Selenium is a trace mineral that is essential to good health but required only in small amounts [1, 2]. Selenium is incorporated into proteins to make selenoproteins, which are important antioxidant enzymes. The antioxidant properties of selenoproteins help prevent cellular damage from free radicals. Free radicals are natural by-products of oxygen metabolism that may contribute to the development of chronic diseases such as cancer and heart disease [2,3]. Other selenoproteins help regulate thyroid function and play a role in the immune system [4-7].
What Foods Provide Selenium?
Plant foods are the major dietary sources of selenium in most countries throughout the world. The content of selenium in food depends on the selenium content of the soil where plants are grown or animals are raised. For example, researchers know that soils in the high plains of northern Nebraska and the Dakotas have very high levels of selenium. People living in those regions generally have the highest selenium intakes in the United States (U.S.).
In the U.S., food distribution patterns across the country help prevent people living in low-selenium geographic areas from having low dietary selenium intakes. Soils in some parts of China and Russia have very low amounts of selenium. Selenium deficiency is often reported in those regions because most food in those areas is grown and eaten locally.Selenium also can be found in some meats and seafood. Animals that eat grains or plants that were grown in selenium-rich soil have higher levels of selenium in their muscle. In the U.S., meats and bread are common sources of dietary selenium[9,10].
Some nuts are also sources of selenium. Selenium content of foods can vary. For example, Brazil nuts may contain as much as 544 micrograms of selenium per ounce. They also may contain far less selenium. It is wise to eat Brazil nuts only occasionally because of their unusually high intake of selenium. Selected food sources of selenium are provided in Table 1 .
Table 1: Selected food sources of selenium 
*DV = Daily Value.
DVs are reference numbers developed by the Food and Drug Administration (FDA) to help consumers determine if a food contains a lot or a little of a specific nutrient. The DV for selenium is 70 micrograms (ug). Most food labels do not list a food’s selenium content.
The percent DV (%DV) listed on the table indicates the percentage of the DV provided in one serving. A food providing 5% of the DV or less is a low source while a food that provides 10-19% of the DV is a good source. A food that provides 20% or more of the DV is high in that nutrient.
It is important to remember that foods that provide lower percentages of the DV also contribute to a healthful diet.
For foods not listed in this table, please refer to the U.S. Department of Agriculture’s Nutrient Database Web site: http://www.nal.usda.gov/fnic/cgi-bin/nut_search.pl.
What Is The Recommended Dietary Intake For Selenium?
Recommendations for selenium are provided in the Dietary Reference Intakes developed by the Institute of Medicine .
Dietary Reference Intakes (DRIs) is the general term for a set of reference values used for planning and assessing nutrient intake for healthy people. Three important types of reference values included in the DRIs are
- Recommended Dietary Allowances (RDA)
- Adequate Intakes (AI)
- Tolerable Upper Intake Levels (UL).
The RDA recommends the average daily dietary intake level that is sufficient to meet the nutrient requirements of nearly all (97-98%) healthy individuals in each age and gender group . An AI is set when there is insufficient scientific data available to establish a RDA. AIs meet or exceed the amount needed to maintain a nutritional state of adequacy in nearly all members of a specific age and gender group. The UL, on the other hand, is the maximum daily intake unlikely to result in adverse health effects . Table 2 lists the RDAs for selenium, in micrograms (μg) per day, for children and adults.
Table 2: Recommended Dietary Allowances (RDA) for selenium for children and adults 
There is insufficient information on selenium to establish a RDA for infants. An Adequate Intake (AI) has been established that is based on the amount of selenium consumed by healthy infants who are fed breast milk . Table 3 lists the AIs for selenium, in micrograms (μg) per day, for infants.
Table 2: Adequate Intake for selenium for infants 
Results of the National Health and Nutrition Examination Survey (NHANES III-1988-94) indicated that diets of most Americans provide recommended amounts of selenium . The INTERMAP study examined nutrient intakes of almost 5,000 middle-aged men and women in four countries in the late 1990s, including the U.S. The primary aim of the study was to evaluate the effect of dietary micronutrients on blood pressure. Each study participant completed four, 24-hour dietary recalls, during which they were asked to record everything consumed (food, beverages, and dietary supplements) over the previous 24 hours. Selenium intake was lowest among residents of China, the country with the highest known rate of selenium deficiency. Mean dietary intake of selenium of U.S. participants was 153 μg for men and 109 μg for women. Both values exceed the recommended selenium intake for adults and are further evidence of adequate selenium intakes in the U.S. .
When Can Selenium Deficiency Occur?
Human selenium deficiency is rare in the U.S. but is seen in other countries, most notably China, where soil concentration of selenium is low . There is evidence that selenium deficiency may contribute to development of a form of heart disease, hypothyroidism, and a weakened immune system [16,17]. There is also evidence that selenium deficiency does not usually cause illness by itself. Rather, it can make the body more susceptible to illnesses caused by other nutritional, biochemical or infectious stresses .Three specific diseases have been associated with selenium deficiency:
- Keshan Disease, which results in an enlarged heart and poor heart function, occurs in selenium deficient children.
- Kashin-Beck Disease, which results in osteoarthropathy
- Myxedematous Endemic Cretinism, which results in mental retardation
Keshan disease was first described in the early 1930s in China, and is still seen in large areas of the Chinese countryside with selenium poor soil . Dietary intake in these areas is less than 19 micrograms per day for men and less than 13 micrograms per day for women, significantly lower than the current RDA for selenium . Researchers believe that selenium deficient people infected with a specific virus are most likely to develop Keshan disease [18,19].
Selenium deficiency has also been seen in people who rely on total parenteral nutrition (TPN) as their sole source of nutrition [20,21]. TPN is a method of feeding nutrients through an intravenous (IV) line to people whose digestive systems do not function. Forms of nutrients that do not require digestion are dissolved in liquid and infused through the IV line. It is important for TPN solutions to provide selenium in order to prevent a deficiency . Physicians can monitor the selenium status of individuals receiving TPN to make sure they are receiving adequate amounts.
Severe gastrointestinal disorders may decrease the absorption of selenium, resulting in selenium depletion or deficiency . Gastrointestinal problems that impair selenium absorption usually affect absorption of other nutrients as well, and require routine monitoring of nutritional status so that appropriate medical and nutritional treatment can be provided.
Who May Need Supplemental Selenium?
In the U.S., most cases of selenium depletion or deficiency are associated with severe gastrointestinal problems, such as Crohn’s disease, or with surgical removal of part of the stomach. These and other gastrointestinal disorders can impair selenium absorption [24-26].
People with acute severe illness who develop inflammation and widespread infection often have decreased levels of selenium in their blood . Physicians will evaluate individuals who have gastrointestinal disease or severe infection for depleted blood levels of selenium to determine the need for supplementation. People with iodine deficiency may also benefit from selenium supplementation. Iodine deficiency is rare in the U.S., but is still common in developing countries where access to iodine is limited .
Researchers believe that selenium deficiency may worsen the effects of iodine deficiency on thyroid function, and that adequate selenium nutritional status may help protect against some of the neurological effects of iodine deficiency [6,7]. Researchers involved in the Supplementation en Vitamines et Mineraux AntioXydants (SU.VI.MAX) study in France, which was designed to assess the effect of vitamin and mineral supplements on chronic disease risk, evaluated the relationship between goiter and selenium in a subset of this research population. Their findings suggest that selenium supplements may be protective against goiter, which refers to enlargement of the thyroid gland .As noted above, selenium supplementation during TPN administration is now routine [21,22].
While specific medical problems such as those described above indicate a need for selenium supplementation, evidence is lacking for recommending selenium supplements for healthy children and adults.
Selenium occurs in staple foods such as corn, wheat, and soybean as selenomethionine, the organic selenium analogue of the amino acid methionine [30,31]. Selenomethionine can be incorporated into body proteins in place of methionine, and serves as a vehicle for selenium storage in organs and tissues. Selenium supplements may also contain sodium selenite and sodium selenate, two inorganic forms of selenium.
Selenomethionine is generally considered to be the best absorbed and utilized form of selenium. Selenium is also available in ‘high selenium yeasts’, which may contain as much as 1,000 to 2,000 micrograms of selenium per gram . Most of the selenium in these yeasts is in the form of selenomethionine. This form of selenium was used in the large scale cancer prevention trial in 1983, which demonstrated that taking a daily supplement containing 200 micrograms of selenium per day could lower the risk of developing prostate, lung, and colorectal cancer . However, some yeasts may contain inorganic forms of selenium, which are not utilized as well as selenomethionine.
A study conducted in 1995 suggested that the organic forms of selenium increased blood selenium concentration to a greater extent than inorganic forms. However, it did not significantly improve the activity of the selenium-dependent enzyme, glutathione peroxidase . Researchers are continuing to examine the effects of different chemical forms of selenium, but the organic form currently appears to be the best choice.
Selenium and Cancer
Observational studies indicate that death from cancer, including lung, colorectal, and prostate cancers, is lower among people with higher blood levels or intake of selenium [34-40]. In addition, the incidence of nonmelanoma skin cancer is significantly higher in areas of the United States with low soil selenium content .
The effect of selenium supplementation on the recurrence of different types of skin cancers was studied in seven dermatology clinics in the U.S. from 1983 through the early 1990s. Taking a daily supplement containing 200 μg of selenium did not affect recurrence of skin cancer, but significantly reduced the occurrence and death from total cancers. The incidence of prostate cancer, colorectal cancer, and lung cancer was notably lower in the group given selenium supplements .
Research suggests that selenium affects cancer risk in two ways. As an anti-oxidant, selenium can help protect the body from damaging effects of free radicals. Selenium may also prevent or slow tumor growth. Certain breakdown products of selenium are believed to prevent tumor growth by enhancing immune cell activity and suppressing development of blood vessels to the tumor .
However, not all studies have shown a relationship between selenium status and cancer. In 1982, over 60,000 participants of the Nurse’s Health Study with no history of cancer submitted toenail clippings for selenium analysis. Toenails are thought to reflect selenium status over the previous year. After three and a half years of data collection, researchers compared toenail selenium levels of nurses with and without cancer. Those nurses with higher levels of selenium in their toenails did not have a reduced risk of cancer .
Two important long-term studies, the SU.VI.MAX study in France and the Selenium and Vitamin E Cancer Prevention Trial (SELECT) study in the U.S., are now underway to further investigate the selenium/cancer prevention link.The SU.VI.MAX Study is a prevention trial looking at the effects of antioxidant vitamins and minerals on chronic diseases such as cancer and cardiovascular disease. Doses of the nutrients provided in the study are one to three times higher than recommended intakes, including a daily supplement of 100 μg selenium. The SU.VI.MAX study, which began in 1994, has followed more than 12,000 adult men and women. This study was designed to continue for eight years, and the research community is eagerly awaiting the results of this study .
The SELECT study, a long-term study sponsored by the NIH, is investigating whether supplemental selenium and/or vitamin E can decrease the risk of prostate cancer in healthy men. Past evidence as well as pre-clinical trials for the SELECT study suggests that these two nutrients may be effective in preventing prostate cancer. A daily supplement containing 200 μg of selenium will be given to individuals in the selenium-only study group, while men in the combined-nutrients group will receive a daily supplement containing 200 μg selenium and 400 mg vitamin E. The study, which will span from 2001 to 2013, will include 32,400 healthy adult men .
Selenium and Heart Disease
Some population surveys have suggested an association between lower antioxidant intake and a greater incidence of heart disease . Evidence also suggests that oxidative stress from free radicals, which are natural by-products of oxygen metabolism, may promote heart disease [47-49]. For example, it is the oxidized form of low-density lipoproteins (LDL, often called “bad” cholesterol) that promotes plaque build-up in coronary arteries . Selenium is one of a group of antioxidants that may help limit the oxidation of LDL cholesterol and thereby help to prevent coronary artery disease [47-49].
Currently there is insufficient evidence available to recommend selenium supplements for the prevention of coronary heart disease; however, the SU.VI.MAX study mentioned earlier is looking at the effects of antioxidant nutrients such as selenium on heart disease.
Selenium and Arthritis
Surveys indicate that individuals with rheumatoid arthritis, a chronic disease that causes pain, stiffness, swelling, and loss of function in joints, have reduced selenium levels in their blood [50-51]. In addition, some individuals with arthritis have a low selenium intake .The body’s immune system naturally makes free radicals that can help destroy invading organisms and damaged tissue, but that can also harm healthy tissue . Selenium, as an antioxidant, may help to relieve symptoms of arthritis by controlling levels of free radicals .
Current findings are considered preliminary, and further research is needed before selenium supplements can be recommended for individuals with arthritis.
Selenium and HIV
HIV/AIDS malabsorption can deplete levels of many nutrients, including selenium. Selenium deficiency is associated with decreased immune cell counts, increased disease progression, and high risk of death in the HIV/AIDS population [55,56]. HIV/AIDS gradually destroys the immune system, and oxidative stress may contribute to further damage of immune cells. Antioxidant nutrients such as selenium help protect cells from oxidative stress, thus potentially slowing progression of the disease . Selenium also may be needed for the replication of the HIV virus, which could further deplete levels of selenium .
An examination of 125 HIV-positive men and women linked selenium deficiency with a higher rate of death from HIV . In a small study of 24 children with HIV who were observed for five years, those with low selenium levels died at a younger age, which may indicate faster disease progression . Results of research studies have led experts to suggest that selenium status may be a significant predictor of survival for those infected with HIV .
Researchers continue to investigate the relationship between selenium and HIV/AIDS, including the effect of selenium levels on disease progression and mortality. There is insufficient evidence to routinely recommend selenium supplements for individuals with HIV/AIDS, but physicians may prescribe such supplements as part of an overall treatment plan. It is also important for HIV-positive individuals to consume recommended amounts of selenium in their diet.
What Is The Health Risk of Too Much Selenium?
High blood levels of selenium (greater than 100 μg/dL) can result in a condition called selenosis . Symptoms of selenosis include gastrointestinal upsets, hair loss, white blotchy nails, garlic breath odor, fatigue, irritability, and mild nerve damage .
Selenium toxicity is rare in the U.S. The few reported cases have been associated with industrial accidents and a manufacturing error that led to an excessively high dose of selenium in a supplement [63,64]. The Institute of Medicine of the National Academy of Sciences has set a tolerable upper intake level (UL) for selenium at 400 micrograms per day for adults to prevent the risk of developing selenosis . Table 4 lists ULs for selenium, in micrograms per day, for infants, children, and adults.
Table 4: Tolerable Upper Intake Levels for selenium for infants, children, and adults 
Selecting a Healthful Diet
The 2000 Dietary Guidelines for Americans states, “Different foods contain different nutrients and other healthful substances. No single food can supply all the nutrients in the amounts you need” . For more information about building a healthful diet, refer to the Dietary Guidelines for Americans 
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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
Another option is stand.
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.
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 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.
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.
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.
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
50-100 mg and are taken with meals
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.
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.
Use an alcohol swab to cleanse the rubber stopper of the progesterone medication.
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.
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 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.
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.
Wash your hands thoroughly and make sure that the surface you work on is clean.
Use an alcohol swab to cleanse the rubber stopper of the vial.
Pull the plunger of the syringe back to the appropriate marking.
Pull off the cap of the needle, and pierce the rubber stopper of the Lupron® vial.
Push the plunger all the way in. Keeping the needle inside the bottle, turn the vial upside down. With the needle in the liquid, pull back the plunger, until the syringe fills to the proper mark. Remove the needle from the vial,
With the needle pointing toward the ceiling, flick the side of the syringe to disperse any air bubbles and the air pocket at the top of the syringe.
Gently push the plunger until one or two drops of liquid are expressed to make sure you have eliminated any air.
You are now ready to administer the lupron as a subcutaneous injection.
Click here to learn how to give a subcutaneous injection
Low Dose hCG
IMPORTANT: The low dose hCG should be premixed by the pharmacy. You should receive it on ice and it needs to be kept in the refrigerator. If you have not received your hCG in this way, please notify us immediately!
It is your responsibility to make sure you have received the correct medications. Do not wait until the last minute!
Do not attempt to use hCG for the trigger injection in place of low dose hCG!!!!
Why use Low Dose hCG?
hCG, or human chorionic gonadotropin, is very similar in structure to the pituitary hormone LH (luteinizing hormone). Many experts beleive that in order to optimally stimulate the ovaries for assisted reproduction technologies (ART), medications containing both FSH (follicle stimulating hormone) and LH are necessary.
Since most of the FSH medications used in ART are produced through recombinant DNA technology, they contain no LH activity. Supplementation with LH is problematic since LH is broken down very quickly in the body and therefore has very little effect.
hCG, however, lasts much longer and therefore has greater biologic activity. Very low dose hCG is used as a replacement for LH to help supplement the stimulation during ART cycles.
How do I use Low Dose hCG?
Here are step-by-step instructions for taking low dose hCG injections:
Low dose hCG is injected subcutaneously-or into the fatty tissue under your skin. The primary sites for injection are your abdomen – 2 inches on either side of the navel, and your upper, outer-thigh where the skin is loose. Wash your hands thoroughly and make sure that the surface you work on is clean.
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.
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.
Wipe the top of the vial with an alcohol swab.
Remove the syringe from its wrapper. The needle is already attached to the syringe. Remove the cap from the needle.
Draw the plunger back on the syringe to the mark that you have been instructed.
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.
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.
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.
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.
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.
Hold the syringe like a pencil in your writing hand.
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.
Press the plunger with your thumb until the syringe is empty.
Then pull the needle straight out and release the skin fold.
Point the needle down and away from yourself and others, and then push down on the plunger to activate the safety shield.
Place the used syringe in the sharps collector.
Letrozole (Femara) for Infertility Treatment
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.
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
- 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.
- Call the office on Day 1 of your period.
- Day 2 or 3 – Office visit- Blood test and ultrasound.
- Take the letrozole 2.5 mg tablet on days 5,6,7,8, and 9.
- Start testing urine on the morning of day 10 or 11.
- Look for the first definite color change. Do not continue to test after the color change.
- Have intercourse the same day you see the color change and the next day.
- 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
- Call the office on Day 1 of your period.
- Day 2 or 3 – Office visit- Blood test and ultrasound.
- Take the letrozole 2.5 mg on days 5,6,7,8, and 9.
- Start testing urine on the morning of day 10 or 11.
- Look for the first definite color change. Do not continue to test after the color change.
- Call the office the same morning you see the color change. Have intercourse that night.
- Schedule the intrauterine insemination for the next day (The day after the color change)
- Schedule an appointment approximately one week later for a blood test to verify ovulation
- Schedule an appointment approximately two weeks later for a pregnancy test
Monitoring in the office with intrauterine insemination or intercourse
- Call the office on Day 1 of your period.
- Day 2 or 3 – Office visit- Blood test and ultrasound.
- Take the letrozole on days 5,6,7,8, and 9.
- Day 10 or 11 – Office visit – Blood test and ultrasound. You will receive instructions that afternoon when to return for the next visit.
- Only when instructed – Take the hCG trigger injection in the evening. Have intercourse that evening also.
- Schedule the insemination for 2 (two) days after the hCG trigger . If you are not doing intrauterine insemination, have intercourse again on this day
- 1 week after hCG trigger – Office visit – Blood test only (Progesterone level)
- 2 weeks after hCG trigger – Office visit – Blood test only (Pregnancy test)
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:
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.
Use an alcohol swab to cleanse the rubber stoppers of both vials.
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.
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.
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.
Using your thumb, flip off the plastic cap of the Gonal-F? Multi-Dose 450 IU vial.
Wipe the top of the vial with an alcohol swab.
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.
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.
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
Swirl the mixture gently until it becomes clear. Do not shake.
Wipe the top of the vial with an alcohol swab.
Remove the wrapper from the custom dosing injection syringe. Carefully
loosen and pull the plastic cap from the needle and avoid touching the
With the vial of reconstituted Gonal-f on a flat surface, insert the
needle straight down through the marked center circle of the rubber
Without removing the needle from the vial, turn it upside down so that the needle points upward.
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.
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.
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.
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.
Using your thumb, flip off the plastic cap of the Gonal-F? RFF vial
Wipe the top of the vial with an alcohol swab.
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.
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.
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.
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.
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.
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.
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.
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.
Recap the needle. The administration syringe is now ready. Use immediately.
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
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.
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:
Wash your hands thoroughly and make sure that the surface you work on is clean.
Pull the cap pen off. Unscrew the yellow section from the blue section. Clean the rubber end of the cartridge with an alcohol wipe.
Insert the cartridge with the rubber end down into the yellow section.
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).
Screw the needle securely onto the end of the yellow section.
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.
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.
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.
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.
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.
Put the cap back on the needle.
Unscrew it from the pen.
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 (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 (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.
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.
Each prefilled applicator of Crinone comes individually wrapped within the Crinone box.
Carefully remove the wrapper from the prefilled applicator.
Identify the thick end of the applicator. Grasp the applicator by the thick end but do not squeeze yet.
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.
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.
Squeeze the bubble and the thick end completely. An amount of gel about the size of a dime will be dispensed into the vagina.
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 (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.
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.
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.
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.
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.
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.
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
- Failure of hormones to adequately stimulate the testicles to produce sperm (also known as Pre-testicular)
- Primary testicular failure in which the sperm producing cells in the testicles are either missing or damaged
- 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
- Vas Deferens
- 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
- Surgical correction of the obstruction,
- 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:
- presence or absence of sperm seen during the surgery
- appearance of the vas fluid as seen during the surgery
- quality of the sperm in the vas fluid
- length of the vas segment between the epididymis and the vasectomy site
- presence or absence of a sperm granuloma (a lump of hardened, old sperm sometimes seen after vasectomy)
- age of the female partner.
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.
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.
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:
- congenital (present at birth)
- scarring from infections
- 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:
- The amount of sperm obtained is usually very small
- 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
- MESA – Microsurgical Epididymal Sperm Aspiration
- PESA – Percutaneous Epididymal Sperm Aspiration
- TESE – TEsticular Sperm Extraction
- TESA -Percutaneous Testicular Sperm Aspiration
- VASA – VAsal Sperm Aspiration
- 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:
- Direct toxic effects on the testicles,
- Disruption of the pituitary gland and its stimulation of the testicles,
- Direct effects on ejaculation and/or erectile function,
- Decrease in libido (sex drive)
- 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.
Blood pressure medication
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)
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.
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 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.
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.
Most varicoceles can be corrected through a surgical procedure called varicocelectomy ( surgically “tying off” the affected veins). The following methods are used.
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 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.
An alternative to tying off the veins is blocking the blood flow to the veins.
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.
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.
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:
- Crouzon’s syndrome
- Pfeiffer’s syndrome
- Apert’s syndrome
- Thanatophoric dysplasia
- Osteogenesis imperfecta
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
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.
Increasing male age may cause a decrease in fertility if the female is also older. The chance for miscarriage also seems to increase but the mechanism is not due to the most common reason for miscarriage which is numerical chromosome abnormalities. The overall impact of male age is far less than the impact of female age. Several diseases caused by gene mutations as well as several with multiple genetic and environmental causes are related to increasing paternal age. Despite these increased risks, the absolute risk of the diseases remains small.
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