Miscarriage & Recurrent Implantation Failure Resources

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.

Navigate the complexities of miscarriage and recurrent implantation failure. Access expert insights and compassionate guidance to empower you through these challenging moments.

Search Miscarriage & Recurrent Implantation Failure Resources

Thank you! Your submission has been received!
Oops! Something went wrong while submitting the form.

Miscarriage & Recurrent Implantation Failure Resources

Chronic Inflammation and Implantation Failure and Miscarriage
Chronic Inflammation and Implantation Failure and Miscarriage
Options
Miscarriage
Miscarriage
Options
Recurrent Implantation Failure
Recurrent Implantation Failure
Options
Causes of Miscarriage
Causes of Miscarriage
Options
Signs and Symptoms of Miscarriage
Signs and Symptoms of Miscarriage
Options
Natural Killer Cells in Miscarriage and Infertility
Natural Killer Cells in Miscarriage and Infertility
Options
Sitagliptin (Januvia) Treatment for Recurrent Miscarriage
Sitagliptin (Januvia) Treatment for Recurrent Miscarriage
Options
Listeria Pregnancy and Miscarriage
Listeria Pregnancy and Miscarriage
Options
PGT for Miscarriage
PGT for Miscarriage
Options

Chronic inflammation and Implantation Failure and Miscarriage

Before we can understand chronic inflammation and its important role in reproduction, we must first understand what inflammation is.

What is inflammation?

Inflammation is the body’s attempt to protect itself against infections, irritants and damaged cells. Inflammation is part of the body’s immune response. Initially, inflammation is beneficial. For example, when your body is trying to fight off an infection from bacteria. However, sometimes inflammation can cause further inflammation; it can become self-perpetuating even after the initial cause is gone. In this situation, inflammation can be harmful.

Acute versus chronic inflammation

Acute inflammation starts rapidly and quickly becomes severe. Signs and symptoms are only present for a few days, but in some cases may persist for longer. There are 5 main signs and symptoms of acute inflammation:

  • Pain – Chemicals that stimulate nerve endings are released which causes pain.
  • Redness – Increased blood flow to the affected area causes the red appearance
  • Warmth – Increased blood flow to the affected area also results in warmth locally
  • Swelling – caused by the leakage of fluid from the local blood vessels
  • Immobility – this mostly applies to inflammation in joints

Acute inflammation is generally easily to recognize and treat.

Chronic inflammation means long-term inflammation, which can last for several months and even years. It can result from the failure to eliminate whatever was causing an acute inflammation (persistent bacteria), a chronic irritant of low intensity that persists or when the immune system attacks healthy tissue mistaking it for harmful pathogens.

Chronic inflammation may be difficult to diagnose and effective treatment is often unknown.

Chronic Inflammation of the uterine lining

Inflammation is an increasingly recognized factor contributing to reproductive dysfunction, including several common causes of infertility such as pelvic inflammatory disease, polycystic ovary syndrome, obesity, endometriosis, and recurrent pregnancy loss. Recently, chronic inflammation affecting the uterine lining has been of special interest. This is called chronic endometritis.

What problems does chronic inflammation of the uterus cause?

The uterine lining is responsible for developing the ability to allow an embryo to implant. Estrogen and progesterone production from the ovaries induce the changes in the uterine lining that are necessary for implantation. The changes that occur in the uterine lining are extremely complex and not well understood. Some studies have identified chronic inflammation in women with implantation failure. It is also believed that inflammation in the uterine lining may increase the risk for a miscarriage.

How can chronic inflammation of the uterus be diagnosed?

Blood tests for chronic inflammation

There are some blood tests which are general, non-specific markers of inflammation. One marker is called the erythrocyte sedimentation rate (also known as ESR or “sed rate”). The sed rate is not very useful when studying reproductive age females because it is affected by estrogen levels. Another marker is called C Reactive Protein or CRP. CRP is not affected by hormone levels so is a much more liable indicator of inflammation in women. Very high levels of CRP (>10) are usually an indicator of an acute infection. Moderately elevated levels can be an indicator of low grade chronic inflammation.

micropolyps

Examination of the uterine lining

The uterine lining can be visualized directly by inserting a fiber optic telescope into the uterine cavity. This is called hysteroscopy. Sometimes, chronic endometritis can be diagnosed be diagnosed by this method. For example, the presence of micropolyps is a reliable indicator of chronic endometritis. These are abnormalities that will not show up on other types of imaging such as an HSG or HSN.

Hysteroscopy can also be used to obtain a sample or biopsy of the uterine lining that can be viewed under a microscope. In the uterine lining, one of the types of white blood cells which is a hallmark of chronic inflammation are the “plasma” cells. Plasma cells can be seen by looking at a piece of the uterine lining under a microscope. However, due to the presence of other similar looking cells, it is not always easy to determine the presence of an abnormal amount of plasma cells. Plasma cells have a marker on their surface which is called CD138. It is possible to stain a sample of endometrial tissue so that the CD138 stands out. This is a more reliable method to diagnose chronic endometritis.

Diagnosing chronic endometritis
Left side standard microscopic image of chronic endometritis. It is difficult to identify the plasma cells. Right side – after staining with CD138. The arrows show the plasma cells.

How can you treat chronic inflammation?

If a specific cause for the inflammation can be identified then treatment of the cause should cause resolution of the accompanying inflammation. For example, if a bacterial infection is found, treatment with antibiotics can be tried.

Recently, a study found an increase in the pregnancy and live birth rates when women with mildly elevated CRP levels were treated before they got pregnant with low dose aspirin. The improvement was not seen in obese women, however.

In study in bovines also found that exposure to platelet rich plasma (PRP) would suppress the production of some of the proteins produced in the uterine lining as a result of inflammation.

Does antibiotic treatment for chronic endometritis really work?

A recent review of several studies looking at antibiotic treatment of chronic endometritis showed that women who had evidence of a cure (repeat biopsy showed the inflammation was clear) had a six fold greater chance for an ongoing pregnancy or live birth compared to women with persistent chronic endometritis.

Miscarriage

Miscarriage is the loss of a pregnancy after conception and implantation has occurred.

Miscarriages can be classified in a number of different ways. The most commonly used system involve how the pregnancy was verified before the loss was identified.

Biochemical pregnancy; Biochemical miscarriage, Chemical pregnancy, Early miscarriage

This is a miscarriage that occurs after a positive pregnancy test but before a pregnancy could be seen on ultrasound.

Clinical miscarriage, Clinical pregnancy

A miscarriage that occurs after or at the same time that it is seen on ultrasound. This is a very broad group. Some very early pregnancies can be detected by sensitive ultrasounds. There are four subcategories of clinical miscarriage that depend on what features were seen on the ultrasound:

  • Gestational sac only
  • Gestational sac and yolk sac
  • A fetus is seen
  • A fetus is seen with a heartbeat

Missed miscarriage, Missed abortion

A missed miscarriage is determined when an ultrasound shows a pregnancy is nonviable and the measurements or features suggest that it occurred a period of time before the ultrasound. For example, an obstetrician is unable to hear the fetal heart beat at 12 weeks gestation. An ultrasound is performed and the fetus is measured but it corresponds to an 8 week gestation.

Threatened miscarriage, Threatened abortion

Any bleeding that occurs in the first twenty weeks of pregnancy is defined as a threatened miscarriage. Approximately 1/2 of these pregnancies will go on to miscarry. However, if ultrasound has previously shown a fetus with a heartbeat a much smaller percentage (1-5% depending on the age of the female) will miscarry.

Incomplete miscarriage, incomplete abortion

A miscarriage that is in progress. Some of the fetal or placental tissue has passed but not all of it. Generally, the cervix is dilated.

Completed miscarriage, completed abortion

A miscarriage in which all of the fetal or placental tissue has passed.

Recurrent Implantation Failure

Recurrent Implantation Failure is a term that encompasses the frustration and uncertainty experienced by individuals who have undergone multiple fertility treatments without achieving a viable pregnancy. As we unravel the mysteries surrounding recurrent implantation failure, we will explore its potential causes and the latest advancements in fertility diagnostics that can offer renewed hope to those facing this formidable hurdle.

Window of Implantation

An important question in the treatment of infertility with IVF is this – When is an embryo able to implant into the uterus? If a normal embryo is placed into the uterus too early or too late based on its stage of development, then implantation will fail. This is known as IVF failure or implantation failure. For many years, it was believed that the “window of implantation” was a small time frame that occurred a fixed number of days after ovulation. Recent studies have shown that for some women – this may not always be true.

Before ovulation, while an egg is developing, the ovary is producing the hormone estrogen. This is called the follicular or proliferative phase. Estrogen causes the uterine lining to thicken. If an embryo were to be placed into the uterus during this time, it would not be able to implant or produce a pregnancy. After ovulation, the ovary produces the hormone progesterone. This is called the luteal or secretory phase. Progesterone causes numerous changes in the uterine lining that allow an embryo to implant. However, it seems that there are only a few days during the secretory phase in which the embryo can implant. This is known as the window of implantation.

Uterine changes with menstrual cycle

How do scientists determine the days that the uterus is able to allow implantation? Many types of tests have been tried. The earliest attempts involved looking at the uterine lining under a microscope. Definite changes can be seen under a microscope in the uterine lining as it goes from the proliferative to the secretory phase. However, detecting the very subtle changes needed to distinguish a receptive uterine lining is very difficult. The pathologists who view the uterine lining under the microscope will often have different assessments from one another. Stated another way, microscopic analysis of the uterine lining is not accurate or reproducible. Another type of test involves looking at specific “markers” in the uterine lining. The cells of the uterine lining have a large number of structures on their surface. It was hoped that there might be a specific marker that would be present only when the lining was receptive and not at other times. The most popular of these markers is called beta-3 integrin. While there was initially great hope for the use of these marker tests as indicators for the window of implantation, they have failed to improve the outcomes in IVF cycles.

Endometrial receptivity array

Developed in 2020, the endometrial receptivity array uses some very sophisticated technology which measures the amount of RNA that the cells of the uterine lining produce.

Remember, each cell in the uterine lining has a nucleus which contains the genetic material known as DNA. DNA is the coded blueprint for the instructions that a cell needs to carry out its function. For example, if a cell’s purpose is to make a certain protein, the DNA contains the code for how to make the protein. The code is “translated” into a slightly different form called RNA and the RNA tells the cell which amino acids to combine to make the protein.

DNA is converted to RNA

The uterine lining cells make more of a certain type of RNA at one time of the cycle and less in another time of the cycle. Scientists have used powerful computer chips to look at the amount of RNA produced at different times of the cycle. Then, using computer algorithms, they could detect patterns in the RNA production. Some RNA levels may not correlate with the window of implantation at all. Other types of RNA may be present in higher amounts and some may be present in lower amounts. In total, scientists have found 138 types of RNA (so far) that help in determining the window of implantation.

This endometrial receptivity array is very reproducible. Studies were done on patients where they took two samples at the same time of the cycle several months apart. Most often, the results of the tests were the same.

The most interesting part of the endometrial receptivity assay is that it has identified that some women might have a receptive uterus at an earlier time than expected and some might be receptive at a later time! Infertility specialists can then use this information to change the time that embryos are placed into the uterus so that it matches up better with the window of implantation!

How commonly is an abnormal test found?

In studies of women with recurrent failed IVF cycles – about 25% of the women were found to have an abnormal ERA result. In infertile women without a history of recurrent in vitro fertilization failures, about 12% of the women were non-receptive.

Of those women with a non-receptive uterine lining, most (85%) were found to have their window of implantation shifted later in the cycle. These women were said to be pre-receptive. The remaining 15% had their window of implantation shifted earlier in the cycle, these patients were called post-receptive.

Endometrial Receptivity Array

How do you correct these problems with uterine receptivity?

There are some case reports and small studies in which doctors changed the timing of the embryo transfer according to the results of the endometrial receptivity assay. One such study looked at women with recurrent IVF failures using donor eggs (which means that all of the patients had high quality embryos to transfer). These patients had failed in anywhere from one to six previous attempts. Most did not become pregnant, a few became pregnant but miscarried – none had achieved a live birth. Doctors then changed the time of the embryo transfer based on the results of the endometrial receptivity assay and found that 67% achieved an ongoing pregnancy.

This was very encouraging evidence that this may be a useful test. However, as more data was collected, and larger and better studies were performed, researchers found that adjusting the time of the transfer was not improving the chance for pregnancy or live birth. As a result, in 2022, the ERA test is no longer recommended for people attempting pregnancy with IVF

How if the test performed?

The endometrial receptivity assay is performed by obtaining the tissue from the uterine lining at a very specific time. This can be done in one of two ways:

1) If a woman ovulates, she can use a home urinary ovulation predictor test to detect the LH surge. This is considered day 0. On day 7, she will go to the fertility doctor for the test.

Endometrial biopsy
The endometrial biopsy does not take very long but most women find it very uncomfortable.

2) Another method is to use medications to prepare the uterine lining using the hormones estrogen and progesterone. This is the method we usually use for performing a frozen embryo transfer cycle. The day the progesterone is started is day 0. The test is done on the fifth day after that.

On the appropriate day (using either method), the doctor or nurse practitioner will perform an endometrial biopsy. First, a speculum is placed into the vagina so that the cervix (opening of the uterus) can be seen. The cervix is stabilized and then a catheter (like a thin, flexible plastic straw) is advanced through the cervix into the uterine cavity. A plunger in the catheter is withdrawn. This creates suction in the catheter which draws endometrial tissue inside the catheter. The catheter is then removed.

The results are available in about three weeks.

At this time, the ERA is no longer a recommend test.

Causes of Miscarriage

Unfortunately, miscarriage is a common problem. About half the women in the U.S. will have at least one miscarriage at some point during their reproductive lives. Even worse, about 5% of women will experience two miscarriages and 1% will have three or miscarriages. These women are said to have recurrent miscarriage or recurrent pregnancy loss. Extensive diagnostic testing is performed in couples having recurrent miscarriage but about half the time, no specific underlying cause is found. In this article, we explores some common and uncommon known causes of miscarriage.

Embryo Chromosomal abnormalities

The vast majority of miscarriages are caused by abnormalities in the number of chromosomes contained in the embryo. Human beings normally have 23 pairs of chromosomes (a total of 46) Very often embryos will have too many or too few chromosomes. These abnormalities are called aneuploidies. The older a woman is when she becomes pregnant, the greater the chance for aneuploidy and the greater the risk for miscarriage.

[imageframe lightbox=”yes” style_type=”glow” bordercolor=”” bordersize=”1px” stylecolor=”” align=”center” link=”” linktarget=”_self” animation_type=”0″ animation_direction=”down” animation_speed=”0.1″ class=”” id=””]

Normal set of human chromosomes

Sometimes, when evaluating a woman for the cause of miscarriages, the physician may attempt to obtain fetal or placental tissue for chromosome analysis. In the past, a procedure called a D&C (Dilation and Curretage) was performed to obtain the fetal tissue. However, a D&C will obtain both the fetal cells (wanted) and the mother’s uterus cells (unwanted). A newer, more accurate method for obtaining fetal cells is to use a hysteroscope to direct the physician to where the fetal cells are. This is called fetoscopy or embryoscopy.

The tissue obtained would be sent to a laboratory which would try to grow the cells in the tissue and then evaluate them for chromosome abnormality. This process is known as karyotyping. Unfortunately, this method had several problems. Sometimes the cells wouldn’t grow so a chromosome analysis couldn’t be performed. In other instances, the chromosome analysis results would be that of a normal female. When this happens, it is impossible to determine if the result is from the fetal cells or the cells of the mother’s uterus. If the mother’s cells get analyzed by mistake, it is called maternal cell contamination or MCC.

More recently, a new type of analysis has begun replacing the standard karyotype. This new analysis to perform a chromosome analysis is called a microarray. Microarrays do not depend on growing cells so a result can be obtained almost 100% of the time. It is also possible to determine whether the results are from the fetus or mother so maternal cell contamination can be ruled out.

When a chromosome analysis is performed, about 70-80% of the miscarriages will be found to have aneuploidy as the cause.

The actual percentage may be even higher. Because of maternal cell contamination, the laboratory can’t tell the difference. When the time comes to evaluate the chromosomes, the result will appear to be results from a female with a normal number of chromosomes. However, it is impossible to determine if this was from the fetus or from the mother.

Many times, doctors or other health professionals will tell a woman that this means the miscarriage was not caused by a chromosomal abnormality. This is incorrect. In fact, when more sophisticated means are used to obtain and analyze the fetal tissue, such as microarray, it has been proven that most of the time when the result reads “normal female” it really is just missing the fetal abnormality and is looking at the mom’s chromosomes instead.

Treatment of miscarriages due to fetal chromosomal abnormalities

There is no treatment that will prevent embryos from having chromosome abnormalities. The older a woman gets, the higher the chances that an embryo will have an abnormal number of chromosomes. This is why women have a higher miscarriage rate as they get older.

However, using a technology known as preimplantation genetic screening also known as PGS or CCS, we can now identify embryos with chromosomal abnormalities during an In vitro Fertilization cycle. By avoiding those embryos that have abnormalities, couples can reduce their risk for a miscarriage caused by chromosomal abnormality.

Otherwise, there is no way to treat a pregnancy that already has been established if the embryo has an abnormal number of chromosomes. This is an extremely important point! If an embryo is abnormal, then no amount of bed rest or progesterone or medications or herbal supplements is going to affect the outcome. Not all embryos with chromosomal abnormalities will miscarry. Some can go on to be live born babies. These babies however, will be born with birth defects such as Down’s syndrome or other syndromes depending on which chromosomes are extra or missing.

Parental chromosomal abnormalities

Less commonly, the male or female parent may have a different type of abnormality in their own chromosomes that causes miscarriage in a fetus. This type of chromosome abnormality is called a translocation abnormality.

Translocations occur when a portion of two different chromosomes, for example chromosomes number 13 and 21, have “swapped” positions with each other. The result (from our example) is that a little piece of chromosome 13 is now on chromosome 21 and a little piece of 21 is now on chromosome 13.
This can occur in the chromosomes of the egg or the sperm.

When fertilization occurs in these couples, a few different possible outcomes may occur:

  • The embryo may be completely normal
  • The embryo may end up with a balanced amount of chromosome material and end up like the parent, essentially, a carrier of the problem
  • The embryo may end up with an unbalanced amount of chromosomal material. These embryos, like the aneuploidies will be miscarried.

These abnormalities can be detected with a fetal karyotype analysis unless the amount of swapped information is very small. These micro translocations (also called telomeric translocations) will be missed by standard karyotype techniques. It is therefore important for couples who have recurrent miscarriage to undergo a high resolution chromosome analysis to look for very subtle abnormalities.

Genetic mutations

Maintenance of pregnancy is an extremely complicated process. It is is likely that hundreds of different genes are involved – each one to a small extent. Because of this complexity, it has been difficult to isolate individual genes or gene mutations that are responsible for miscarriage.

Recently, researchers using new bioinformatics techniques, have identified a gene responsible for recurrent miscarriage called FOXD1. They were able to show that women who had certain variants in this gene were ten times more likely to suffer from recurrent miscarriage than those without the variants. FOXD1 acts as a sort of master controller for other genes that are involved in creating the blood vessels necessary to “feed” the placenta oxygen and nutrients and for fine tuning the balance between a mother’s immune system and the placenta. FOXD1 is now referred to as the miscarriage gene.

Testing for FOXD1 is a blood test. There are some ideas for possible treatment but no studies which show benefit yet.

Treatment of recurrent miscarriage due to translocations

As in the case of embryos with aneuploidies, embryos with unbalanced translocations cannot be fixed. They can be prevented if the affected parent’s gametes (sperm or eggs) are not used. This is an indication for egg donation or sperm donation.

Preimplantation genetic diagnosis can also be used to identify embryos with translocation abnormalities during an in vitro Fertilization cycle assuming that the translocation is known ahead of time.

Thrombophilias

Women can have disorders that make it more like to have problems with blood clotting. Blood clotting can be an important cause of miscarriage since the growth and development of the embryo is highly dependent on obtaining oxygen and nutrients from the mother’s blood supply.
Some of the more common causes for increased blood clotting risk are genetic mutations that a woman is born with. For several years now, we have been performing testing for the presence of these mutations:

  • Factor 5 Leiden Mutation
  • Factor 2 (Prothrombin) Mutation
  • Variants in the Methyl tetra hydrofolate reductase (MTHFR) gene

Thrombophilias can also result from deficiency or excess amounts of the factors in the blood that control the balance between bleeding and clotting. These include:

  • Protein C Deficiency
  • Protein S Deficiency
  • Antithrombin III Deficiency
  • Hyperhomocysteinemia
  • Folate Deficiency
  • Plasminogen activator inhibitor

Treatment of miscarriage caused by thrombophilias

In some cases, treatment for these problems entails the use of anti-coagulant medications, that is, medications that lower the risk of blood clotting. Unfortunately, there still isn’t a lot of data about the best way to give the medications so you end up with a fair amount of variability from physician to physician. For example, should the medication be started before pregnancy or only after a pregnancy has been diagnosed? How long should the treatment continue? what is the ideal dose? Until further studies are performed, we can only guess as to the correct answers.
Some problems, like hyperhomocysteinemia, may be treated with high dose supplementation of a B vitamin called folic acid. This technique has proven to be successful with other problems caused by hyperhomocysteinemia.

Immune Causes of miscarriage

Problems with a woman’s immune system make up a much smaller proportion of the causes of miscarriage. There are several types of problems:

  • Auto-immunity
  • Allo-immunity
  • Non-specific

Autoimmune causes of miscarriage

Normally a person’s immune system functions to “fight off” foreign invaders like bacteria and viruses and rid the body of abnormal cells such as cancer. Occasionally, however, the immune system may malfunction causing it to attack and destroy a persons own normal body tissues or cells. In medicine, there are many examples of diseases causes by this autoimmunity: Rheumatoid arthritis, Lupus, and asthma are just a few examples.

Evidence for autoimmunity has been detected as a possible cause of miscarriage. Overall immune problems as a cause for miscarriage are infrequent but autoimmunity makes up the largest proportion of immune mediated miscarriages. Tests performed to detect an autoimmune problem are blood tests that look at the levels of various antibodies. These antibodies are present in all individuals. They are though to represent a problem is the levels are significantly higher than that seen in the general population. It is not known whether these antibodies are directly involved with the loss of the pregnancy or whether they are just a marker for a woman who has an “autoimmune problem”.

Anti-phospholipid antibodies

The most common type of autoantibodies thought to be involved with miscarriage are known as Anti-phospholipid antibodies:

  • Anti-cardiolipin antibodies – There are three subclasses: IgG, IgA and IgM. Unfortunately, many of the “abnormal” results that we get can be falsely positive. For example, the IgG subclass is elevated in 6.5% of general population and in 10.6% of women with completely normal pregnancies. The IgM subclass is elevated in 9.4% of the general population and 17% of women with completely normal pregnancies. To further complicate matters, the levels of these antibodies can fluctuate and so it is recommended that a positive test be repeated in six weeks to determine if the elevated antibody levels are persistent.
  • Lupus anticoagulants – These are a group of antibodies that are commonly identified in individuals with the disease Lupus. Many women can have evidence for the presence of lupus anticoagulants without actually having the full blown disease. Accurate measurement of this group of antibodies is difficult since there is no direct test. Typically, a woman first has a screening test. The test is based on the fact that when lupus anticoagulants are present, a standard test to look at blood clotting activity called aPTT (activated partial thromboplastin time) becomes abnormal. However, this screening test alone is inadequate to establish the presence of a lupus anticoagulant because many affected patients, especially pregnant women, have normal aPTT’s and sometimes women with an abnormal test have a different type of problem. Thus, additional tests are needed both to establish and exclude the presence of a lupus anticoagulant. Other tests that aid in the recognition and confirmation of lupus anticoagulants include tests for the dilute Russell viper venom time (dRVVT, the hexagonal lipid neutralization test, and testing for alpha-2 glycoprotein I.
Treatment of miscarriages caused by anti-phospholipid antibodies: Anticoagulation

As in the case with thrombophilias, women with recurrent miscarriage and evidence for anti phospholipid antibodies are treated with anticoagulant medications such as Lovenox and baby aspirin. There are two theories as to why this might work.

There is some evidence that anti phospholipid antibodies increase blood clotting risk. Anticoagulants decrease blood clotting risk. Other data point to the possibility that anti-phospholipid antibodies actually interfere with the cells of the developing placenta known as trophoblastic cells. Medications like Lovenox may prevent the antibodies from interfering.

Anti-Thyroid Antibodies

Another type of autoantibody that may be a cause for miscarriage are antibodies which attack the thyroid gland. These are known as anti-thyroid antibodies. Little is known about this class of antibodies. Several studies have suggested that elevated levels are associated with a higher risk of miscarriage. Treatment with thyroid hormone (Synthroid) has been suggested as a way to reduce the risk.

Alloimmune causes of miscarriage

It was once thought that some causes of miscarriage could be explained by immunologic “rejection” of the fetus as an allograft. An allograft is when an organ or tissue is transplanted from one individual to another of the same species. If you think about it, an embryo is part allograft since it contains material (called antigens) that comes from the father and is thus foreign to the mother. It is thought that the mother must have the ability to suppress her immune system so it will not automatically reject this “transplant” as foreign. This is called immune tolerance. If the mother fails to achieve immune tolerance then the fetus will be rejected (aborted). It was thought that immune tolerance was brought about by the mother first recognizing the foreign father’s antigens, then producing “blocking antibodies” which would “coat” the fetal cells and protect them from damage from the mother’s immune “killer” cells.

Treatment of miscarriages due to Alloimmune factors: Paternal Leukocyte Immunization

In the past, a few researchers thought that injecting white blood cells from the father would make it easier for the mother to produce blocking antibodies and reduce the risk of miscarriage. This treatment became known as Paternal Leukocyte Immunization. Unfortunately, we now know that this treatment does not work and in some cases, actually increases the risk for miscarriage. Because it was ineffective and due to safety concerns, in the United States, this therapy was halted by the Food and Drug Administration.

Nonspecific immune causes of miscarriage

In addition to antibodies, the immune system is composed of more than 30 types of white blood cells. A few of these cells have been studied to determine their role in causing miscarriage. They include T lymphocytes and natural killer (NK) cells. The cells can be differentiated by the presence or absence of specific markers on the surface of the cells. These markers are written as abbreviations followed by a (+) or (-) to indicate their presence or absence.
For example, there is a special class of Natural killer (NK) cells (CD3-, CD16-, CD56+).

Natural killer (NK) cells are the main type of lymphocyte in the uterine lining at the time of implantation and during early pregnancy. Uterine NK cells are different from those circulating in peripheral blood. The function of uterine NK cells in pregnancy is still largely unknown. Tests to measure NK cells in the blood may not give useful information on uterine NK cells. Use of powerful therapies to reduce levels of NK cells in women with infertility or recurrent miscarriage is unjustified and is associated with known side effects to mother and fetus.

Uterine abnormalities and miscarriage

A woman can be born with or develop abnormalities of her uterus. Some of these abnormalities have been strongly associated with an increased risk of miscarriage. Others have only weak evidence associating them with miscarriage.

Congenital abnormalities (problems a woman is born with):

  • Uterine septum
  • Bicornuate uterus
  • Unicornuate uterus
  • Uterus didelphus
  • Various combinations of the above
  • Intrauterine adhesions (Asherman’s syndrome)
  • Uterine fibroids
  • Uterine polyps
  • Uterine infections

Treatment of miscarriages due to uterine abnormalities

Treatment of uterine abnormalities is usually surgical. When possible, hysteroscopy is used. Hysteroscopy is the passage of a fiberoptic telescope into the uterine cavity. Through operative channels in the telescope, instruments can be introduced to allow the surgeon to cut, vaporize or remove abnormalities.

In some cases, however, surgical repair must be performed through an open surgery going through the abdominal wall.

Progesterone deficiency and miscarriage

After ovulation, the ovaries produce large amounts of the hormone progesterone. Progesterone has an important role. It prepares the uterine lining for implantation of the embryo and maintains the uterine lining afterward. In experiments in primates, if the ovaries are removed soon after the establishment of a pregnancy, it will lead to miscarriage. This forms the basis of the presumption that progesterone production by the ovaries is important for the maintenance of the pregnancy and prevention of miscarriage.

Progesterone levels are difficult to measure accurately, however. There have never been any studies that have been able to accurately correlate progesterone levels with miscarriage risk. Most physicians believe that progesterone supplementation is low in risk so it is often given to women as a treatment to prevent miscarriage. In reality, it may be of limited benefit.

Environmental causes of miscarriage

Several factors have been associated with an increased risk of miscarriage. Tobacco, alcohol and caffeine use by a woman or even her partner increase miscarriage risk. Several herbal remedies can also trigger an abortion. Mercury in the diet, mostly from certain types of seafood, have been associated with miscarriage and birth defects. Even chlorine compounds in the drinking water are thought to play a role.

Signs and Symptoms of Miscarriage

The symptoms of miscarriage can vary widely. In some cases, a pregnancy can be lost so early that a woman was not even aware she was pregnant. In other cases, the only sign of miscarriage may be that a woman’s period came a few days later than normal. On the other side of the spectrum the symptoms of miscarriage can be quite obvious or severe.

Early Miscarriage Signs and Symptoms

The most common finding in women who have had a very early miscarriage is having no symptoms at all. Various signs and symptoms might include one or more of the following:

Menstrual cycle abnormalities

  • Late period
  • Heavier than normal period
  • A period that lasts more days than usual

Testing abnormalities

  • A home test was positive but has now turned negative
  • A serum pregnancy test was positive but has now turned negative
  • A serum pregnancy test measuring hCG levels was previously increasing but has now started dropping

Other physical sensations

  • Loss of breast tenderness
  • Loss of nausea
  • Subjective feeling of "not being pregnant"

Later Miscarriage Signs and Symptoms

The further a pregnancy has progressed the more likely it is that a woman may experience signs and symptoms that are commonly associated with miscarriage.

Abnormal bleeding

  • Dark brown spotting
  • Light pink spotting
  • Bright red spotting
  • Bright red bleeding
  • Passing blood clots – many women who aren’t used to seeing blood clots normally during their menstrual flow may think that they are passing pregnancy tissue. While this is true occasionally, it is far more common to pass clots alone.

Physical symptoms

  • Lower pelvic cramping
  • Severe pelvic cramping
  • Generalized or diffuse pelvic pain

Note: Pain in a pregnant patient may also be a symptom of a more serious problem such as an ectopic pregnancy or a ruptured ovarian cyst. Any severe pain or pain that is localized to one side or the other should be thoroughly investigated.

Testing abnormalities

  • A serum pregnancy test measuring hCG levels was previously increasing but has now started dropping
  • Ultrasound reveals a fetus without a heartbeat
  • Two Ultrasounds a week apart have failed to show any change
  • An ultrasound previously showed a pregnancy in the uterus but it is no longer visible

Note: At this point a lost pregnancy may still result in a positive home test or blood test. A quantitative level is needed to show the numbers are decreasing.

Other physical sensations

  • Loss of breast tenderness
  • Loss of nausea
  • Subjective feeling of "not being pregnant"

Natural Killer in Miscarriage and Infertility

There has been much interest in the possible role of the immune system in determining the outcome of fertility treatment and pregnancy. Unfortunately, there has been much misinformation about the role of natural killer cells in miscarriage and infertility. Natural killer cells, also known as NK cells or CD56 cells, have been perhaps misnamed and this contributes to the confusion surrounding them.  Natural killer cells are a diverse group of cells that can be found in the blood and other areas of the body including the uterus. They earned the name “killer” cells because it was found that the type of natural killer cells found to circulate in the blood were able to bind to and kill certain cancer cells and virus infected cells. However, other types of NK cells lack this ability or only to a much lesser extent.

Blood tests for Natural Killer Cells are not helpful

Based on the assumed similarities between NK cells in blood and uterine NK cells, it has become increasingly common for fertility doctors to recommend blood tests for Natural Killer cells in women with infertility and recurrent miscarriage. These recommendations are based on the unproven assumption that women with recurrent miscarriage and infertility have abnormalities in the function of their uterine NK cells and that the measurement of NK cells in the blood can somehow identify those women who suffer from a malfunction of their uterine NK cells.

Both of these assumptions appear to be wrong.

First, measurement of the number of percentage of Natural Killer Cells in the blood do not reflect the number in the uterus. The percentage of NK cells in blood can be affected by many factors including sex, ethnicity, stress, and age, but there is no indication that elevated concentrations are ever harmful. On the other hand, uterine NK cells will see their numbers change based on a woman’s hormone production during her menstrual cycle. The levels are low before ovulation and increase dramatically, day by day, after ovulation.

Second, blood NK cells are quite different from uterine NK cells. They look different under a microscope, the react differently and they function differently. For example, uterine NK cells have very weak activity in killing cancer cells. Recently, studies of large groups of women have failed to find any relationship between the levels of NK cells in the blood and either infertility or miscarriage.

These incorrect assumptions have led doctors to recommend ineffective and sometimes dangerous therapies to women to suppress their NK cells such as prednisolone, intravenous Ig (IVIG), intralipid, and TNF-α–blocking agent. This is based on a idea that there is a correlation between excessive number or activity of NK cells and adverse reproductive outcome. As noted above, high quality studies have not found this to be true.

What do uterine NK cells do?

NK Cells remodel the uterine spiral arteries

The function of uterine NK cells is not completely understood. Studying the function of uterine NK cells is complex and difficult. The best evidence currently points to uterine NK cells being an important mediator between the placenta and the uterus. To understand this role, it is important to understand some basics about the placenta, the uterus and how the two interact with each other.

The placenta comes from the fetus – not the mother. It is composed of cells called trophoblast cells which literally invade into the mother’s uterine lining. In the mother’s uterus, there are blood vessels called spiral arteries. In order for a pregnancy to be successful, the trophoblast cells must come close to the mother’s spiral arteries and then cause changes in the arteries to ensure that they receive a good blood supply. This is called arterial remodeling. The likely function of uterine NK cells is to “cooperate” with trophoblast cells to guarantee correct arterial remodeling ensuring the supply line to the growing fetus. The uterine NK cells must recognize that fetal cells are present in the uterus and they must be activated to produce the molecules necessary for correct spiral artery remodeling.

Should you undergo treatment for elevated or abnormal NK cells?

Use of the treatments noted above (prednisolone, intravenous Ig (IVIG), intralipid, and TNF-α–blocking agent) is an attempt to suppress the number of uterine NK cells. This is based on a misunderstanding of the basic science. It is not inhibition of uterine NK cells that is needed, but rather the right degree of activation  that is of importance. These treatment therefore could potentially have serious adverse side effects. Incorrect or insufficient remodeling of the spiral arteries can lead to complications of pregnancy such as pre-eclampsia, fetal growth restriction and stillbirth.

Conclusions

  1. Blood tests for natural killer cells are not an indicator of uterine natural killer cell numbers or function and do not predict miscarriage or infertility.
  2. Tests to determine levels or “activity”of uterine natural killer cells are of no benefit either since the exact way that natural killer cells work is not known.
  3. Treatments to suppress natural killer cells lack any scientific validity and are potentially harmful.

Sitagliptin (Januvia) Treatment for Recurrent Miscarriage

Recent evidence has pointed to the possibility that some miscarriages may be due to defects in the function of the uterine lining. Women with recurrent miscarriage, especially those that have had a miscarriage of a chromosomally normal embryo, have been found to have low levels of a type of stem cell – endometrial mesenchymal stem-like progenitor cells (eMSC) in the basal (bottom) layer of the endometrium (uterine lining). They also appear to have problems converting the cells in the uterine lining (endometrial stromal cells – EnSC) into a form that will support pregnancy (decidual cells – DC ) and away from a type that may cause miscarriage (senescent decidual cells – SASP). Treatments that increase the eMSC and restore a healthy ratio of decidual cells may reduce the risk for miscarriage.

What is sitagliptin?

Sitagliptin, also known as Januvia, belongs to a class of medications called DPP-4 inhibitors. DPP-4 is an enzyme that breaks down certain proteins. One of the proteins that DPP-4 breaks down is called incretin. This prolongs the action of incretin in the body which helps control blood sugar. Thus, the primary use currently for sitagliptin is to treat people with Type 2 diabetes. Sitagliptin is FDA approved in the United States as a treatment for Type 2 diabetes.

How does sitagliptin help the uterus?

Another protein that is broken down by DPP-4 is called SDF-1. By blocking the action of DPP-4, sitagliptin can prolong the action of SDF-1. SDF-1 is produced in the uterine lining. When an follicle / egg is maturing in the ovary, the follicle produces estrogen. Estrogen makes the uterine lining thicker but it also increases the amount of SDF-1 that is produced by the endometrium. SDF-1 circulates in the blood and reaches the bone marrow. As a result, the bone marrow produces a type of stem cell called BMDC (Bone Marrow Derived Cells). The BMDCs lodge in the basal layer of the endometrium and are converted into eMSCs which help with regeneration of the uterine lining.

How does sitagliptin reduce the chance for miscarriage?

It is thought that sitagliptin improves the health of the uterine lining by increasing the eMSCs which are low in some women with recurrent miscarriage, and convert more endometrial stromal cells into healthy decidual cells instead of unhealthy senescent cells. The embryo may therefore have a better chance for survival after implantation.

Is there any evidence that sitagliptin reduces the risk for miscarriage?

Yes. This year (2020), scientists in England recruited a number of women aged 18 to 42 with a history of 3 or more miscarriages. Half the group received sitagliptin and half received a placebo (phony, inactive capsules). Subjects receive this treatment for three months. Neither the doctors nor the patients knew who got the real pills. This is known as a double-blind, randomized, placebo-controlled trial. This is considered this highest quality type of medical study because it reduces the chance for other variable to affect the results.

The researchers found that the women who received sitaglitpin: 1) Increased the number of eMSCs in their endometrium 2) Increased the number of decidual cells compared to senescent cells and 3) were more likely to have live births.

Specifically, in the group who received and completed treatment with sitagliptin, there were 8 live births out of 17, one termination of pregnancy at 16 weeks for a fetal abnormality and 3 spontaneous pregnancy losses before 12 weeks of gestation. A chromosome analysis was performed in 2 of 3 miscarriage cases and both showed a chromosome abnormality.

In the placebo group, there were 7 live births and 6 spontaneous pregnancy losses before 12 weeks out of 19 patients. Chromosome analysis was performed in only one of the losses. The results was normal. No chromosome abnormality.

Conclusion

Sitagliptin appears to be a novel way to improve the uterine lining prior to implantation by recruiting more bone marrow cells to help with endometrial regeneration. Treatment was well tolerated. although the group was very small, there appeared to be a greater chance for a live birth.

If you are interested in trying sitagliptin therapy, register to become a patient now.

Listeria pregnancy and miscarriage

In 2008, the United States Department of Agricultural stepped up a media education campaign regarding food safety in general and infection with Listeria in particular. They stressed that pregnant women are at high risk for getting sick from Listeria and that listeriosis (Listeria infection) can cause miscarriage and other complications of pregnancy.

What is Listeria?

Listeria is a type of bacteria found everywhere – in soil and ground water and on plants. Women can carry Listeria in their bodies without becoming sick. Most infections in women result from eating contaminated foods. Most people are not at increased risk for listeriosis. Hormonal changes during pregnancy have an effect on the mother’s immune system that lead to an increased susceptibility to listeriosis in a pregnant woman. In fact, Listeria infection is about 20 times more common in pregnant women than in the general population. Pregnant women account for 27% of all listerial infections.

Listeria symptoms in pregnant women

Because the symptoms of listeriosis can take a few days or even weeks to appear and can be mild, you may not even know you have it. In pregnant women, listeriosis may cause flu-like symptoms with the sudden onset of fever, chills, muscle aches, and sometimes diarrhea or upset stomach. The severity of the symptoms may vary. If the infection spreads to the nervous system, the symptoms may include headache, stiff neck, confusion, loss of balance, or convulsions. A blood culture can be performed to find out if your symptoms are caused by listeriosis.

Listeria can cross the placenta and affect a fetus.

Listeriosis and miscarriage

I reviewed the medical literature and found there is actually very little data linking listeriosis to miscarriage in human beings. Most of the research on the effects of Listeria in pregnancy that is available mostly involves problems later in the 2nd or third trimester or the study reported on a few isolated cases. In 1991, the only large scale study of women with recurrent early miscarriage was conducted.

Uterine tissue and swabs from the cervix were obtained and tested for the presence of Listeria. During the 10-year study period, none of the patients with recurrent miscarriage were found to have the bacteria. The study authors concluded that Listeria may contribute to miscarriage, but probably not on a recurrent basis. Routine testing for Listeria in an asymptomatic woman in a clinical setting is not cost-effective and is therefore unwarranted. They also concluded that it is unwarranted to give routine administration of antibiotics to treat Listeria to women who have had a history of recurrent miscarriage.

That being said, it is not unreasonable for a pregnant woman to follow the safety measures for reducing the chance of becoming sick with a food borne illness.

  • Do not eat hot dogs, luncheon meats like bologna, or deli meats unless they are reheated until steaming hot.
  • Do not eat soft cheeses such as feta, Brie, Camembert, blue-veined cheeses, and Mexican-style cheeses such as “queso blanco fresco” unless it is labeled as made with pasteurized milk. Make sure the label says “Made with Pasteurized Milk”.
  • Hard cheeses, semi-soft cheeses such as mozzarella, pasteurized processed cheese slices and spreads, cream cheese, and cottage cheese can be safely consumed.
  • Do not eat refrigerated pâté or meat spreads. Canned or shelf-stable pâté and meat spreads can be eaten.
  • Do not eat smoked seafood found in the refrigerated section of the store unless it is an ingredient in a cooked dish such as a casserole.

Examples of refrigerated smoked seafood include salmon, trout, whitefish, cod, tuna, and mackerel which are most often labeled as ‘nova-style,” “lox”, “kippered”, “smoked”, or “jerky”. This fish is found in the refrigerated section or sold at deli counters of grocery stores and delicatessens. Canned fish such as salmon and tuna or shelf-stable smoked seafood may be safely eaten.

  • Do not drink raw (unpasteurized) milk or eat foods that contain unpasteurized milk.
  • Use all perishable items that are precooked or ready-to-eat as soon as possible.
  • Clean your refrigerator regularly using hot water and soap.
  • Clean up all spills in your refrigerator right away – especially juices from hot dog packages or raw meat or chicken or turkey.
  • Use a refrigerator thermometer to make sure that the refrigerator always stays at 40º F or below and a freezer temperature of 0º F or below.
  • Wash your hands after you touch hot dogs, raw meat, chicken, turkey or seafood or their juices.

According to the CDC website, “if you have eaten a contaminated product and do not have any symptoms, most experts believe you don’t need any tests or treatment, even if you are pregnant. However, you should inform your physician or healthcare provider if you are pregnant and have eaten the contaminated product, and within 2 months experience flu-like symptoms.”

PGT for miscarriage

Preimplantation Genetic Testing (PGT) is a method used to identify genetic and chromosomal abnormalities in embryos. There are many potential applications for PGD / PGT in the field of reproductive medicine. One of the most exciting uses for PGD / PGT is the ability to decrease the rate of miscarriage.

Miscarriage due to chromosome abnormalities

The vast majority of miscarriages are due to abnormalities in the number of chromosomes contained in the embryo. Many of these are currently detectable by PGT. The biologic process by which embryos receive their chromosomes is complex. Prior to ovulation, an egg has two extra sets of chromosomes. At the time of ovulation, one set of chromosomes is pushed out of the egg into a tiny cell called the first polar body. In an IVF cycle, this occurs when a woman takes the hCG trigger injection. At the time of fertilization, the second extra set of chromosomes is pushed out into the second polar body. This second extra set of chromosomes is essentially replaced by the chromosomes contained in the sperm. When fertilization is completed, therefore, the egg should have contributed one set of 23 chromosomes and the sperm should have contributed one set of 23 chromosomes. Thus, an embryo that contains 23 pairs of chromosomes, for a total of 46, is considered normal or euploid.

Unfortunately, during this complicated process, occasionally an embryo will lose or gain one or more chromosomes. These embryos are abnormal and are called aneuploid. Certain chromosomes seem to be more prone to gain or loss. So for example, embryos with extra copies of chromosomes 13, 18 or 21 occur much more commonly than embryos with extra chromosomes 1, 2 or 3.

PGD miscarriage Trisomy

If an embryo contains an extra or missing chromosome in all of its cells, there are only three possible outcomes for that embryo. Most of these aneuploid, abnormal embryos will never implant into the uterus and produce a pregnancy. If the abnormal embryo does implant, the majority will be lost during the early portion of the pregnancy. This is the most common cause of miscarriage in human beings. If an abnormal embryo does not miscarry, the baby born will have birth defects. One of the most well known birth defects is when an extra copy of chromosome 21 is contained in the embryo. These babies are born with a disorder called Down’s syndrome.

As women age, the percentage of embryos with chromosomal abnormalities increases. This is the primary reason why older women have lower fertility rates, higher miscarriage rates and higher rates of birth defects.

Currently, there is no known method to prevent embryos from developing these chromosome abnormalities. PGD / PGT can be used, however, to detect embryos with these abnormalities before they are placed into the uterus.

Preimplantation Genetic Testing

The PGT method most commonly used to detect the number of chromosomes in an embryo is called Next Generation Sequencing (NGS). This is a rapid and highly efficient technique for accurately determining the number of chromosomes.

Next Generation Sequencing for PGD
Next Generation Sequencing showing an embryo with a missing chromosome

PGT for miscarriage

The couples who are at highest risk for chromosome abnormalities and miscarriages include those in whom the female is older. In fact, the older the female, the higher the rate of abnormalities found and the higher the miscarriage rate. Others at high risk include couples who have had recurrent miscarriage.

PGT for recurrent miscarriage

In 4-5% of couples with recurrent miscarriage, either the male or female has a structural abnormality involving two of their chromosomes known as a translocation. A translocation involves breakage of two chromosomes with the pieces going to the other chromosome. For example, a 13:21 translocation means that a small bit of chromosome 13 is attached to chromosome 21 and a small piece of chromosome 21 is attached to chromosome 13. The individual who carries a translocation may be completely unaffected because the total amount of DNA is normal. This is called a balanced translocation.

However, if a translocation carrier tries to reproduce, the embryos produced may have too much or too little DNA. This is called an unbalanced translocation and will lead to miscarriage.

PGT can be used to detect translocations in embryos.

Next Generation Sequencing showing a translocation in an embryo

In studies of couples with recurrent miscarriage that have a translocation, the risk of miscarriage was reduced by over 90%.

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

alt

Another option is stand.

alt

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.

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.

alt

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.

alt

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.

alt

Wipe the top of the vial with an alcohol swab.

alt

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

alt

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

alt

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.

alt

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.

alt

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.

lovenox_step_4.jpg

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

lovenox_step_5.jpg

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

lovenox_step_6.jpg

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

lovenox_step_7.jpg

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

chorionic-gonadotropin.png

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.

alt

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:

alt

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

alt

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

alt

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

alt

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).

alt

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

alt
alt

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.

alt

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.

alt

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.

alt

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.

alt

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.

alt

Put the cap back on the needle.

alt

Unscrew it from the pen.

alt

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.

alt

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.

alt

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.

alt

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.

alt

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.

IVF1 Flower Pattern

Start Your fertility journey with iVF1 Today.

Schedule A Consultation

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

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

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

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

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

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

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

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

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
IVF1 Testimonial QuotesIVF1 Testimonial Quotes