle on the tip of the prefilled syringe and remove the needle cap.

Pullplungerback

With the syringe pointing upward, gently tap on the syringe and slowly push the plunger until all air bubbles are gone and a drop of liquid appears on the tip of the needle.

GonalFrecap

Recap the needle. The administration syringe is now ready. Use immediately.

Click here to learn how to administer the subcutaneous injection of Gonal F

Glucophage

There are many reasons why a woman may not ovulate regularly. It appears that some women are resistant to the hormone insulin. Insulin is normally thought of as the hormone produced by the pancreas that helps regulate blood sugar. While this is true, insulin also has many other effects in the body. The ovary has receptors for insulin and thus insulin is capable of modifying hormone production from the ovaries.

The are several conditions that may result in a woman becoming resistant to the effects of insulin. Among these are  PCOS – Polycystic Ovary Syndrome – genetics and obesity. When insulin resistance occurs, the body needs a higher level of insulin to accomplish the same tasks. High insulin levels are frequently seen in this condition.

If insulin resistance is the cause for a woman’s anovulation (not ovulating) then it stands to reason that improving the insulin resistance or lowering the insulin levels may be successful at causing ovulation to return.

In fact some studies in overweight women with insulin resistance demonstrated that Metformin (Glucophage) was successful in getting ovulation to occur without any other additional medications. It also seemed to improve the response to a fertility medication called clomiphene citrate.

Results of the World’s Largest Metformin Study

Recently, a study was published comparing metformin to clomid in patients with PCOS. This study was conducted on over 600 patients and involved several academic centers. There were three groups of patients that were compared. Group 1 took metformin alone. Group 2 too clomid alone. Group 3 took a combination of metformin and clomid.

The outcome being measured in this study was the live birth rate. Patients were treated for 6 months or until an ongoing pregnancy occurred. The results were somewhat surprising. The total cumulative live birth rate in the metformin group after 6 months was only 7%. The clomid group had a live birth rate of about 25%. The live birth rate in the combination group was similar to the rate with clomid alone.

The results of this study indicate that while it is possible to ovulate and achieve pregnancies with metformin – this treatment is not nearly as efficient as clomid. Furthermore, combining clomid and metformin did not do any better than clomid alone. The main advantage of metformin therefore, is that the rate of multiple pregnancies was lower than in the clomid groups.

A secondary outcome looked at in this study was whether metformin was able to lower the miscarriage rate in women with PCOS. In fact, the results were just the opposite. The metformin groups had a higher rate of miscarriage although, when analyzed statistically, the results could have been due to chance.

Metformin (Glucophage) Instructions

Glucophage comes as either a short acting or extended release (Glucophage XR). I like to use the XR for a few reasons:

  • The tablets can all be taken together at the same time. It is not necessary to spread the dose out as was done with the short acting variety
  • The side effects seem to occur less frequently

Glucophage XR comes as 500 mg tablets. Most women will start with the 500 mg tablets. The starting dose is one tablet a day for one week. If this dose has been tolerated, then two tablets a day are taken during the second week. Finally, three tablets a day are taken during third week and continues thereafter. Some women will tolerate the medicine well and can increase their dose more quickly. Others may need to go more slowly.

Metformin also comes in a liquid preparation known as Riomet. There is also a long acting formulation that comes in a higher dose. Fortamet come in 1000 mg tablets. If a PCOS patient had demonstrated that she can tolerate the higher dose of metformin, switching to Fortamet can make pill taking a little easier since only two pills are required to reach the desired 2000 mg dose.

Metformin Side Effects

Gastrointestinal disturbance: Approximately 1/3 of the people who take glucophage will experience one or more of the following symptoms: nausea, diarrhea, vomiting bloating, or flatulence. Starting on a lower dose (1 tab / day) may reduce the likelihood of this problem. Taking glucophage with meals also may help. Symptoms do resolve with continued treatment.

Lactic acidosis: This is a rare but serious metabolic condition that results from accumulation of lactate in the blood. It can be seen in persons with diabetes, kidney problems and other problems. Glucophage may cause Lactic acidosis in 3 in 100,000 patients taking Glucophage over the course of a year. Lactic acidosis can be fatal when serious.

The symptoms of lactic acidosis are often subtle and non-specific. They include malaise, muscle aches (myalgia), difficulty breathing, increasing sleepiness (somnolence), and non-specific abdominal distress. IF YOU EXPERIENCE THESE SYMPTOMS, CONTACT THE OFFICE IMMEDIATELY.

Because of the risk of lactic acidosis, you should not take Glucophage if:

1. You have chronic kidney or liver problems
2. You drink alcohol excessively
3. You are scheduled to undergo a hysterosalpingogram or have surgery
4. You are pregnant

Metformin effects on pregnancy

A small series suggested that using metformin during pregnancy may have a benefit in terms of reducing the risk of miscarriage or gestational diabetes. Metformin is considered pregnancy category B. Animal studies in rats and rabbits at very high doses did not result in a higher than expected incidence of birth defects. There are no good, well-controlled trial in women. One study suggested that the use of metformin in pregnancy resulted in a higher incidence of some pregnancy complications. It is recommended that Metformin be stopped immediately upon the diagnosis of pregnancy. However, studies are currently ongoing to try to determine the safety and effectiveness of metformin in pregnancy.

A recent study has found pre-eclampsia, a complication of pregnancy involving high blood pressure, was over four times higher when metformin was used to treat gestational diabetes. You should read more about metformin risks here.

Follistim AQ Pen Injector

Follistim contains follicle stimulating hormone (FSH), one of the hormones that stimulates the ovary to make mature eggs. Follistim is used to stimulate the development of multiple follicles in women undergoing assisted reproductive technology treatments (ART). This medication may also be used to induce ovulation in women for certain types of ovarian dysfunction.

How Do I Use Follistim?

Tear off a single applicator.

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Follistim?-AQ comes in 300 IU,  600 IU and 900 IU cartridges. Here are step-by-step instructions for taking Follistim? using the Follistim?-AQ cartridges:

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Wash your hands thoroughly and make sure that the surface you work on is clean.

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Pull the cap pen off. Unscrew the yellow section from the blue section. Clean the rubber end of the cartridge with an alcohol wipe.

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Insert the cartridge with the rubber end down into the yellow section.

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Screw the yellow and blue sections back together. Line up the blue triangle (on the yellow section) and the yellow rectangle (on the blue section).

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Screw the needle securely onto the end of the yellow section.

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Pull off the cap, and pull the inner sheath off. Hold the Follistim pen with the needle pointing upward. Tap the pen gently to help air bubbles rise to the top.

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Look for a droplet at the end of the needle. If you do not see a droplet, dial the dosage knob one notch on the dosage scale until you hear a click. With the needle pointing upward, push the orange injection button in all the way and look again for a droplet at the needle tip. Repeat until a droplet appears at the tip of the needle.

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To dial your dose turn the dial gently until the desired dose is in the clear section of the window. If you dial past your dose DO NOT turn it back. Turn it all the way forward until the dial is loose, push the injection button in all the way, and dial again.

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Wipe the injection site with alcohol. Let it dry.When the alcohol is dry, pinch a fold of skin. Holding the needle like a pencil, insert the needle.

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Inject the medication by pushing down on the dial. Once the dial is completely pushed down, hold the pen with the needle in place for 5 seconds. Pull the needle straight out.Gently press an alcohol pad on the injection site for five seconds.Check the pen dial. It should be at zero. If the dosage window does not read “0” it means there was not enough medication in the cartridge. The number in the window will give you the amount of medicine needed to complete your dose.

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Put the cap back on the needle.

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Unscrew it from the pen.

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And place it into a biohazard container such as a Sharps container – or in a sealable, unbreakable plastic container such as a laundry detergent bottle. Never Reuse Needles or Syringes!

Put the cap back on the pen. Save pen and cartridge for your next injection (if it still contains medication).

Please be aware that some of these instructions may vary slightly based upon your particular situation or preference.

Endometrin

Endometrin (progesterone vaginal insert) is a specially formulated vaginal tablet that contains the female hormone progesterone, which is one of the hormones essential for preparation of the uterus for implantation and maintenance of a pregnancy. Once the tablet is inserted into the vagina, it quickly dissolves and is available to be absorbed into the circulation to be taken to the uterus.

How Do I Use Endometrin

Each insert of Endometrin and each applicator comes individually wrapped within the Endometrin box. Here are step-by-step instructions for taking Endometrin:

Carefully unwrap the applicator and the Endometrin insert.

Put one Endometrin insert into the space provided at the end of the applicator. The insert should fit snugly and not fall out.

Choose a comfortable position for inserting the applicator. You may be sitting or laying on your back with your knees bent. You may stand

Gently slide the thin end of the applicator 2-3 inches into the vagina.

Push the bottom of the applicator upward to release the Endometrin insert. Remove the applicator and throw it away.

Side effects reported by women who used Endometrin in clinical studies reported the following side effect more than 2% of the time: uterine spasm (3-4%) vaginal bleeding (3%). Vaginal irritation, itching, burning, rash or swelling were reported less than 2% of the time.

Crinone 8%

Crinone (progesterone gel) is a specially formulated vaginal gel that contains the female hormone progesterone, which is one of the hormones essential for preparation of the uterus for implantation and maintenance of a pregnancy. The moisturizing gel of Crinone forms a coating on the walls of the vagina that allows for absorption of progesterone.

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How Do I Use Crinone 8%?

Here are step-by-step instructions for taking Crinone 8%:
Wash your hands thoroughly and make sure that the surface you work on is clean.

Crinone

Each prefilled applicator of Crinone comes individually wrapped within the Crinone box.

Crinone

Carefully remove the wrapper from the prefilled applicator.

crinone

Identify the thick end of the applicator. Grasp the applicator by the thick end but do not squeeze yet.

crinone

With your other hand, grasp and bend the tab located at the opposite end of the applicator. Bend and twist the tab until it breaks away from the applicator.

Choose a comfortable position for inserting the applicator. You may lay on your back or stand.

crinone
crinone

Insert the applicator into the vagina as far as it will comfortably go or when one half of the applicator has been inserted whichever is less.

crinone

Squeeze the bubble and the thick end completely. An amount of gel about the size of a dime will be dispensed into the vagina.

crinone

Remove the applicator. The gel will remain in the vagina. Dispose of the used applicator. Do not reuse the applicator.

Typically, the gel stays attached to the vaginal walls for a few days as the progesterone is absorbed. Do NOT be concerned is small, white globules appear as a discharge after serveral days of usage. It is common and not harmful, to have some gel residue build up.

If you wish, you may remove the residual gel by inserting your finger into the vagina and clearing the gel manually.

Cetrotide and Ganirelix (Antagon) in IVF

Cetrotide and Antagon in IVF

Cetrotide (cetrorelix) and ganirelix (Antagon) are examples of a type of medication that is used to prevent premature ovulation. This class of medications is referred to as GnRH antagonists or simply antagonists. Cetrotide and Antagon are newer medications than Lupron but have become tremendously popular as a result of their easy of use and high pregnancy rates.

Medications which work rapidly

Cetrotide and Ganirelix exert their action on the pituitary gland. The pituitary is responsible for producing the hormones which stimulate egg growth and development and for triggering ovulation of a mature egg. During an in vitro fertilization cycle, the physician needs to prevent ovulation from occurring so the eggs can be removed directly from the ovary.

In the early days of IVF, before medications to prevent ovulation were available, about 25% of IVF cycles would be cancelled for premature ovulation. Then a medication called Lupron was used to block the pituitary from causing premature ovulation. Lupron caused a few problems, however. When Lupron is first administered to a woman, it would stimulate her pituitary gland for several days before it would eventually suppress it. This is known as the stimulation or flare phase. The flare phase required that women start Lupron a few weeks before she could begin the fertility medications required for stimulation of the ovary. In some women, the flare effect can cause the development of cysts in the ovaries that could further delay the start of fertility medications.

A primary advantage of Cetrotide and Ganirelix is that they do not have a “flare phase”. Down regulation (suppression) of the pituitary occurs immediately. Therefore, it is not necessary to start these medications before the fertility medications begin (see picture). Cetrotide or Ganrelix would normally be started after 4-6 days after the start of the fertility medications. This shortens the number of days that a woman must take injections.

Protocol for using Cetrotide and Ganirelix

Fertility medications such as Follistim or Gonal F are the first injections which are administered in an antagonist cycle. The fertility medications may be started on the second or third day after the onset of a period or after a woman has been on birth control pills (oral contraceptives). A baseline assessment of hormones by blood test and the ovaries by ultrasound are performed at some point before the fertility medications are started.

Ganirelix Acetate Injection is available in disposable, pre-filled, ready to inject syringes containing 250 micrograms of ganirelix acetate. Mixing is not required. Ganarelix is designed to be self-injected using the supplied syringe for injection just under the skin (subcutaneous).

There are two protocols for beginning the Cetrotide or Ganirelix. One method, called the flexible start, utilizes the results of the blood and ultrasound monitoring of egg development. Once development of the eggs has started to occur, the Cetrotide or Ganirelix is started. A second method, called the fixed start, will begin the Cetrotide and Ganirelix after a certain number of days of fertility medication have been given regardless of the results of blood and ultrasound monitoring.

The GnRH antagonists are continued along with the fertility medication until the last day of fertility medication is given. Typically this means a woman will have 4-6 days of Cetrotide or Ganirelix before the egg retrieval.

Some experts believe that IVF cycles that use Lupron for pituitary suppression, may cause some women to become “over-suppressed” and therefore not respond as well to the fertility medications. Whether this occurs or not is subject to some debate. However, with the use of antagonists, there is no concern for this problem.

Cetrotide (cetrorelix acetate)

Cetrotide™ is a medication known as a gonadotropin-releasing hormone antagonist and is used to prevent premature ovulation in women undergoing fertility procedures.

How do I use Cetrotide™?

Here are step-by-step instructions for taking Cetrotide™ (cetrorelix) injections:

Cetrotide™ is injected subcutaneously-or into the fatty tissue under your skin. The primary sites for injection are your abdomen – 2 inches on either side of the navel, and your upper, outer-thigh where the skin is loose.

Wash your hands thoroughly and make sure that the surface you work on is clean.

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Flip off the plastic cover of the vial and wipe the rubber stopper with an alcohol swab. Put the injection needle with the yellow mark (20 gauge) on the pre-filled syringe.

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Push the needle through the rubber stopper of the vial and slowly inject the solvent into the vial. Leaving the syringe in the vial, gently swirl the vial until the solution is clear. Avoid making bubbles. Do not shake.

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Invert the vial and pull back the needle as far as needed to withdraw all of the liquid in the vial. You might not be able to withdraw every drop.

Replace the needle with the yellow mark with the (27 gauge) inch syringe. Remove any air bubbles.

Click here to learn how to give a subcutaneous injection

Ganirelix (Antagon)

Ganirelix acetate (Formerly known as Antagon) is a medication known as a gonadotropin-releasing hormone antagonist and is used to prevent premature ovulation in women undergoing fertility procedures.

How do I use Ganirelix?

Here are step-by-step instructions for taking ganirelix injections:
Ganirelix is injected subcutaneously-or into the fatty tissue under your skin. The primary sites for injection are your abdomen – 2 inches on either side of the navel, and your upper, outer-thigh where the skin is loose.

Wash your hands thoroughly and make sure that the surface you work on is clean. Uncap the needle of the pre-filled Ganirelix Acetate Injection syringe. Click here to learn how to give a subcutaneous injection

Cell phone use and male fertility

A recent study has suggested that cell phone use might be associated with infertility by causing abnormalities in the semen analysis.

Cell phones and male infertility – could there be a link?

Cell phones are commonly used by both males and females. It is estimated that there are over 700 million cell phone users in the world. Mobiles phones contain small transmitters that emit radio frequency electromagnetic waves (EMW). These phones operate at different frequencies in different countries and continents. Analog phones operate at 450–900 MHz, digital phones (Global System for Mobile Communications [GSM]) at 850–1900 MHz, and third-generation phones at approximately 2000 MHz. Higher frequency phones result in greater exposure to the body. Reports of potential adverse effects of radio frequency EMW from cell phones have appeared in the news in recent months.

The results of animal studies have yielded conflicting results. One study in mice, found that radio frequency EMW had harmful effects on the cells that produce sperm but another study found no harm. A study in rates did not find any adverse effect of cell phone exposure on sperm count, morphology, or the microscopic appearance of the testicles.

There have been two previous studies on this subject in human men. One recent study on 371 men undergoing infertility evaluations, found that increasing duration of possession and the daily transmission times of cell phones was associated with a lower proportion of sperm with rapid forward movement and an increase in the proportion of slow moving sperm.  The second study looked at only 13 men. They found that  using GSM phones for 6 hours per day for 5 days decreased the numbers of sperm with fast, forward movement.

New Study on Cell Phone Use and Sperm

The study examined 361 men who were being seen at an infertility clinic from September 2004 to October 2005. The average age of these men was 31-21. .Importantly, men who had a history of tobacco or alcohol  use were excluded.  Men with other medical problems that could affect their sperm were also excluded.

The men in the study collected a semen specimen after an abstinence period of 5 days. The information on cell phone usage was obtained and they were divided into 4 groups according to the daily duration of use.

  • Group A: no use (40 men)
  • Group B: Less than 2 hours per day (107 men)
  • Group C: 2–4 hours per day (100 men)
  • Group D: More than 4 hours per day (114 men)

The technicians analyzing the semen samples did not know the patients cell phone use.

Results: Cell phone use linked with sperm abnormalities

When analyzed, there was a correlation found with increasing duration of cell phone use and abnormalities in the semen analysis. Specifically, sperm count, percentage motility, viability, and normal morphology were worse in the groups that  reported higher cell phone use. But as the graph below shows, there was no difference found in the volume of ejaculate, the time it took sperm to liquefy, the pH or viscosity of the semen.    

Effects of cell phone use on sperm

Discussion

It is difficult to say how great a danger cell phones may cause toward male fertility. First, the study has several limitations that make it difficult to rely on the results. For example, the researchers did not actually verify the amount of cell phone use that the men reported. Very importantly, they did not take into account the occupations of the men and whether they might have had EMW exposure from other sources such as radio towers, PDAs, Bluetooth devices or computers. They also did not report whether the men predominantly used their cell phone by holding them to their ears or when attached to the waist using an ear phone. Theoretically, due to the closer proximity, a cell phone attached to the waist during use might result in increased EMW exposure to the testicles.

Furthermore, although the use of cell phones may cause a decrease in some sperm parameters, this does not necessarily correlate with infertility. For example,  the average sperm count in the group that reported no cell phone use was 85 million sperm per mL. The concentration in the group that reported more than four hours per day of use was about 50 million per mL. This is still well above the level that is considered normal which is 20 million sperm per mL.

More studies on this subject are clearly needed. Until we have better data, it seems reasonable to recommend to men who are trying to conceive that they should try to limit their cell phone use. Alternatively, keeping the cell phone away from the testicles may also offer some protection.

Obstructive Azoospermia

Azoospermia, defined as complete absence of sperm from the ejaculate, is present in less than 1% of all men and in 10-15% of infertile men. There are many causes of azoospermia

  1. Failure of hormones to adequately stimulate the testicles to produce sperm (also known as Pre-testicular)
  2. Primary testicular failure in which the sperm producing cells in the testicles are either missing or damaged
  3. Obstruction of the sperm delivery system (also known as Post-testicular)

Obstruction is responsible for approximately 40% of cases of azoospermia. Obstructive azoospermia may result from blockage in any of the tubes leading from the testicle to the opening in the tip of the penis. These tubes are

  1. Epididymis
  2. Vas Deferens
  3. Ejaculatory duct

Causes of Sperm Obstruction

Vasectomy is the most common cause of obstruction in the vas deferens. Severe genital or urinary infections, injury during scrotal or inguinal surgery and birth defects are other common causes of obstructive azoospermia.

Treatments For Sperm Obstruction

Men with obstructive azoospermia may father children by

  1. Surgical correction of the obstruction,
  2. Retrieval of sperm from the male reproductive system for in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI).

Microsurgical Vasectomy Reversal

In the United States, estimates are that 500,000 to 750,000 vasectomies are performed annually; as many as 4%to 10% of these men later request reversal. A very important factor influencing the likelihood of sperm returning to the semen and of pregnancy after vasectomy reversal is the number of years between vasectomy and attempted reconstruction. Other factors influencing the success of vasectomy reversal include the:

  1. presence or absence of sperm seen during the surgery
  2. appearance of the vas fluid as seen during the surgery
  3. quality of the sperm in the vas fluid
  4. length of the vas segment between the epididymis and the vasectomy site
  5. presence or absence of a sperm granuloma (a lump of hardened, old sperm sometimes seen after vasectomy)
  6. age of the female partner.
 Vasal fluid Patency ratePregnancy rate
 Motile sperm 94%63%
 Nonmotile sperm 90%54%
 Sperm heads only 75%44%
 No sperm 60% 31%

There are two microsurgical procedures used for vasectomy reversal:  vasovasostomy  and vasoepididymostomy. Vasectomy reversal is usually performed with the patient under general anesthesia. Alternatively, the procedure can be performed with a local anesthetic (with or without sedation) or with a spinal or epidural anesthetic.

Vasovasostomy

This method of microsurgery removes an obstruction and connects one part of the vas deferens to another part.  In addition to vasectomy reversal , this type of microsurgery is also  performed for blockage caused by injury during a hernia repair.

In a report by the Vasovasostomy Study Group, overall patency rate and pregnancy rate for more than 1200 vasovasostomy procedures were 86% and 52%, respectively. The patency rate and pregnancy rate fell from 97% and 76% at less than 3 years after vasectomy to 71% and 30% at 15 years or longer after vasectomy.

 Obstructive interval Patency ratePregnancy rate
 < 3 years 97%76%
 3-8 years 88%53%
 9-14 years 79%44%
 >15 years 71% 30%

Vasoepididymostomy

This method of microsurgery removes an obstruction and connects the vas deferens to the epididymis. Vasoepididymostomy is considered one of the most challenging microsurgical procedures, requiring significant microsurgical experience. In addition to vasectomy reversal, it can also be performed for the following types of obstructions:

  1. congenital (present at birth)
  2. scarring from infections
  3. Unexplained blockage of the epididymis

Following this type of microsurgery, the patency rate and pregnancy rate range, respectively, from 67% to 85% and from 27% to 49%.

Repeat Vasectomy Reversals

A history of a previous vasectomy reversal attempt does not preclude a new attempt. Patency and pregnancy rates of 79% and 31%, respectively, have been reported for repeated reversals.

Transurethral Resection of the Ejaculatory Ducts (TURED)

This method is used to treat blockage in the ejaculatory duct. This condition is uncommon. Ejaculatory duct obstructions (EDO)can be congenital, (due to abnormal development as a fetus) or acquired. Acquired obstructions may be secondary to trauma or infection/inflammation. Obstructed ejaculatory ducts are usually diagnosed by transrectal ultrasound imaging or by special radiographic tests called vasograms.

Transurethral resection of the ejaculatory duct results in the appearance of sperm in the ejaculate in 50-75% of cases. The pregnancy rate achieved by this surgery is about 25%.

Sperm Retrieval Techniques and IVF/ICSI

ICSI or intracytoplasmic sperm injection is a method to fertilize eggs during IVF in which a single sperm is injected into a single mature egg. ICSI must be used in all cases in which sperm are retrieved from the testes or epididymis. This is necessary for two reasons:

  1. The amount of sperm obtained is usually very small
  2. Sperm from the testicles and most of the epididymis have not developed the capability to fertilize an egg without help

ICSI provides fertilization rates of 45-75% per injected oocyte when surgically retrieved epididymal or testicular spermatozoa are used.

Sperm Retrieval for ICSI

There are different methods employed for retrieving sperm for ICSI

  1. MESA – Microsurgical Epididymal Sperm Aspiration
  2. PESA – Percutaneous Epididymal Sperm Aspiration
  3. TESE – TEsticular Sperm Extraction
  4. TESA -Percutaneous Testicular Sperm Aspiration
  5. VASA – VAsal Sperm Aspiration
  6. SESA – SEminal vesicle Sperm Aspiration

Microsurgical methods utilize an incision and surgery tiny instruments with the assistance of large, high powered surgical microscopes.

Percutaneous methods do not make an incision but rather, use a tiny needle directed in the appropriate place to aspirate sperm. This is sometimes aided by transrectal ultrasound. The choice of sperm retrieval method in men with obstructive azoospermia depends primarily on the experience and preference of both the urologist.

There are not enough data to conclude that either the technique of sperm retrieval (microsurgical or percutaneous) or the source of sperm (testicular, epididymal, vasal or seminal vesicular) significantly affects pregnancy rates. Each technique and sperm source usually provides a sufficient number of sperm for ICSI and may provide enough viable sperm for cryopreservation (freezing).

Sperm retrieval may be performed prior to or simultaneously with the female’s egg retrieval. Sperm retrieval is most commonly performed before the female starts fertility medication injections for IVF.

Microsurgical Reconstruction Versus Sperm Retrieval with IVF/ICSI

In good prognosis cases, microsurgical reconstruction may be more cost-effective than sperm retrieval with IVF/ICSI, and allows couples to have subsequent children without additional medical treatment.

Many couples will opt for IVF/ICSI however. In couples with good prognosis, a higher percentage of couples will achieve pregnancy more quickly with IVF/ICSI. Also, the presence of female infertility factors may reduce the chance for pregnancy after microsurgical reconstruction.

Medications That Interfere With Male Fertility

Male fertility can be adversely affected through any of 5 basic mechanisms:

  1. Direct toxic effects on the testicles,
  2. Disruption of the pituitary gland and its stimulation of the testicles,
  3. Direct effects on ejaculation and/or erectile function,
  4. Decrease in libido (sex drive)
  5. Blocking the sperm’s ability to fertilize an egg

Medications that have a direct toxic effect on the testicles can damage the cells which produce sperm. This can result in lower sperm counts or in severe cases – cause a complete absence of sperm. Damage to the sperm producing cells can be temporary or permanent.

Normally, the pituitary gland, which is located just beneath the brain, will produce hormones that will stimulate the cells in the testicles. These cells will, in turn, produce sperm and produce hormones such as testosterone. The testosterone that is produced, along with some other hormones from the testicles, will regulate the level of stimulation to the testicles.

In some cases, medications may disrupt the connection between the pituitary gland and the testicles and result in inadequate stimulation to the testicles. This can result in lowered sperm counts and abnormal hormone levels.

In order for sperm to be delivered into the female reproductive tract, the male must be able to achieve an erection and subsequently, he must ejaculate. The coordination of these events is very complex and can be disrupted in a number of different ways.

Some medications may act to decrease male sexual interest in intercourse, or libido. Other medications may interfere with the ability of a man to get an erection or ejaculate.

Finally, some medications may affect the sperm directly. For example, a group of medications which are commonly used to treat high blood pressure called calcium channel blockers have been shown in some studies to block the ability of the sperm to fertilize an egg.

Listed below are several categories of medications and their effect on the five areas influencing male fertility. Men should not stop any prescription medication before discussing it first with his prescribing physician.

Recreational drugs

Medication Directly toxicAffects pituitary axis
Decreased libido
Erectile dysfunction
Blocks fertilization
 Alcohol ++++
 Cigarettes + –+
 Marijuana + + –
Opiates – + +
Cocaine + – +

Blood pressure medication

Medication Directly toxic
Affects pituitary axis
Decreased libido
Erectile dysfunction
Blocks fertilization
Thiazide diuretics+
Spironolactone+++
Beta-blockers++
Calcium channel blockers+
Alpha blockers+

Hormone medications

Medication
Directly toxic
Affects pituitary axis
Decreased libido
Erectile dysfunction
Blocks fertilization
Testosterone++
Androgen blockers –++
Progesterone derivatives –+++
Estrogens+++
Anabolic steroids –++

Psychiatric medications

Medication Directly toxic
Affects pituitary axis
Decreased libido
Erectile dysfunction
Blocks fertilization
 Anti-psychotics – + + + –
 Tricyclic anti-depressants – + + + –
 MAO Inhibitors – – – + –
 Phenothiazines – + – – –
 Lithium – – + + –

Antibiotics

Medication Directly toxic Affects pituitary axis
Decreased libido
Erectile dysfunction
Blocks fertilization
 Nitrofurantoin ++
 Erythromycin +
 Tetracycline –+
 Gentamycin +

Miscellaneous

Medication Directly toxic
Affects pituitary axis
Decreased libido
Erectile dysfunction
Blocks fertilization
Cimetidine+
Cyclosporine –+
Colchicine –+
Allopurinol –+
Sulfasalazine ++
      

Male fertility and Y chromosome Microdeletions

Normal human beings have 23 pairs of chromosomes. One pair of these are called the sex chromosomes. Women have two X chromosomes and men have one X chromosome and one Y chromosome. Most, if not all of the genes that are responsible for sperm production in men are found on the Y chromosome. Abnormalities involving the sex chromosomes can result in sperm production problems and infertility. For example, men who have an extra X chromosome (XXY) are often lacking in sperm and are infertile. Men who have portions of the Y chromosome are missing (deletions) or redundant (duplications) can also show sperm production problems and infertility.

Microdeletions occur when very small pieces of the Y chromosome are missing. These problems cannot be detected through a routine chromosome analysis (karyotype). Microdeletions of the Y chromosome have been found in:

  • 2% or men with normal fertility
  • 7% of infertile men
  • 16% in men with azoospermia (no sperm in their ejaculate) or severe oligozoospermia (less than 1 million sperm)

To identify these microdeletions, special testing must be performed using a technology known as the polymerase chain reaction.

All chromosomes, including the Y chromosome, are divided into a “short arm” and a “long arm”.  Most deletions causing azoospermia or oligozoospermia occur in regions of the long arm known as the azoospermia factor (AZF) regions.  The AZF regions are further divided into

  • AZFa (proximal)
  • AZFb (central)
  • AZFc (distal)
Y chromosome

It appears that these regions, and possibly other regions of the Y chromosome, contain multiple genes necessary for normal sperm production. The specific location of the deletion along the Y chromosome and its size influences its effect on spermatogenesis.

AZFc Microdeletions

Men with microdeletions in the AZFc region have sperm production but they will commonly have very low sperm concentration while other men will not have any sperm visible in their ejaculate. However, areas of sperm production can still be found with a testicular biopsy. If testicular sperm are found, they can be used during IVF to fertilize eggs and produce pregnancies.

AZFa and AZFb Microdeletion

Men who have deletions involving the entire A2Fb region will rarely, if ever, have sperm in the ejaculate and doctors will rarely be able to find sperm with a testicular biopsy. The same may be true for men having deletions involving the entire A2Fa region of the Y chromosome.

What Is The Impact of The Father’s Y Chromosome Microdeletion On His Children?

Since daughters do not inherit a Y chromosome from their fathers, they will not have any fertility or health problems themselves. The sons, however, will inherit the abnormality and, therefore, may also have the same type of fertility problems as their fathers. What about other health issues? Unfortunately, there haven’t been a lot of studies on the children born to men with these microdeletions.  A study from 2011 found that some men with Y chromosome microdeletions also had abnormalities of another part of the Y chromosome (the pseudoautosomal regions or PARs). Abnormalities in one of the genes in this region, called the SHOX gene,  has been associated with short stature, mental retardation, and arm and wrist deformities. More work needs to be done in this area

Which Men Should Have Microdeletion Testing?

Men who have no sperm in their ejaculate which is not due to a known obstruction, should have Y chromosome microdeletion testing. In addition, men who have otherwise unexplained low sperm concentration (less than 1 million) should also be tested unless they have fathered children in the past without any fertility treatments.

Varicocele and Male Fertility and Infertility

Varicocele is the presence of enlarged or dilated veins in the blood vessels of the scrotum. Normally the scrotal veins have valves that regulate the blood flow. However, in some cases, the valves are absent or defective and the blood does not circulate out of the testicles efficiently. This results in swelling of the veins above and behind the testicles. 85% of varicoceles develop in the left testicle.

Varicocele

Varicocele and Infertility

It is estimated that varicoceles are present in about 20% of the normal fertile male population and up to 40% of an infertile population. It is clear, then, that the finding of a varicocele is not necessarily abnormal. At the present time, there is no way to determine whether a varicocele in an individual is the cause of infertility problems.

Scientists believe that at least some varicoceles are associated with infertility because they are found more commonly in infertile men. It is uncertain how varicoceles may cause infertility. Some evidence points to the increased temperature of the blood raising the temperature of the testes, which then damages the sperm. Heat can damage or destroy sperm. The increased temperature may also impede production of new, healthy sperm. Another theory is that in men with varicoceles, the testicular fluid which carries sperm has an increased concentration of chemicals which can damage sperm. The chemicals are called reactive oxygen species or ROS.

Varicocele Diagnosis

A varicocele may be detected on a physical exam. It is describes as looking or feeling like a “bag of worms”. It is more obviously seen or felt when a man is standing then when he is lying down. Sometimes, a varicocele may become more apparent when a man “bears down” to try to increase the intra-abdominal pressure.

The American Urological Association states that only varicoceles that can be felt have been documented to be associated with infertility. Not everyone agrees with that position. Scrotal ultrasound can be used to diagnose a smaller, less obvious varicocele. Echo color Doppler is a type of ultrasound that can measure blood flow in the veins of the scrotum.

Varicocele Treatment

Surgery

Most varicoceles can be corrected through a surgical procedure called varicocelectomy ( surgically “tying off” the affected veins). The following methods are used.

Surgical ligation

This procedure is performed under general anesthesia (the patient is asleep). In this procedure, a 2 to 3 inch incision is made in the groin or lower abdomen, the affected veins are identified and the surgeon cuts the veins and ties them off. This surgery can usually be performed on an outpatient basis. Full recovery takes about 6 weeks.

Laparoscopy

Laparoscopy is a technique in which a fiber optic telescope is inserted through the belly button into the abdominal cavity through a small incision. The surgeon can view what is happening by connecting a video camera to the laparoscope and watching a monitor. Once the varicocele has been located, the surgeon will introduce special instruments through small incisions near the pubic hair line to tie off the dilated veins. Most men can resume normal activities in a few two days.

Non-Surgical Methods

An alternative to tying off the veins is blocking the blood flow to the veins.

Embolization

Since embolization is a non-surgical procedure, it does not require general anesthesia but often the patient will be sedated. A small catheter is inserted into the veins just beneath the varicocele. A special dye is used to highlight the varicocele on x-ray and to visually guide the catheter. This is known as venography. Tiny coils are then advanced through the catheter to block the blood flow to the dilated veins. Most men can resume normal activities in a few two days.

Varicocele treatment with embolization coil

There is no evidence to suggest that any of these procedures work better than any other. However, the risks and recovery times are different.

There are two endpoints that are discussed after a varicocele repair: improvement in sperm counts and pregnancy. Unfortunately, many of the studies looking at varicocele repair have been poorly done. Consequently, there are mixed results as to whether more couples achieve pregnancy. There have been two well designed and well performed studies looking at varicocele repair. One study showed an improvement in pregnancy rates and one study did not.

Varicocele and In Vitro Fertilization – IVF and Intracytoplasmic Sperm Injection -ICSI

For couples in whom the men who have mild to moderately low numbers of moving sperm , intrauterine insemination (placing the sperm in the uterus) at the time of ovulation can be performed with reasonable success. For couples with any severity of sperm problems, in vitro Fertilization – IVF with intracytoplasmic sperm injection -ICSI is a highly effective method to achieve fertilization. Pregnancy rates are no longer dependent on the number of sperm but rather on female factors such as her age and response to fertility drugs.

Effects of male age on reproduction

In 1993, fathers aged <35 years accounted for 74% of live births within marriage, while only 25% of such births were to fathers aged 35–54 years. Ten years later, these percentages were 60% and 40%.  When the reproductive potential of older men is discussed, several celebrities who became fathers at advanced age such as Rod Stewart, Pablo Picasso, Charlie Chaplin, Warren Beatty, Tony Randall and Anthony Quinn are often cited as examples.

While the public regards these cases with a mixture of admiration and skepticism, birth statistics show that there are quite a number of children born to fathers aged >50 years in the general population and this is true of Eastern and Western cultures alike. However, it is well known that practically no children are born to mothers aged >50 years and it is common to all older fathers that they have younger partners.    

The effect of aging on the sperm

Semen is studied under the microscope. A typical semen analysis will evaluate a specimen for the total volume of the ejaculate, the number of sperm (concentration), the percentage of moving sperm (motility) and the percentage of sperm with a normal appearance (morphology). Studies have tried to determine if any of these semen parameters decrease over time. These are difficult studies to perform since many variables are present. The majority of studies seem to indicate that the volume of the ejaculate decreases with age as well as the percentage of moving sperm. There is no definite conclusion about whether the concentration of sperm or the microscopic appearance of the sperm (morphology) changes or not.

Age-dependent alterations of semen parameters may have several causes. In addition to age per se, factors such as infections, vascular diseases or an accumulation of toxic substances may be responsible for a deterioration in semen parameters. In a study of almost 4000 infertile men, researchers showed an infection rate in some of the reproductive  glands in 6.1% in patients aged <25 years but in 13.6% of patients >40 years. More importantly, total sperm counts were significantly lower in men with infections compared to those without.

Fertility of older men

Fertility has been documented scientifically in men up to an age of 94 years. If fertility in men decreases with age, it may in part be due to erectile dysfunction. In a large survey of Italian men, the frequency of erectile dysfunction rose from 4.6% in men <25 years to 37.6% in men >74 years. A history of cigarette smoking essentially doubled the risk of erectile dysfunction as men aged.

Several studies have been performed that tried to control for these and other variables in male fertility. For example, a study of birth rates in married couples in Ireland before the widespread use of contraception found that the probability of birth decreased for men starting from 42–43 years of age. Another study found that men >45 years old are 4.6-fold more likely to take over 1 year to get their partners pregnant relative to men aged < 25 years old.

With the use of fertility treatments , age related sperm problems may be bypassed. In fact, the more invasive the treatment, the less important male age appears to be. For example, several studies looking a the success rates of intrauterine insemination where sperm is injected directly into the uterus of a woman on the day of ovulation,  found an adverse impact of increased male age. On the other hand, several studies looking at the use of ICSI in which sperm is injected directly into an egg, did not find an effect of male age.  However, recently a group of researchers analyzed data from a German IVF registry from 1998 to 2002. They found a significantly reduced pregnancy rate in couples with male age >50 years and female age between 31 and 40 years, compared to couples with a male age <50 years. They suggest that this effect may have escaped the notice in previous studies because of a lower number of couples in this male age category.

There may also be an increase in the risk of miscarriage in older men. A recent study of over 5000 pregnant women in California concluded that the risk of miscarriage increased with increasing paternal age, and found that the association was stronger for miscarriages that happened in the first trimester. A study completed in 2002 found that the risk of miscarriage increased in older men but only when the women were also older.

Miscarriage risk according to father's age

This study suggests that for women under age 30, the age of the father does not increase the risk of miscarriage. Women who are aged 30 to 34 are at increased risk for miscarriage if the male is over age 40. Women who are over age 35 are at particularly high risk if their partners are over age 40. In this group, the risk for miscarriage was 6 times higher.

The causes for the increase in miscarriages with male aging is unknown. It is well known that the risk for chromosomal abnormalities in fetuses increases as women age and that these chromosomal abnormalities are responsible for the increase in miscarriage risk. No studies have ever found an increase in the rate of chromosomal abnormalities in fetuses with increasing male age however.

Risks to babies with older fathers

Women have all of the eggs they are ever going to have in their lives before they are born. The cells in the ovary which are destined to become eggs will go through several cell divisions and then stop. The eggs will then remain in this “off position” for the entire duration of a woman’s life until the egg is ovulated. It is this process that is thought to be responsible for the increased risk of chromosome abnormalities in eggs and embryos as women age. Men, on the other hand, produce sperm continuously all through their lives. The cells that produce sperm are constantly dividing during a man’s life. Every time a cell divides, the DNA must be exactly copied so that each “daughter cell” is identical to the “parent cell”. However, the more times a cell divides, the greater the chances for an error to be made when the DNA is being copied. These errors in DNA are called mutations.

It is possible, therefore, that older men may be at greater risk for having sperm with small errors (mutations) in the DNA and that these errors could cause certain diseases in the children of older men.

Risk of chromosome abnormalities

Two studies have found that older men have a greater risk for producing children with Down’s Syndrome (Trisomy 21).  In one study, men over age 40 were compared to men under age 25. The other study compared men 50 and older to men aged 25 to 29. Both studies found the risk for producing Down’s syndrome was higher.

Risk of genetic mutations

In August 2012, a study found that dads pass on an average of 25 new mutations at age 20, increasing to 65 mutations at age 40.   In the last several years, studies have focused on diseases caused be genetic mutations in the DNA and whether their is a relationship to the age of the father. Genetic diseases which are strongly thought to be related to the age of the father include:

  • Achondroplasia
  • Crouzon’s syndrome
  • Pfeiffer’s syndrome
  • Apert’s syndrome
  • Thanatophoric dysplasia
  • Osteogenesis imperfecta
  • Neurofibromatosis
  • Retinoblastoma

A Danish population based study of 1920 affected births of 1.5 million live births concluded that paternal age is associated with cleft lip and cleft palate, independently of maternal age. Single gene mutations are the suggested mechanism. Other diseases may have both a genetic and an environmental component and are referred to as complex or multi-factorial diseases. Some of these diseases have been identified as possibly occurring more commonly in older father.

  • Acute lymphoblastic leukemia
  • Congenital heart disease
  • Ventricular septal defect
  • Atrial septal defect
  • Alzheimer’s disease
  • Schizophrenia

A population based study of childhood brain cancers reported to the Swedish Cancer Registry between 1960 and 1994 concluded that there is a paternal age affect, estimated to confer about 25% excess risk in fathers >35 years of age.

Advanced paternal age has also been associated with increased risk of breast cancer and prostate cancer in their children.

Risk of Autism From Older Fathers

The cause of autism and related disorders (ASDs) is unknown; however, results from twin and family studies provide evidence for a strong genetic contribution. Environmental influences may also be important. The reported prevalence of ASDs has increased significantly during the past few decades. In this same period, the average age of men and women at the time of conception has also increased.  

The results of several large, well performed studies on the effects of parental age have yielded conflicting results. In an Australian population, one study found that increased female age, but not male age, was associated with autism. In a Danish population, a study found that the risk of autism was associated with increasing male age but not female age. A second Danish study reported no association between risk of autism and either male or female age. In April, 2007, the results of a large American study were published. This study concluded that both male and female age were associated with an increased risk of autism and related disorders even after adjusting for other factors. The older the parent, the greater the increase in risk.   In August, 2012, a study of families with an autistic child concluded that a father’s age could account for 15% to 30% of cases of autism due to the occurrence of new mutations the occur as men age.

Conclusion

Increasing male age may cause a decrease in fertility if the female is also older. The chance for miscarriage also seems to increase but the mechanism is not due to the most common reason for miscarriage which is numerical chromosome abnormalities. The overall impact of male age is far less than the impact of female age. Several diseases caused by gene mutations as well as several with multiple genetic and environmental causes are related to increasing paternal age. Despite these increased risks, the absolute risk of the diseases remains small.

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Patient Testimonials

I honestly can’t praise this company enough. Dr. Randy Morris bedside manner is absolutely amazing, his staff professionalism and customer service is also amazing. Your experience with this company will be nothing but perfect. From the initial call to the receptionist. To speaking with the nursing staff, billing, etc. everyone wants to help you with family planning. No matter what my outcome is, I know I’m with a co that will make sure I have the best chances. Thank you to Dr Randy Morris and Staff a bunch!

Misty Johnson

Dr. Morris is by far the best fertility doctor! When I transferred to IVF1 from my previous fertility doctor, he read all my medical records in depth. Never once did I feel stressed or unsure of what was happening. The entire staff there is so nice and make you feel so comfortable. It was so easy to schedule appointments, get medications, or ask a nurse a question. My calls were always returned within 20 minutes. I highly recommend IVF1! Dr. Morris made it possible for us to get pregnant!

Lisa

Thanks to Dr.Morris I am holding today my little dream girl. I don't have enough words to express how thankful I am to him and everyone working in IVF1 Naperville. Highly recomend Dr.Morris and his clinic to everyone looking for real professional help and attitude!

Petya Vasilev

He is a very professional and good doctor. the whole clinic is very nice. all the staff are amazing. The doctor operated on me for endometriosis and I got pregnant during the second IVF. we have a wonderful 1 year old son. thank you doctor we still have an embryo, I think I will definitely come back to you in a year or two.

Ziva Ru

Amazing staff. They made us feel like family. They cried when I called to tell them the birth of our daughter. Starting round two next month. Simply the best. They care!

BT Warner

Dr. Morris and staff were very friendly. Dr. Morris was very informative and patient with answering all questions I had. We were uncertain on the options and next steps to take and Dr. Morris explained all the details and options we have. Excellent staff and a great doc.

Jenita Crawford

The staff is amazing here. I’m in the middle of IVF and had an issue with a medication and they went above and beyond to make sure everything was done to continue our journey (on the weekend no less); truly above and beyond. The staff are very caring and professional. Definitely recommend Dr. Morris and this amazing practice.

Megan Buetikofer

I’m so grateful to have been referred to Dr. Morris and his team! I’ve spent the last month or so working with the team and they’ve made what is naturally a hard process both mentally and physically as comforting and easy as possible. Dr. Morris’s success rates speak for themselves, but what I want to let everyone know is that he is equally comforting. A special thank you to Jocelyne, Pam and Barbie, these three women on his staff from front desks to RNs really have made the experience an extremely positive one. PS. My cousin who referred me to Dr. Morris has a smart, healthy and beautiful baby boy who he helped bring into this world!

Alex Villa

I don't even know where to start...THANK YOU! Thank you for giving us our son. We went through a year of IVF. Although there may have been things I didn't want to hear (chances of pregnancy, factors out of our control, etc.) it was important to hear the truth and know what our chances were. The staff was always great with us and they were very patient. They really have everything figured out and what the best options out for outcomes. I never felt pressured to make certain decisions and always felt well informed. Again, I can't thank Dr. Morris and all his staff for everything!!!

Lauren Throm
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