Ovarian reserve is an expression of the number and quality of eggs available for conception. As a parameter for predicting pregnancy, ovarian reserve testing is often part of a fertility evaluation. Such testing requires specific measurement, and clinical judgment to interpret the results.

Egg numbers are at a maximum before birth, at around 20 weeks gestation. After birth, there is a progressive decline in the number of eggs from roughly one million at birth to 300,000 at puberty. Through the reproductive years the remaining eggs are lost, with the rate accelerating around the mid-30s, resulting in few eggs left at menopause, around age 50-52. The number of eggs available for reproduction at a certain age is the ovarian reserve, which is the target of the diagnostic tests described here.

Age is the most accurate predictor of egg health, but within age groups, there is considerable variation in the number of eggs remaining for reproduction. Age alone as a predictor of ovarian reserve is not sufficient, since, for individuals, fertility may be better or worse than the average for that age. Extreme examples of this variability include the teenager in menopause and the 59 year-old that delivered a natural pregnancy in 1997. This variability in pregnancy rates within an age group is present in all reproductive age groups.

To predict an individual woman’s fertility rate, in addition to her age, both clinical and laboratory methods are available to evaluate ovarian reserve. The best tests are direct measures of the ovary, such as the Antral Follicle Count (AFC) and Anti-mullerian Hormone (AMH) level; indirect measures, such as clinical history and levels of pituitary hormones, are common tools for prediction of ovarian reserve.

The simplest method of predicting fertility rates is clinical history, of both the individual and her closely related family. The number of months spent attempting to conceive predicts fertility. A couple that has been trying for some time will naturally have a lower fertility rate than a woman that has not had unprotected intercourse. Response to ovarian stimulation can also be used as a marker, as it is fairly consistent between cycles. Family history, i.e., the fertility of the woman’s mother or sisters reflected in age at menopause and age at conception are useful predictors. Such factors from clinical history can help define the risk of a problem with ovarian reserve.

Ultrasound is a useful tool for predicting ovarian reserve, as in measuring the Antral Follicle Count (AFC). Antral follicles are the smaller follicles, visible on ultrasound, between 2 and 10 mm, that are lost as a woman ages. In younger women, the AFC is 10-20, declining by 5% per year through age 37, and then accelerating to a loss of 10% per year thereafter. Women show a fairly consistent AFC loss rate of one follicle every two years.

AFC predicts the response to ovarian stimulation at least as well as blood tests, but its ability to predict pregnancy outcomes is limited, particularly when low. A woman with a higher AFC will show a better response to fertility drug treatments. A high AFC seems to predict pregnancy rates, but data remains limited, as there are no prospective studies published. A low AFC seems to be a less accurate predictor of ovarian reserve, particularly in older age groups. AFC may help predict outcomes, but should not be used to exclude patients from treatment.

Anti-mullerian hormone (AMH) is a blood test that directly measures ovarian reserve. Produced directly by early stage ovarian follicles, high levels (over 1.0) are favorable, while low levels (less than 1.0) indicate decreased ovarian reserve. AMH may be the best measure of the menopausal transition and ovarian age. It may also be useful in predicting ovarian hyperstimulation syndrome, the effects of chemotherapy, and in determining the treatment of PCOS.

AMH seems a superior predictor of ovarian response compared to other markers, including age, and day 3 FSH and estradiol. It offers similar predictive value compared to AFC. AMH can be drawn at any time in the menstrual cycle, and is not affected by hormonal therapy, including oral contraceptives.

AMH still requires further study. The range of normal variation is still being determined, and the true predictive value of the test requires a great deal more analysis. The specific range of reliability and predictive value by age is yet to be established.

Cycle day three FSH and estradiol, and, to a lesser extent, the clomiphene challenge test, remain viable tests for estimating ovarian reserve. These tests are established as predictors of response to ovarian stimulation. Prediction of pregnancy rates is more difficult. Recent studies concentrating on the predictive value of these tests have shown that they cannot be used to determine which patients cannot conceive, but are useful for screening and counseling.

All in all, these tests are only rough predictors of ovarian reserve. They are moderately good predictors of ovarian response to stimulation, and relatively poor predictors of pregnancy outcome. In a particular patient, the tests can be used to counsel about potential response to ovulation induction, but it remains difficult to predict pregnancy outcome based on the test results.

The ultimate test of ovarian reserve is response to treatment and whether a pregnancy results from that treatment. Stay tuned as we evaluate further research to establish the validity of ovarian reserve testing methods.

At Pacific Fertility Center we aim to help our patients build a healthy family. To build healthy families, maximum pregnancy rates are a goal, but maximum pregnancy rates must be balanced by consideration of risk, the chance of an adverse outcome. High pregnancy rates with minimal risk is PFC’s goal.

The risk of multiple pregnancy has increased as fertility therapy has improved. The wider use of gonadotropins in the 1990s to induce ovulation of multiple follicles, as well as the use of more effective laboratory and clinical IVF methods, resulted in production of more and healthier oocytes and more embryos, and increased the chances of multiple pregnancy. The very dramatic improvement in success rates over this time period resulted in many more children being delivered after fertility therapies, but also more twins, triplets, and higher order multiples.

Over the last twenty years, the incidence of multiple birth has increased nationally. According to the National Vital Statistics Report and the March of Dimes, the incidence of twins has increased by two-thirds, and the number of triplets and quadruplets has increased four-fold since 1980.

It is thought that about one-third of multiple pregnancies arise because women are waiting until later in life to conceive; age is a well-known risk factor for multiples. Another third arise from use of ovulation induction with gonadotropins (Pergonal, Follistim, Gonal-F, Repronex) alone. Less than one fifth of multiples are from assisted reproduction techniques (IVF and related procedures). Assisted reproduction in 2003 accounted for 18% of multiple pregnancies, 16% of twins and 44% of triplets ¹.

The risks to the children of multiple pregnancy are numerous. Low birth weight and very low birth weight are increased in children born as multiples. The chance of low birth weight (<2500g) is increased 8 times in twins. Cerebral palsy is increased 4 times, neonatal death risk by 7 times ^{2, 3}.

The risk to the mother from multiple pregnancy is also increased. Pre-eclampsia, high blood pressure, preterm labor, and premature rupture of membranes are all more common with multiple pregnancy ⁴ .

Multiple pregnancy is also expensive. It is estimated that twins alone cost the healthcare system some $600,000,000. There is clear evidence of an increase in parenting stress and divorce in families of multiples ^{5, 6} .

The need to assure our patients of the highest quality care requires that we bear this in mind – the healthiest pregnancy is a singleton pregnancy.

Pregnancy requires the cooperation of sperm and egg, accurate transcription of the early genetic code in the developing embryo, a fertile spot for attachment to the mother in the uterus, and a route for getting there. All other factors being equal, pregnancy rates almost double when two embryos are transferred instead of one, and increase again when a third and fourth embryo are added. The desire for high pregnancy rates has driven a desire for more embryos to be transferred ⁷ .

Improvements in insemination technique, embryo culture methods, and transfer efficiency have added substantially to pregnancy rates. Each embryo transferred today has a considerably higher chance of producing a pregnancy than an embryo transferred twenty years ago. Such improvements have enabled us to think about ways to reduce the risk of multiple pregnancy by transferring fewer embryos.

The development of blastocyst (day 5 embryo) culture techniques allows the selection of high quality embryos for transfer. The blastocyst stage requires advanced incubation techniques with low oxygen incubators and specialized culture media. A tight quality control system is also required. The blastocyst stage is a more advanced stage in which the genetic code of the embryo is fully activated and working. Only the healthiest of embryos can move to the more advanced stages, allowing selection of the best embryos for transfer.

In 2006 the ASRM published guidelines for number of embryos to transfer:

These guidelines encourage all of us to transfer ‘just enough’ embryos to achieve pregnancy.

Pacific Fertility Center has pioneered techniques of transferring fewer embryos. Last year, in 2007, our program of single embryo transfer in oocyte donation recipients produced a 66% pregnancy rate. The multiple pregnancy rate in this group was minimal. Utilizing a single embryo, two-thirds of patients were able to conceive a singleton pregnancy. This pregnancy rate was very similar to the overall pregnancy rates regardless of the number of embryos transferred.

Today half of our patients using oocyte donation elect to transfer a single embryo. Single embryo transfer is not always possible. Our criteria include age and embryo quality. A young woman (under age 35) with high quality blastocyst stage embryos and a healthy uterus can reliably transfer a single embryo and achieve high pregnancy rates. An older woman (over 40) may need to transfer 3 or more embryos to achieve a good pregnancy rate. Because of the higher number of embryos transferred, the risk of multiple pregnancy remains higher in these older age groups⁹ .

Pacific Fertility Center is very pleased to offer these techniques of single embryo transfer as some of the best and most advanced fertility treatment technology available. We are moving closer to our goal of growing families, one healthy baby at a time.   Philip Chenette, MD

1. Martin, Births: Final Data for 2003. National Vital Statistics Reports, volume 54, number 2, 2005
2. Scher, Ped Res, Vol. 52:671-81, 2002
3. Rutter, J Child Psychol Psych, Vol. 44:326-41, 2003
4. Pinborg, Human Reproduction, Vol. 18:1234-43, 2003
5. Griesinger, Hum Reproduction, Vol. 19:1239-1241, 2004
6. Glazebrook, Fertil Steril, Vol. 81:505-11, 2004
7. Paulson RJ, Fertil Steril., Vol. 53:870-874 , 1990
8. Fertil Steril, Vol. 85, Suppl. 4, 2006
9. Pacific Fertility Center 2007 IVF Statistics

Interested in self-diagnosis of fertility? The ability to screen for fertility in private, on one’s own schedule, with an at home diagnostic kit is an appealing option. A company from the UK, Genosis, has developed such a kit, called Fertell.

Fertell is a testing kit that offers a basic assessment of male and female fertility.

Fertell for the male is a specimen collection and testing kit that measures the concentration of motile sperm. A sperm specimen is collected into a cup and allowed to liquefy and then warmed to body temperature. Motile sperm pass through a filter and are colored red by exposure to a gold-coated antibody. Appearance of two red lines in a testing chamber indicates a sperm count over 10 million total motile.

Fertell for the female is a conventional urine test strip very similar to an ovulation prediction kit. The female places the absorbent tip in her urine stream for 5 seconds. FSH in the urine reacts with antibodies on the test strip and shows as a red line in the result window. The intensity of this line reflects the FSH concentration (the darker the line, the more FSH present in urine). High FSH levels are indicated by two dark red lines.

Traditional semen analysis measures sperm volume, count, and motility. Multiplied together, these numbers yield the total motile sperm count, that is, the number of moving sperm in the ejaculate. Total motile sperm count is a reasonable predictor of fertility for men. Fertell establishes that the sperm count is over a specific value of 10 million total motile, a reasonable threshold for male fertility.

The male test kit is not able to determine subtle gradations of male fertility. It cannot detect the effects of treatment or change in lifestyle that may cause improvement in sperm count, nor can it detect alterations in sperm morphology (shape). More sophisticated testing is available at a sperm lab.

The female test kit is used as a screening test, and cannot detect subtle gradations in FSH levels, or the relationship of FSH to other important hormones such as estradiol. Such issues have dramatic effect on the patient’s prognosis.

Neither of these tests can replace an expert’s opinion. An expert’s ability to interpret test results with a broad knowledge base and experience remains the best way to diagnose and treat infertility problems.

Of primary importance is that, while both test kits have been correlated with existing assays, neither has been evaluated for its ability to predict pregnancy. Such research takes time, and hopefully will be forthcoming. For now, Fertell is an interesting option for those seeking a private screening assessment of their fertility.

Every year, several Pacific Fertility Center professionals participate in ASRM’s national meeting. They evaluate the research and share their findings with PFC and Fertility Flash.

Among those attending the conference from PFC were Dr. Philip Chenette and Dr. Isabelle Ryan and Peggy Orlin, MFT. Their reviews cover the following topics: Update #1: Ovarian Stimulation Techniques, Update #2: PGD and Aneuploidy Screening Techniques, Update #3: Egg Freezing, Update #4: Acupuncture, and Update #5: Men and ART.

ASRM Update #3: Egg Freezing

Oocyte cryopreservation is the storage of the female gamete, the egg, prior to fertilization. Preservation of fertility for single women that must undergo cancer therapy or surgery, or that must delay or choose to delay childbearing, and donated oocyte banking are all applications of oocyte cryopreservation. The need for this technology is clear, but reports of success with oocyte cryopreservation have been limited.

Highly successful oocyte cryopreservation is now attainable. New studies are showing pregnancy rates with oocyte cryopreservation that are equal to traditional IVF techniques.

The key to this technology is oocyte vitrification – an ultrarapid cryopreservation technique. Researchers from Atlanta described their experience with vitrification. Out of 11 patients with transfers, nine conceived, with an implantation rate of 65%.

Pregnancies after oocyte cryopreservation have developed normally. An Italian study of 105 children born after oocyte cryopreservation showed no problems. A Chicago study of the genetics of oocytes, embryos, and children born after oocyte cryopreservation was reassuring. No increase rates of aneuploidy or malformations were reported, and normal development was found in post-natal follow-up.

These results are similar to those we have previously reported from our own research at Pacific Fertility Center (see December 2007 Fertility Flash). Oocytes are now cryopreserved with high success rates. Oocyte cryopreservation technology has matured, and we look forward to providing these techniques for our patients.

Philip Chenette, MD

Every year, several Pacific Fertility Center professionals participate in ASRM’s national meeting. They evaluate the research and share their findings with PFC and Fertility Flash.

Among those attending the conference from PFC were Dr. Philip Chenette and Dr. Isabelle Ryan and Peggy Orlin, MFT. Their reviews cover the following topics: Update #1: Ovarian Stimulation Techniques, Update #2: PGD and Aneuploidy Screening Techniques, Update #3: Egg Freezing, Update #4: Acupuncture, and Update #5: Men and ART.

Update #2: PGD and Aneuploidy Screening Techniques

Preimplantation genetic diagnosis (PGD) has been one of the hallmark technologies of modern reproductive medicine. The ability to look inside a cell, beyond its visual appearance to the actual genes controlling the cell, has provided insight into the workings of the embryo and a valuable clinical tool to improve fertility care.

The most common use of PGD is to count chromosomes using FISH probes. Using labels that glow under ultraviolet light, a limited number of chromosomes can be identified and counted. Missing or duplicated chromosomes are indicators of abnormalities in the embryo, a condition known as “aneuploidy.” FISH has a significant error rate, and while clinically useful, results must be interpreted with caution.

A new technique discussed at the ASRM meeting is SNP analysis. SNPs are common tags in DNA that can be measured by automated systems. Microarrays of thousands of SNPs have been prepared that provide a clear picture of the chromosome structure of a cell. Microarray-based aneuploidy screening has excellent reliability and accuracy, and holds enormous promise for identifying genetically normal embryos. This study represents the first validated method of analyzing the entire set of chromosomes in a single cell. Stay tuned for more on this exciting technology.

Array CGH uses thousands of very small DNA probes along with computer software to describe the structure of DNA in a single cell. A very sensitive test, it is fast enough to be used during an IVF treatment cycle, and far more accurate than conventional fluorescent probe (FISH) analysis. Array CGH may lead to improved IVF outcomes as embryos containing an error in any chromosome can be detected, which would allow better selection of healthy embryos.

PGD has proven useful for the treatment of recurrent miscarriage. In an analysis of 279 patients with recurrent miscarriage (women who had previously experienced 3-5 miscarriages), researchers in New Jersey found an improved miscarriage rate of 19.5% after PGD versus their 40.9% expected rate.

Philip Chenette, MD

Every year, several Pacific Fertility Center professionals participate in ASRM’s national meeting. They evaluate the research and share their findings with PFC and Fertility Flash.

Among those attending the conference from PFC were Dr. Philip Chenette and Dr. Isabelle Ryan and Peggy Orlin, MFT. Their reviews cover the following topics: Update #1: Ovarian Stimulation Techniques, Update #2: PGD and Aneuploidy Screening Techniques, Update #3: Egg Freezing, Update #4: Acupuncture, and Update #5: Men and ART.

Update #1: Ovarian Stimulation Techniques: Changes in ovarian stimulation techniques evolve as a better understanding of the medications and their effects on eggs and ovaries develops.

Letrozole (Femara) is increasingly being used as a mild stimulation for ovarian follicle growth and as an additional medication with gonadotropins (e.g. Follistim). In a study on the use of letrozole in preparation for IVF in breast cancer patients, a group from New York showed that breast cancer recurrence or the incidence of invasive carcinoma in the opposite breast does not appear to be increased after stimulation using letrozole and FSH for fertility preservation.

For patients with PCOS, researchers from France compared stimulation with a GnRH agonist, similar to Lupron, with oral contraceptives plus agonist. In these preliminary results, dual suppression does not provide any obvious effect in harmonizing the group of developing follicles nor in improving the quality of oocytes and embryos. This study is still ongoing in order to test these results in a larger population.

In patients that produce an excessive number of follicles in response to stimulation, ovarian hyperstimulation syndrome (OHSS) is possible. To prevent this, the fertility drugs are sometimes stopped mid-stimulation; the follicles are “coasted” – they grow without stimulation, with a lower risk of OHSS. An alternative to “coasting” is the use of Ganirelix, a GnRH antagonist, in a “salvage protocol.” Probability of live birth with the Ganirelix salvage protocol was similar to controls. High-grade embryos were more common with this regimen, in contrast to “coasting”. The miscarriage rate was slightly higher, but not statistically significant. These results suggest that the Ganirelix salvage regimen is a superior alternative to “coasting” in women at risk for OHSS.

A group in Montpelier, France is interested in gene expression in the follicle after use of fertility drugs. Using gene chips they measured gene expression in patients exposed to urinary FSH products and recombinant FSH. Significant differences were found meaning that different genes are being expressed in follicles of women receiving pure FSH (Gonal-f or Follistim) as compared to genes being expressed in follicles of women receiving urinary FSH (Repronex or Menopur)– the meaning of these changes will have to await further study.

On the other hand, a long debate about the effectiveness of urinary and recombinant FSH products is a bit closer to resolution. A meta-analysis from a group in Egypt examined pregnancy outcomes and risks in a group of previously published studies. No significant differences were found. Their conclusion was that urinary gonadotropin (hMG) is as effective as recombinant gonadotropin with regards to clinical outcomes and patient safety.

Philip Chenette, MD

Introduction

Sara (a hypothetical patient) found a breast lump. 36 years of age, she was a single active professional, otherwise healthy, careful about her diet, and carefully evaluating her options after a diagnosis of breast cancer. Along with the discussion on surgery, chemotherapy, and radiation therapy came the question “Were you planning to have children?”

A diagnosis of cancer presents many decisions that must be made quickly. Confirming the diagnosis and planning therapy will be the primary concerns, but the implications of therapy on long-term quality of life must be assessed. One of the primary issues facing women with a diagnosis of cancer is future fertility.

Candidates

Cancer treatment can interfere with future fertility. Toxicity varies by treatment. Cyclophosphamide, an alkylating agent used in many chemotherapy regimens, is highly toxic to sperm and eggs; methotrexate and 5-flouro-uracil (5FU) are not. Medications used for longer time intervals create a higher risk of fertility problems than shorter time intervals; effects on women in older age groups are more severe than younger. Radiation therapy, in high doses, can have effects on eggs and sperm. Surgery and anesthesia are not known to have direct effects.

It is difficult to give specific fertility risks for chemotherapeutic regimens, since studies are not yet definitive. Among the more toxic treatments are stem cell transplantation for leukemia in which total body irradiation and cyclophosphamide are used, beam radiation to a field that includes the ovaries, and extended chemotherapy of up to 6 cycles using cyclophosphamide in combination with other agents. After conventional chemotherapy for breast cancer for women under 40, the chance of infertility is roughly 50%, in older women the risk is over 80%.

Treatment options

What are the options for fertility in patients diagnosed with cancer? The best choices are available to those that have not yet initiated treatment and involve cryopreservation. During treatment, the risk of problems rises, and after treatment, there may not be adequate recovery of fertility to achieve pregnancy.

Cryopreservation allows cells to be stored with great stability for long periods of time. The record time from sperm cryopreservation to pregnancy is 28 years; there probably is no real limit to the time that cells can be stored. To store cells requires technology that reduces the formation of ice crystals, which disrupt cells, and prevents the rapid rise in salt concentration that occurs as water freezes. Cryopreservatives and management of temperature changes (slow freeze or vitrification) are used to reduce the risk of these problems.

Male

The option for fertility preservation in men is straightforward, cryopreservation of sperm. Sperm is obtained by masturbation and frozen in multiple vials in liquid nitrogen. 2-3 sperm samples can be obtained per week, with 2-4 vials stored per ejaculate; two weeks worth of donations could yield 8-24 vials of sperm. Costs vary widely, but would range from $1500-$3000 for processing and 3 years of storage.

Testicular sperm extraction is an option for individuals with azoospermia. Testicular tissue cryopreservation remains a theory that has not yet produced a human pregnancy. It has been proposed as an option for preservation of fertility in children, but has yet to be proven in clinical practice.

Female

Women have the option of cryopreservation of oocytes or embryos. For women without a partner, oocyte cryopreservation holds promise as a means to preserve fertility potential without committing to a specific sperm source or partner. For women with a partner or sperm donor, embryo cryopreservation is a proven technology.

To create cryopreserved oocytes, Follicle Stimulating Hormone (FSH) is administered over a ten day time period to stimulate ovarian follicles. The oocytes are retrieved under sedation with a needle guided by ultrasound and then stored in liquid nitrogen.

Newer techniques of oocyte vitrification secure good pregnancy rates for those with good oocyte quality. Traditional oocyte cryopreservation is performed using a slow freeze technique, but more rapid vitrification procedures optimize results. The trick with cryopreservation is to lower the temperature while avoiding ice crystals that disrupt cell membranes and proteins. Vitrification, an ultrarapid freezing process utilizing a minimal fluid volume, reduces the risk of these problems and optimizes cell quality.

For those women with a partner, or that are willing to commit to a specific sperm donor, embryo cryopreservation is an excellent option. After stimulation and retrieval, oocytes are inseminated and cultured in an incubator for 1-5 days, followed by cryopreservation. The embryos can be thawed and transferred at a later date, after clearance from the oncologist. Embryo cryopreservation is the best established of the fertility preservation techniques, with years of experience in its applications. Good pregnancy rates can be anticipated.

Ovarian tissue cryopreservation, the cryopreservation of whole pieces of the ovary, as opposed to cells, remains experimental. Complex tissues are more difficult to cryopreserve than cells, though rare success has been reported.

Cancer recurrence

Is there risk to the use of fertility drugs in patients with cancer? It does not appear in studies to date that breast or ovarian cancer risk is affected by use of fertility drugs. Studies indicating an increased risk are balanced by other studies indicating a reduction in risk. Studies to date have been limited, and treatment decisions still must be individualized.

Does pregnancy increase the risk of cancer recurrence? In theory, certain types of cancer could be aggravated by the hormones of pregnancy, but studies have not confirmed an overall risk. Certain types of cancer are less common in women that have delivered a pregnancy. Treatment decisions must be individualized, as future studies gather more information.

Pregnancy

Certain cancer treatments create organ toxicity that must be evaluated in considering patients for pregnancy. Heart output is limited in patients that have received doxorubicin. Uterine irradiation is associated with miscarriage and pre-term labor.

Children

Children born after fertility preservation procedures do not carry any increased risk for birth defects. There are hereditary syndromes that can be associated with cancer that could be transmitted to children, but there does not appear to be any other increased risk for cancer or genetic disease in children of cancer survivors.

Patients contemplating conception must consider life span expectations as part of their decision on whether to conceive. Such considerations are not, however, a reason to withhold treatment, and are ultimately the individual and family should decide.

Philip E. Chenette, MD

Resources:

www.fertilehope.org Fertile Hope

www.livestrong.org Lance Armstrong Foundation

www.cryobank.com California Cryobank

www.PacificFertilityCenter.com Pacific Fertility Center

The Trans fat, found in processed foods, may play a role in infertility. Implicated in prostate cancer, heart disease, and diabetes, and long thought to be a significant hindrance to good health, trans fat has been associated with ovulation disorders, according to a new publication¹.

Trans fats are created in food processing. To avoid rancidity in foods, manufacturers heat oils under pressure to convert natural unsaturated fat to partially saturated fat, adding hydrogen molecules to change the bonds between carbon atoms in the long fatty molecule. Saturated and partially saturated fats are sometimes called partially hydrogenated fats. Saturated fats melt at a higher temperature, and are more stable on the grocer’s shelf. Partially saturated fat is resistant to oxidation and damage, melts at a higher temperature, and does not take on rancid odors and taste. Crisco, partially saturated cottonseed oil, was the first commercial product to be produced with the technique in the early 1900s.

Foods prepared with partially saturated fats can contain up to 45% trans fats. French fries, cheeseburgers, fried chicken, cookies, and chips are common offenders. An order of large French fries can contain 15g of trans fat. Oreo cookies contained trans fat until a lawsuit in 2003 induced Kraft Foods to alter its recipe.

Ideal for a manufacturer interested in long-term storage, saturated fats are not so well tolerated by the human body. Raising levels of LDL and lowering levels of HDL cholesterol, saturated fats have been implicated as a prime cause of the rising risk of coronary heart disease through the 20th century. According to the Nurses’ Health Study², each 2% increase in trans fat calories doubles the risk of coronary artery disease. Since trans fats carry no health benefits and are potentially risky, experts have recommended reducing trans fats to trace amounts in the diet.

Infertility has been associated with trans fat intake. A study published in the January issue of American Journal of Clinical Nutrition from a group of researchers at Harvard University found that women with ovulation-related fertility problems tended to eat more trans fats than fertile women. Obtaining just 2 percent of total calories from trans fats was associated with a doubled risk for this type of infertility. The study showed that each 2% increase in dietary trans fat calories was associated with a 73% increased risk of ovulatory infertility³.

It has been difficult to separate out the effects of total fat and trans fat, since a diet high in trans fat diet is often high in total fats. In contrast to trans, higher total fat is known to decrease the risk of ovulation problems, improving ovulation, whereas women with a diet high in trans fat have an increased risk of ovulation disorders.

Dietary fats have been linked to markers of inflammation, a possible mechanism of trans fat effects⁴. In a randomized crossover study, 50 men consumed diets for five weeks that varied in trans fat content. Inflammatory protein markers were higher in men after the trans fat diet, showing that dietary fatty acids can modulate markers of inflammation.

The data is preliminary, but concerning. Since trans fats have no benefit and carry potential risks, they are best limited in the diet. Labeling requirements now include listing of trans fat content for foods. Lawmakers in several major US locales have passed regulations banning trans fats. Tiburon, California, on a voluntary basis was the first city to have trans fat free restaurants. Restaurants in New York City and Philadelphia are barred from using trans fat containing frying oils and spreads. The ban will be expanded to all restaurant foods next year. California is considering a statewide ban on trans fats.

Reducing processed foods and avoiding trans fats in your diet is an excellent goal for all, but patients with infertility may have special concerns. While more research is required regarding infertility and diet, there is no question a healthy diet is important. A diet of diverse and balanced carbohydrates, proteins, and fats, including omega-3 fats, will provide personal and possibly reproductive benefits for years to come.

Philip Chenette, MD

References:

1. Chavarro JE et al., May 2007, A prospective study of dairy foods intake and anovulatory infertility, Human Reproduction, 22 (5): 1340-1347.

2. Hu, FB et al. 1997 “Dietary fat intake and the risk of coronary heart disease in women”. New England Journal of Medicine, 337 (21): 1491-1499.

3. Chavarro JE et al., January 2007, Dietary fatty acid intakes and the risk of ovulatory infertility. American Journal of Clinical Nutrition, 85 (1), 231-237.

4. Baer DJ et al., June 2004, Dietary fatty acids affect plasma markers of inflammation in healthy men fed controlled diets: a randomized crossover study. American Journal of Clinical Nutrition, Vol. 79, No. 6, 969-973.

Sperm are clearly sensitive to environmental conditions. It is possible, through changes in lifestyle and activity, to improve sperm health. The studies available to evaluate environmental effects are unfortunately limited, but they offer insight into sperm sensitivity and ways to optimize their performance.

Temperature The scrotum where sperm are produced is 2 degrees lower than core body temperature. Raising the temperature by a few degrees results in a decline in sperm count and motility. Men suffering from cryoptorchidism, where the testicles are located above the scrotum, closer to central body temperatures, frequently suffer from low sperm counts. Infertile men tend to have a higher scrotal temperature⁽¹⁾, a characteristic that seems to be genetically determined⁽²⁾.

Common illnesses and every day activities can be sources of an increase in scrotal temperature. Acute fever associated with illness causes a significant decline in sperm quality⁽³⁾. In one study, total sperm count decreased within two weeks after a fever and required 79 days to return to normal. The DNA component of these sperm showed high levels of DNA fragmentation. Researchers in France installed temperature sensors to nine volunteers, and recorded scrotal temperatures while driving⁽⁴⁾. Scrotal temperature increased gradually over several hours, peaking 2.5 degrees higher at three hours. Another study showed that scrotal temperature was lowest while standing naked, and highest while clothed, seated, with legs crossed⁽⁵⁾. Higher scrotal temperatures have been associated with use of a laptop computer⁽⁶⁾. A group in Germany looked at scrotal temperatures with a variety of underwear⁽⁷⁾. As expected, tight underwear increased the temperature more than loose or no underwear. The effect was most pronounced while walking and less noticeable while sitting, since sitting temperature was somewhat elevated regardless of type of underwear worn.

The common sense approach is to avoid activities which can increase scrotal and testicular temperature, use loose-fitting underwear, and provide adequate ventilation to the scrotum. Exposure to hot tubs or saunas should be avoided. Take showers rather than baths, because heat conductance is lower when the testicles are not immersed in hot water. Sitting or driving for extended periods should be minimized.

Stress The effects of stress on sperm are complex. Under conditions of extreme stress, sperm counts decline. Analyses of prisoners awaiting sentencing have shown complete suppression of spermatogenesis on testicular biopsies⁽⁸⁾. A study of semen characteristics after the Slovenian war in 1991 showed a reduction in sperm count and motility, and a reduction in the proportion of male children born⁽⁹⁾. In 1995 a strong earthquake of magnitude 7.2 on the Richter scale occurred in Kobe, Japan killing 5,502 people. Sperm motility declined immediately, with low motility lasting for months⁽¹⁰⁾. The sperm of a man who lost his home and his father had still not recovered 10 months after the earthquake.

Stress associated with fertility therapy affects sperm and sexual function. Sperm parameters may decline in patients undergoing in vitro fertilization⁽¹¹⁾. Male fertility patients have a higher incidence of erectile dysfunction, ejaculatory disorders, loss of libido and a decrease in the frequency of intercourse⁽¹²⁾. One study of infertility patients showed an increase in burnout in male patients⁽¹³⁾.

Unfortunately, studies of the effect of stress reduction on sperm are rare,^(14)(15) so the treatment of stress has not been conclusively shown to improve sperm parameters⁽¹⁶⁾. In spite of the lack of clear data, stress reduction therapy is recommended for fertility patients and may reduce problems with sexual dysfunction.

Exercise The risk of developing male fertility problems appears to increase with the intensity of exercise. Intense exercise, such as endurance running, will lower levels of luteinizing hormone (LH) and testosterone.^(17)(18) Studies of semen characteristics have shown variable results. DeSouza⁽¹⁹⁾ developed the concept of a training volume threshold, in which running more than 100 km or 62.14 miles per week was associated with decreased levels of testosterone and sperm motility.

A detailed prospective study comparing competitive cyclists and triathletes with sedentary controls⁽²⁰⁾ was unable to show any suppressive effect of competitive exercise on FSH, LH, or testosterone levels. Although those with the highest levels of training had higher levels of circulating testosterone at baseline, these levels did not change with training. Competitive cyclists developed lower sperm motility during competition, however, motility values returned to normal following competition.

The best advice regarding exercise and sperm is moderation. While attempting conception, it is not advisable to undergo high intensity sports training. Good nutritional standards should be always be maintained when following an exercise program. An existing maintenance exercise program may be continued without concern for its effects on sperm.

Diet is a difficult topic to study in isolation, so fertility data is limited. A recent study of beef consumption showed that maternal consumption⁽²¹⁾ of beef resulted in lower sperm concentrations in sons. The proportion of men with low sperm counts was three times higher in the sons of women that consumed high levels of beef. Lifestyle, pesticide exposure, and xenobiotics (chemicals found in organisms that are foreign to them) were all considered potential factors. Heterocyclic amines (carcinogenic chemicals formed from the cooking of muscle meats), which are estrogenic, may also play a role⁽²²⁾.

Alcohol has long been associated with male reproductive dysfunction. Impotence, infertility, and male secondary sex characteristics are all affected by chronic alcohol use. Testosterone levels are lower, sperm production is reduced, and FSH and LH levels are affected⁽²³⁾. A study of chronic alcoholics demonstrated low levels of pituitary and testicular hormones, and significantly decreased sperm concentration and morphology⁽²⁴⁾. Sperm chromosomes are altered in men that consume alcohol⁽²⁵⁾.

Little data exists on the moderate consumption of alcohol. Data from the Ontario Farm Family Health Study did not show an adverse effect of alcohol consumption⁽²⁶⁾. In another study, alcohol or cigarette consumption did not alter sperm parameters, but when patients both smoked and drank alcohol a significant reduction in seminal volume, sperm concentration, percentage of motile spermatozoa, and a significant increase of the nonmotile viable gametes were detected⁽²⁷⁾.

Smoking tobacco affects sperm parameters, with reduced sperm counts, motility, and morphology reported in several studies⁽²⁸⁾. Whether these changes affect the male fertility remains uncertain. According to ASRM, “The effect of smoking on male fertility is … difficult to discern. The available data do not conclusively demonstrate that smoking decreases male fertility… Few studies have or can address the question, because of the confounding effects of partner smoking habits and fecundity. Although sperm concentrations, motility, and/or morphology are often reduced compared to results observed in non-smokers, they often remain within the normal range. Nevertheless, to the extent that the zona-free hamster egg penetration test reflects the ability of sperm to successfully fertilize a human oocyte, the available evidence suggests that smoking may have adverse effects on sperm function.”

Caffeine studies have revealed inconsistent effects on sperm, with at least one study showing no effect⁽²⁹⁾. Caffeine has been used as a sperm stimulant, increasing the motility prior to insemination. There does not appear to be any substantial adverse effect of caffeine on sperm.

Common Medications The list of medications with effects on sperm is long, and worthy of review. Noteworthy medications are the SSRI anti-depressants (Cipramil, Lustral, and Effexor were the reported medications), which were associated with near-azospermia in a case report⁽³⁰⁾. Ibuprofen (Advil, Nuprin) does not seem to cause adverse effects on sperm⁽³¹⁾.

Vaginal lubricants can interfere with sperm. FemGlide, Replens, and Astroglide lubricants demonstrated a significant decrease in motility, whereas Pre-Seed did not affect motility or DNA integrity⁽³²⁾.

Treatments for erectile dysfunction may have an effect on sperm motility. A significant increase in sperm progressive motility was observed after sildenafil (Viagra) administration as compared with baseline; in contrast, a significant decreased motility was observed after tadalafil (Cialis).

Antihypertensive drugs have numerous effects on sperm. Beta-blockers and diuretics have been associated with impotence. Calcium channel blockers (nifedipine, Procardia) have been associated with infertility⁽³³⁾. If you are on heart medications, review them with your physician.

Reports on the effects of marijuana use on sperm are conflicting. Early studies had poor controls, later studies showed reductions in testosterone and sperm quality⁽³⁴⁾ while other studies showed no effect on testosterone levels in chronic heavy smokers⁽³⁵⁾. A recent study revealed a direct effect of THC, the active ingredient in marijuana, on sperm motility and fertilization capacity⁽³⁶⁾. The conclusion of the study was that “the use of THC as a recreational drug may impair crucial sperm functions and adversely affect male fertility, especially in those who are already on the borderline of infertility.”

Conclusion Sperm are a biological substance, produced in a complex interplay of genetic predisposition, specific temperature and pH, and in association with specific cells and secretions. If the system is insulted, problems will often arise. The sheer numbers of sperm in an ejaculate provide a wide margin for maintaining fertility even after such insults occur, but repeated attacks on the reproductive system can ultimately result in male fertility problems.

Philip Chenette, MD

References:

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Progesterone is the hormone that prepares the uterus and endometrial lining to support an early pregnancy (Progesterone = “Pro-gestation hormone”). Produced in the ovary between ovulation and the following menstrual period, and by the placenta in the early embryo, progesterone stimulates cells in the endometrial lining to become receptive to the early embryo and, after implantation, to support growth of the embryo. Without progesterone, implantation could not occur; if progesterone were to be removed in early pregnancy, miscarriage would be certain to follow.

Hormones are produced in the ovary by the developing follicle, or egg sac. In the first two weeks of the menstrual cycle, as the egg sac matures, stimulated by Follicle Simulating Hormone (FSH) and Luteinizing Hormone (LH) from the pituitary, the follicle increases its production of estrogen to a peak just before ovulation. At the mid-cycle surge of LH, the follicle abruptly shuts down its estrogen production pathway, converting over to producing large amounts of progesterone. The follicle becomes the corpus luteum, a richly vascularized progesterone production factory.

As the pregnancy is established, the placenta produces chorionic gonadotropin, hCG, a hormone that stimulates the corpus luteum to produce additional progesterone. hCG is very similar to LH, binds to the same receptors, and stimulates the ovary much like LH. Rising hCG stimulates rising progesterone, which strengthens the pregnancy and allows it to produce more hCG, again increasing progesterone; this feedback loop is essential to enabling a strong pregnancy.

Progesterone is essential to the development of the early embryo. Progesterone from the corpus luteum circulates through the bloodstream to the uterus, where the endometrium that has been prepared by estrogen starts to change to support the early pregnancy. This change in the endometrial lining, luteinization, is essential for the embryo. The role of the corpus luteum was demonstrated years ago in experiments where the ovary containing the corpus luteum was removed; miscarriage immediately followed. More recently, progesterone antagonists, such as RU-486, which block the progesterone receptor, have been used in animal studies to induce miscarriage when given in early pregnancy.

Progesterone also has effects on the immune system, stimulating protective proteins, such as HLA-G, in the early pregnancy (Yie, Xiao et al. 2006). Without HLA-G the maternal immune system would reject the embryo, therefore, production of HLA-G antigens are critical to protecting the early pregnancy. Progesterone plays an important role in stimulating HLA-G and preventing rejection of the embryo.

Progesterone also acts as a chemoattractant for sperm (Albano, Smitz et al. 1999; Teves, Barbano et al. 2006). Progesterone in tiny amounts will draw sperm, and may attract sperm to the egg after ovulation. Uterine contractions, which play a role in sperm movement, are also controlled by progesterone.

Because it aids in creating a receptive environment for the embryo, insufficient progesterone can be a source of infertility and miscarriage. Low progesterone levels will result in luteal phase defect, a condition in which there is insufficient hormonal support for the early pregnancy. Failure of implantation of an otherwise healthy embryo, or loss of an early pregnancy, may occur with luteal phase defect. Some women do not produce any progesterone at all, for example, after menopause, or when a menopausal state is temporarily induced using medications to prevent ovulation. Without progesterone, pregnancy cannot occur.

The progesterone receptor mediates the action of the hormone and is critically important to pregnancy; some cases of infertility may be related to abnormalities in the progesterone receptor (Spandorfer, Normand et al. 2006). A simple alteration in the genetic code for the progesterone receptor is common in patients with infertility, and appears to be associated with poorer pregnancy outcomes.

The method of In Vitro Fertilization (IVF) is associated with luteal phase defects and low progesterone levels (Albano, Smitz et al. 1999). With IVF treatment, many of the cells that produce progesterone are removed from the ovary in the course of oocyte retrieval. In addition, the use of GnRH agonists and antagonists (leuprolide, ganirelix, cetrorelix) prevent the release of LH and FSH from the pituitary, removing the primary stimulus for progesterone production from the ovary. Progesterone levels may not be adequate to support the pregnancy, resulting in a luteal phase defect, implantation failure, and early miscarriage.

For treatment, progesterone usage falls into two broad groups, progesterone supplementation, where progesterone is produced in the ovary and supplemented with medication, and progesterone replacement, where there is no natural progesterone production. Progesterone replacement would be used in an oocyte donation recipient. Since ovulation occurs in the donor, and there is no natural progesterone in the recipient, all progesterone must be administered. Progesterone replacement is also common for cryopreserved embryo transfers, though natural cycles can also be used in many women with regular menstrual cycles. Medical supplementation might be used in a variety of conditions associated with luteal phase defect or to reduce the risk of early miscarriage associated with low progesterone levels.

Progesterone is supplemented medically to reduce the risk of pregnancy problems arising from low progesterone levels. Progesterone may be given orally, by vaginal supplement, by injection, or its production enhanced by injection of hCG, which stimulates the corpus luteum to produce additional progesterone(Pouly, Bassil et al. 1996).

Oral progesterone is relatively weak in its effect. Absorbed through the upper intestine, progesterone taken orally is metabolized in the liver. This is known as “first pass effect”, because the hormone passes through the liver first before traveling to its site of action. These metabolites are not effective in inducing luteinization and can induce effects on the central nervous system such as sedation. Very little active progesterone is available after oral use (Friedler, Raziel et al. 1999).

Vaginal progesterone, in the form of creams, gels, and suppositories, is highly effective in supplementing or replacing natural progesterone, and has been the most popular form of progesterone supplementation. Progesterone is absorbed through the vaginal wall and moves through local circulation directly to the endometrium. Levels are sufficient to induce the normal changes in endometrial lining to support the early pregnancy (Pritts and Atwood 2002). The primary clinical concern with vaginal progesterone is the variability in absorption. While most women absorb progesterone vaginally without difficulty, some may not; as an indirect mode of administration, one cannot be certain of the amount that is absorbed.

Progesterone by intramuscular injection is well absorbed, and in some ways closest to natural ovarian secretion (Lightman, Kol et al. 1999). High serum levels of progesterone are achieved with effective preparation of the endometrium. Traditional intramuscular injections, in an oil base, require a relatively large needle; local reactions to the oil base at the site of injection are common. Newer preparations of intramuscular progesterone, such as progesterone ethyl oleate, are considerably easier to inject, but still require daily administration. Injectable progesterone remains the primary progesterone for those patients that produce no natural progesterone, such as for a donated oocyte recipient, or for a frozen embryo transfer in a medicated cycle.

hCG, by acting directly on the ovary, is a good stimulant to progesterone production (Herman, Raziel et al. 1996). Its use requires that an active corpus luteum be present, so it can only be used in a natural or stimulated ovulation cycle. It produces good progesterone levels and reduces the risk of luteal phase defect (Mochtar, Hogerzeil et al. 1996). hCG requires periodic injections and may increase the risk of ovarian hyperstimulation syndrome in patients that have been on fertility drugs. As the hormone that is measured in a pregnancy test, hCG causes a false positive pregnancy test, potentially confusing the diagnosis of early pregnancy. hCG is used occasionally to supplement progesterone production in women with an active corpus luteum.

Vaginal and injectable progesterone appear to be similar in actions on the endometrial lining (Khan, Richter et al. 2007); while the amount of progesterone absorbed can be dramatically different, the clinical effects are similar. Progesterone receptors appear to be saturated at fairly low levels of progesterone in the blood, and additional progesterone does not seem to increase pregnancy rates or reduce miscarriage rates. The specific route or agent for progesterone supplementation is probably not as important as assuring that at least some progesterone is present. Equivalent pregnancy rates have been shown using vaginal gels, progesterone vaginal capsules, and progesterone in a dissolving effervescent vaginal tablet (Schoolcraft, Miller et al. 2007). Vaginal and injected progesterone, in general, show higher bioavailability than oral progesterone.

In patients with no ovarian function, recipients of egg donors, or those patients utilizing cryopreserved embryos in medicated (estrogen/progesterone replaced) cycles, all progesterone must be supplied medically. These patients require a reliable source of progesterone, and injectable progesterone has been established as the best standard (Prapas, Prapas et al. 1998). Vaginal progesterone has also been used successfully, though less commonly. In these patients, progesterone replacement must be continued for an extended period. Because there is no corpus luteum in the ovary, the rising hCG from the placenta cannot stimulate progesterone production, as it would in a conventional pregnancy.

In those patients with an active corpus luteum, such as after in vitro fertilization, external progesterone is required for only a limited time period. In the first two weeks after ovulation, the pregnancy is critically dependent on ovarian progesterone. After a positive pregnancy test, progesterone administration can be stopped entirely (Proctor, Hurst et al. 2006), relying on the embryo to stimulate the corpus luteum through the placental hCG effect on the ovary.

Leuprolide, a GnRH agonist, seems to supplement progesterone and its actions. A single injection of a GnRH agonist releases LH from the pituitary, stimulating progesterone production in the ovary, and may act directly on the endometrium and the embryo, enhancing implantation (Pirard, Donnez et al. 2006). With more study, this may prove to be a useful adjunct to use of progesterone.

Philip Chenette, MD

References

Albano, C., J. Smitz, et al. (1999). “Luteal phase and clinical outcome after human menopausal gonadotrophin/gonadotrophin releasing hormone antagonist treatment for ovarian stimulation in in-vitro fertilization/intracytoplasmic sperm injection cycles.” Hum. Reprod. 14(6): 1426-1430.

Friedler, S., A. Raziel, et al. (1999). “Luteal support with micronized progesterone following in-vitro fertilization using a down-regulation protocol with gonadotrophin-releasing hormone agonist: a comparative study between vaginal and oral administration.” Hum. Reprod. 14(8): 1944-1948. Herman, A., A. Raziel, et al. (1996). “The benefits of mid-luteal addition of human chorionic gonadotrophin in in-vitro fertilization using a down-regulation protocol and luteal support with progesterone.” Hum. Reprod. 11(7): 1552-1557.

Khan, Richter, et al. (2007). “Case-Matched Comparison of Intramuscular Versus Vaginal Progesterone for Luteal Phase Support After In Vitro Fertilization and Embryo Transfer.” Fertility and Sterility 87(4): S13-S13.

Lightman, A., S. Kol, et al. (1999). “A prospective randomized study comparing intramuscular with intravaginal natural progesterone in programmed thaw cycles.” Hum. Reprod. 14(10): 2596-2599.

Mochtar, M. H., H. V. Hogerzeil, et al. (1996). “Endocrinology: Progesterone alone versus progesterone combined with HCG as luteal support in GnRHa/HMG induced IVF cycles: a randomized clinical trial.” Hum. Reprod. 11(8): 1602-1605.

Pirard, C., J. Donnez, et al. (2006). “GnRH agonist as luteal phase support in assisted reproduction technique cycles: results of a pilot study.” Hum. Reprod. 21(7): 1894-1900.

Pouly, J. L., S. Bassil, et al. (1996). “Endocrinology: Luteal support after in-vitro fertilization: Crinone 8%, a sustained release vaginal progesterone gel, versus Utrogestan, an oral micronized progesterone.” Hum. Reprod. 11(10): 2085-2089.

Prapas, Y., N. Prapas, et al. (1998). “The window for embryo transfer in oocyte donation cycles depends on the duration of progesterone therapy.” Hum. Reprod. 13(3): 720-723.

Pritts, E. A. and A. K. Atwood (2002). “Luteal phase support in infertility treatment: a meta-analysis of the randomized trials.” Hum. Reprod. 17(9): 2287-2299.

Proctor, Hurst, et al. (2006). “Effect of progesterone supplementation in early pregnancy on the pregnancy outcome after in vitro fertilization.” Fertility and Sterility 85(5): 1550-1552.

Schoolcraft, Miller, et al. (2007). “Efficacy of a Novel Form of Vaginal Progesterone on Continuing Pregnancy Rates in Women Undergoing IVF with Elevated BMI and Advanced Age.” Fertility and Sterility 87(4): S24-S24.

Spandorfer, Normand, et al. (2006). “O-7 A G->A POLYMORPHISM AT POSITION +331 IN THE PROGESTERONE RECEPTOR GENE IS STRONGLY ASSOCIATED WITH IVF OUTCOME.” Fertility and Sterility 86(3): S3-S4.

Teves, Barbano, et al. (2006). “Progesterone at the picomolar range is a chemoattractant for mammalian spermatozoa.” Fertility and Sterility 86(3): 745-749.

Yie, S.-m., R. Xiao, et al. (2006). “Progesterone regulates HLA-G gene expression through a novel progesterone response element.” Hum. Reprod. 21(10): 2538-2544.