This past summer, I had the opportunity to travel to Amsterdam, Holland for the annual meeting of the European Society for Human Reproduction and Embryology (ESHRE). Though largely attended by Europeans, this scientific meeting draws physicians, embryologists and scientists from around the world to discuss their research, attend courses and lectures, and discuss the latest topics in our field. Although I don’t think this year’s meeting was as quite as good as last year’s ESHRE in Barcelona, there were still some good learning opportunities. Here are some of the highlights of the meeting:

“From Gamete to Heartbeat: The Missing Link”

This was a post-graduate course offered in conjunction with the meeting. The course covered sperm and egg evaluation,

expression of genes in the early embryo and in the endometrium (uterine lining) and some of the latest research into basic embryo implantation mechanisms.

One of the interesting talks was on gene expression in the early embryo. We have come to believe that the differences in pregnancy rates between younger and older women is mainly due to an increase in the number of abnormal chromosomes in embryos from women as they age (such as increased risk for Down Syndrome). However, this only explains part of the differences in successful pregnancy in younger compared to older mothers. New research into expression of proteins from embryonic genes is showing that in both chromosomally normal and abnormal embryos, there are differences in the number and types of genes encoding proteins in younger and older women. This suggests that it is not just changes in the number of chromosomes but subtler differences in the way individual genes are being expressed that affect the developmental competence of their embryos. Determining which genes and proteins are involved, and what the mechanisms are for regulating the expression of these genes in early embryos, will be an area of focused research in the coming years.

“Hyaluronic Acid (HA) favors selection of spermatozoa with intact DNA and normal nucleus, resulting in improvement of embryo quality” (Bologna, Italy)

This presentation (Parmegiani, et al.) looked at the percentage of sperm showing DNA fragmentation based on several methods of sperm preparation for IVF-ICSI (in vitro fertilization with intracellular sperm injection). They compared sperm in the fresh specimen 30 minutes after ejaculation, sperm that had been processed with a standard “swim-up” technique, and sperm that were placed in PVP (polyvinyl propylene), a substance used to slow sperm down so they can be picked up from a culture dish just prior to injection into the eggs. Lastly, they looked at sperm that had been placed into dishes that contain a ring of hyaluronic acid at the bottom of the dish, a substance to which some sperm will automatically bind. They looked at the percentage of sperm showing total or partial fragmentation of the DNA with each of these steps in the sperm preparation process. In the freshly ejaculated sperm, the DNA fragmentation was 16.5% of tested sperm. In the “swim-up” sperm prep, 11% were fragmented and in the PVP-exposed sperm, it was also 11%. Sperm that had bound to hyaluronic acid showed the least amount of fragmentation, at 5.3%.

These findings suggest that using HA binding to select sperm for sperm injection may result in fewer abnormalities in embryos, and possibly higher pregnancy rates. PFC is currently investigating HA binding on our own to see if it is something we would wish to routinely incorporate into IVF. The downside (like everything else!) is that HA plates are expensive.

Stress and Fertility – an enlightening symposium

Jacky Boivin, PhD., a researcher from Cardiff University in Wales, presented some very interesting data about the stresses of infertility treatment. She discussed a new study from Alice Domar’s group in Boston that surveyed why women/couples discontinued IVF treatment before achieving pregnancy (Fertility and Sterility, in press 2009). In this study, 132 women who had insurance coverage for IVF were surveyed. The two main reasons given for dropping out of treatment were the toll that infertility took on the couples’ relationship and being too anxious or depressed to continue. Among the less common reasons for dropping out were medication-related issues (such as difficulty with injections) and feeling the need for a female doctor. Dr. Boivin also discussed results from her own study that was published in the journal Human Reproduction in 2008. In that study, she developed a copingstratagem for women awaiting results of their treatment (i.e. the time between embryo transfer and first beta hCG). It is known that this is a most anxious time for women and the stress of waiting can become overwhelming. She utilized something called the “positive reappraisal coping intervention” card, or “PRCI” card. This is a small printed card that a patient can carry around in his or her pocket and it is meant to be read 2 times per day, every day during the 9-11 days between embryo transfer and first pregnancy test. The card has several little sayings such as: “During this experience I will try …to do something that makes me feel positive” and “During this experience I feel that….I’m energized or I’m creative.” This is a way of programming thoughts towards the positive and away from the negative. She and her colleagues were able to show that patient felt less stressed and felt that the PRCI was helpful during this period.

Currently, at PFC, we have begun a task force to look into ways to better incorporate counseling and tools for stress management for our patients. Please also see this recent Patient Odyssey. Support groups are a wonderful way to diffuse stress and feel more positive.

Corifollitropin: a modification of Follistim to allow a once-a-week injection.

As most people know, the medication we most commonly use for fertility treatment, Follistim, is pure human FSH, manufactured using recombinant DNA technology. The company that makes Follistim, Schering Plough, is working towards FDA approval of a modified version of Follistim, called Corifollitropin, that will make the drug very long-acting.

For those interested in the details; Corifollitropin is the recombinant FSH molecule + 22 C-terminal peptides from betahCG. It does not bind to the LH receptor. This modification lengthens the half-life of Follistim from 22-34 hours to 60-74 hours for Corifollitropin. The recommended regimen will be one dose per week, starting at baseline, then switch to daily recombinant FSH after that. After injection, peak levels are reached in 2 days then they slowly level. It may be possible to only take one injection per week!

A symposium at ESHRE presented information from the ENGAGE trial with data from 14 European and 5 Asian IVF centers, using women with body mass indices (BMIs) between 18 and 32 (generally less than 60 kg -132 lb). The patients were randomized to receive either Corifollitropin or conventional daily recombinant FSH for oocyte recruitment. The number of days of stimulation was the same in both groups (9). The number of eggs retrieved was significantly higher in the Corifollitropin group (13.3) vs. the FSH group (10.6). The rates of ovarian hyperstimulation syndrome were the same in both groups (about 3%). The pregnancy rates were 25% in the Corifollitropin group and 34% in the FSH group, a difference that did not quite reach statistical significance.

Data were also presented on a second study of Corifollitropin from the U.S. and Europe, comparing two doses of the drug. In the study, 100 mcg/dose was given to women less than or equal to 60 kg and women greater than 60 kg were dosed at 150 mcg. Over 1500 patients were included in this large trial. In this study, the average number of eggs recovered was 13.7 for the Corifollitropin group and 12.5 for the Follistim group. The mature egg and fertilization rates were the same. The percentage of good quality embryos was the same.

The clinical pregnancy rate in the Cori group was 38.9% and was 38.1% in the Follistim group. These rates were statistically the same. We expect that Corifollitropin will likely be available in the U.S. in 2010 or 2011.

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

Polycystic ovary syndrome (PCOS) is the most common endocrinologic disorder in women of reproductive age. Approximately 5-10% of reproductive age women have PCOS. The various symptoms of PCOS can be irregular or absent menstrual cycles, infrequent or absent ovulation, excess facial and body hair, obesity, and infertility. The key components defining this disorder are chronic anovulation (inability to ovulate an egg), clinical hyperandrogenism (elevated male type hormones) and more recently discovered, insulin resistance.

Insulin resistance, the precursor state to diabetes, is present in 35-40% of women with PCOS, even if they are not overweight. Insulin resistance is diagnosed by blood testing, either as fasting glucose to insulin ratio, or as a complete glucose tolerance test. Long term follow up of women with PCOS reveals that up to 40% develop impaired glucose processing or diabetes by age 40. The prevalence of diabetes in women with PCOS is seven times higher than for the non-PCOS population. Excessive insulin production is thought to promote excess male hormone production, though the actual mechanism explaining this observation is still unclear. Insulin resistance may increase the long-term risks of heart disease and hypertension.

Interventions that reduce circulating insulin levels in women with PCOS may restore normal reproductive endocrine function. Non-pharmacologic methods, such as weight loss and exercise, have clearly led to reduced insulin and male hormone levels, resulting in resumption of ovulatory function. However, these regimens are at risk for poor compliance and, over time, the benefit of weight loss is rarely maintained.

Insulin-sensitizing (anti-diabetic) medications can be used to decrease insulin levels, which may help restore the normal ovarian hormone profile (i.e. reduce male hormone), thus allowing for spontaneous ovulation to occur in about 75% of patients. The most commonly used medication is metformin (Glucophage®). Side effects of metformin include gastrointestinal symptoms, which are dose-related and tend to resolve after several weeks. While there are no well-controlled studies of safety during pregnancy, metformin has been administered to a small number of women with diabetes throughout their pregnancies, and no fetal abnormalities have been described⁽¹⁾.

Clinical studies have shown that metformin (500 mg three times per day or 850 mg twice daily with meals) administration to women with PCOS increased the frequency of spontaneous ovulation, menstrual cyclicity, and ovulatory response to clomiphene citrate (CC) (Clomid^®). Benefit has been demonstrated with metformin treatment in PCOS patients both with and without insulin resistance⁽²⁾. Metformin alone may be less effective in obese PCOS women.

Women with PCOS are considered to be at increased risk of miscarriage, as high as 30 – 50 %. When women were treated with 1000-2000 mg daily of metformin throughout pregnancy, rates of early pregnancy loss were 11.6% in the metformin group compared with 36.3% in the control group (p < 0.0001). Administration of metformin throughout pregnancy to women with PCOS may decrease miscarriage rates⁽³⁾.

Controversy exists when comparing metformin to clomiphene citrate (CC) for treating infertility. A well-designed study showed metformin is better for ovulation induction than CC alone and equivalent for pregnancy achievement. The authors suggest that metformin can be used first for ovulation induction in patients with PCOS regardless of their weight and insulin levels because of its efficacy and known safety profile⁽⁴⁾. Alternatively, another study found benefit with metformin if obese (BMI >30 kg/m⁽²⁾ subjects and women older than 34 years were excluded⁽⁵⁾. Another paper pooled the results of 6 studies to examine whether metformin is efficacious when given to patients resistant to CC. They found the addition of metformin in the CC-resistant patient is highly effective in achieving ovulation induction⁽⁶⁾. Most studies showing benefit were small with fewer than 100 patients.

Conversely, two large multicenter trials, one conducted in the US (PPCOS)⁽⁷⁾ and one in the Netherlands⁽⁸⁾, have shown no benefit from metformin either as a single agent or as adjuvant therapy in combination with clomiphene for the treatment of infertility in women with PCOS. They found metformin increased the occurrence of ovulation but did not increase the chance of becoming pregnant. The PPCOS study is large and well designed, with 626 participants. It differs from other studies by using the extended release form of metformin. One very notable result was the absence of any statistically significant effect of this extended release form of metformin on insulin levels or insulin resistance. There were none of the expected metabolic effects of metformin. Extended-release metformin has not previously been studied in women with PCOS. Thus, it has not been ascertained that its efficacy is comparable to regular metformin in PCOS⁽⁹⁾.

Additionally, metformin and clomiphene citrate (CC) differ in their therapeutic time frames (the period of time from initiating therapy to achieving maximum effectiveness). CC produces higher rates of ovulation and pregnancy in the early months of treatment than that of metformin and might be preferable to women who wish to become pregnant quickly ⁽⁵⁾. However, a patient with more time to become pregnant may benefit from metformin’s metabolic effects. During the 3 to 6 months that it takes for metformin to become maximally effective, the patient can prepare for pregnancy by losing weight through diet and exercise. Reducing a patient’s weight might considerably optimize her pregnancy⁽⁹⁾.

Metformin induces normal ovulation, and the risk of multiple gestation is no more than that in the general population. Conversely, CC can precipitate the release of multiple eggs in a given menstrual cycle and carries a risk of multiple gestation: in the PPCOS study, multiple gestation was 6% in the clomiphene group and 0% with metformin.

Metformin may significantly increase the incidence of multiple pregnancy when used in combination with gonadotropins⁽¹⁰⁾.

Short-term co-treatment with metformin for patients with PCOS undergoing IVF/ICSI cycles does not improve the response to stimulation but significantly improves the pregnancy outcome and reduces the risk of ovarian hyperstimulation⁽¹¹⁾.

Conclusions:

• PCOS patients should be screened for diabetes before becoming pregnant. Hemoglobin A1c levels should be normal.
• Metformin alone can induce ovulation and may improve the effectiveness of CC. Extended release metformin may not be as effective.
• Metformin may decease miscarriage rates.
• Weight loss may improve the effectiveness of metformin.
• Time to achieve pregnancy may be longer with metformin than CC.
• Metformin may be less effective in older women.
• Metformin does not increase multiple pregnancy rates when used alone.
• Metformin may increase multiple pregnancy rates and decrease ovarian hyperstimulation when used with gonadotropins.
• Long-term benefits of metformin in preventing hypertension and heart disease need further study.

Eldon Schriock, MD

References:

1. The Practice Committee of the American Society for Reproductive Medicine Committee Opinion. Use of insulin sensitizing agents in the treatment of polycystic ovary syndrome. Fertility and Sterility
2. Nawrocka J, Starczewski A. Effects of metformin treatment in women with polycystic ovary syndrome depends on insulin resistance. Gynecol Endocrinol. 2007 Apr;23(4):231-7.
3. Khattab S, Mohsen IA, Foutouh IA, Ramadan A, Moaz M, Al-Inany H. Metformin reduces abortion in pregnant women with polycystic ovary syndrome. Gynecol Endocrinol. 2006 Dec;22(12):680-4.
4. Neveu N, Granger L, St-Michel P, Lavoie HB. Comparison of clomiphene citrate, metformin, or the combination of both for first-line ovulation induction and achievement of pregnancy in 154 women with polycystic ovary syndrome. Fertil Steril. 2007 Jan;87(1):113-20.
5. Palomba S, Orio F Jr, Falbo A, et al. Prospective parallel randomized, double-blind, double-dummy controlled clinical trial comparing clomiphene citrate and metformin as the first-line treatment for ovulation induction in nonobese anovulatory women with polycystic ovary syndrome. J Clin Endocrinol Metab. 2005;90:4068-4074.
6. Siebert TI, Kruger TF, Steyn DW, Nosarka S. Is the addition of metformin efficacious in the treatment of clomiphene citrate-resistant patients with polycystic ovary syndrome? A structured literature review. Fertil Steril. 2006 Nov;86(5):1432-7.
7. Legro RS, Barnhart HX, Schlaff WD, et al. Clomiphene, metformin, or both for infertility in the polycystic ovary syndrome. N Engl J Med. 2007;356:551-566.
8. Moll E BP, Korevaar JC, Lambalk CB, van der Veen F. Ovulation induction in women with polycystic ovary syndrome: A randomized double blind clinical trial comparing clomiphene citrate plus metformin with clomiphene citrate plus placebo. BMJ. 2006;332:1485.
9. Baillargeon JP, Legro RS. Should metformin be used as front-line therapy for fertility in women with PCOS. Sexuality, Reproduction, and Menopause 2007; 5(2):17-19.
10. Shibahara H, Kikuchi K, Hirano Y, Suzuki T, Takamizawa S, Suzuki M. Increase of multiple pregnancies caused by ovulation induction with gonadotropin in combination with metformin in infertile women with polycystic ovary syndrome. Fertil Steril. 2007 Jun;87(6):1487-90.
11. Tang T, Glanville J, Orsi N, Barth JH, Balen AH. The use of metformin for women with PCOS undergoing IVF treatment. Hum Reprod. 2006 Jun; 21(6): 1416-25.

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.

Infertility clinics around the country as well as OB/GYN centers are reporting favorable results from letrozole for extremely specific treatment options for a small percentage of patients. It is by no means a medication that is or will become standard until more studies are conducted.

Both clomiphene citrate (marketed as Clomid) and letrozole (marketed as Femara) are oral medications used to stimulate ovulation. Letrozole was originally developed for breast cancer treatment, as certain types of breast cancer cells slow their growth in response to decreasing estrogen levels. Letrozole falls in the category of drugs known as non-steroidal aromatase inhibitors, meaning it is highly specific in suppressing estrogen synthesis. Aromatase is an important enzyme prompting the creation of estrogen. If the body makes less estrogen at the start of the cycle, a woman’s FSH level increases and ovulation is stimulated or enhanced. Letrozole is considered as an alternative to Clomid for women undergoing ovulation induction especially for women whose uterine lining may be thinned out by Clomid. As an anti-estrogen, Clomid can limit the development of the endometrial lining making it difficult for an embryo to implant. For reasons that are not yet quite clear, letrozole appears less likely to affect the uterine lining, perhaps because of a short half-life and therefore, a shorter effect on estrogen production. Letrozole has a short life span in the body whereas Clomid can last for 4-6 weeks following an oral dose.

For more information, see A Closer Look At Letrozole

– Carolyn Givens, MD

Infertility and OBGYN professionals across the U.S. and Canada appear to be united in agreeing that there is an undue amount of fear and controversy concerning the use of letrozole (under the trade name Femara) for fertility treatment. Letrozole is a drug that is used for the prevention of recurrence of estrogen-receptor positive breast cancer. Its “off-label” use for ovulation induction is increasingly common, although not approved by the FDA for this application.

In late 2005, Novartis Pharmaceuticals, the Swiss company that developed letrozole for treatment of breast cancer reacted to a single study that showed higher than normal adverse reactions. Novartis sent out a warning letter to infertility clinics asserting that the company does not advocate the use of this medication for infertility treatment. Despite the drug’s successful track record as an alternative to clomid for ovulation induction, at least one Canadian clinic has stopped using it.

As for the background, it started with the presentation of a study conducted by the Montreal Fertility Clinic at the 2005 annual meeting of the American Society for Reproductive Medicine (ASRM). The study reported a much higher rate of serious fetal abnormalities among patients who had been prescribed letrozole. The author’s analysis of only 150 babies born after letrozole therapy revealed a 4.7% rate of major anomalies. This rate was compared to the 1.8% rate of a “control group” of more than 36,000 babies born at a nearby hospital.

Our reading of this study leaves us skeptical about forming any conclusion that letrozole causes an increase in birth defects. First, it is generally agreed that within an unselected population, the background rate of birth defects is 3% for major anomalies and 6% when including minor anomalies. So the background rate in the “control” population seems low. Second, the comparisons between these groups are not indicative of a true controlled study whereby patients of like demographics and health are provided the same treatment protocol, ideally through a double-blind placebo study.

Common sense would remind us that infertility centers treat a higher percentage of women who have delayed childbirth and their older status is typically associated with higher rates of birth defects. The control group in the letrozole study of 36,000 women at a standard hospital would likely include a high percentage of younger women who, by nature, and backed by statistics, have fewer births with congenital anomalies. Indeed, in this study, the mean age of the women treated with letrozole was 35.2 years and the mean age in the control population was 30.5 years. Further, there may be “ascertainment bias” as there may have been under-reporting of defects in the “control” population. Comparing these two groups and drawing a conclusion that sends such alarm through the infertility community is questionable. Lastly, the limited size of the study makes drawing any conclusion very premature.

Novartis has not led any independent studies of its drug with applicability as an infertility medication. But it took the opportunity to analyze its own database with regard to safety. The company claims there were 13 cases involving “adverse reactions” involving letrozole and congenital birth anomalies.

No control groups or comparison to the background rates of congenital anomalies were made. Given this day and age of class action lawsuits, it is understandable for a pharmaceutical company to issue a warning at the hint of any trouble. In light of this, it has been up to the professional associations and communities of medical professionals handling infertility cases to sort through the data carefully, make up their own minds and provide full disclosure to patients.

Just this month, a new study on this subject is appearing in the primary infertility journal of the U.S., Fertility and Sterility. Again from Canada, researchers from Toronto reported on 911 babies conceived with the assistance of either letrozole or clomiphene. In this study, 14 of 514 newborns (2.4%) in the letrozole group and 19 of 397 newborns (4.8%) in the clomiphene group were found to have any congenital anomaly.

For major malformations, the rates were 6/514 (1.2%) for letrozole and 12/397 (3.0%) in the clomiphene group. These rates were not statistically significantly different, and were felt by the authors to be similar to rates of congenital anomalies seen in the general population.

In the field of medicine, there are hundreds of medications that were originally discovered to treat one condition and are subsequently found to be useful for other conditions. Once a drug is approved for a specific indication, most pharmaceutical companies will not go through the trouble and expense to have their drug officially approved for another indication. We at Pacific Fertility have carefully reviewed the data and circumstances around the controversy and we continue to believe that the use of letrozole is appropriate in certain circumstances and with full disclosure. Hundreds of infertility centers and OBGYN clinics worldwide are doing the same.

Although no broad scientific studies have yet established the efficacy of letrozole as the first course standard treatment for treating ovulatory problems, preliminary studies have shown letrozole to be useful, especially for women whose uterine lining may be thinned out by clomiphene (Clomid).

Please see the Science Pulse Extra to learn more about how letrozole works. The only other alternative to clomiphene for ovulation induction is the use of injectable fertility medications (gonadotropins). Use of these drugs in anovulatory women can be tricky, as it is often difficult to induce just one or two eggs to mature with these powerful drugs. So the risks of ovarian hyperstimulation and multiple gestation are significantly higher in anovulatory women on gonadotropins.

We at Pacific Fertility Center carefully explain to those women who might benefit from its treatment the controversy as well as the potential for adverse reactions. Letrozole is generally prescribed to be taken from days 3-7 of the menstrual cycle and has a short life span in the body. There are no traces of the medication in the body by the time an embryo will be implanting.

– Carolyn Givens, MD

The public’s appetite for promising pills that purportedly slow down the aging process is stronger than ever. Sensationalized claims revolving around Dehydroepiandrosterone (DHEA), a natural steroid hormone produced from cholesterol by the adrenal glands, has followed this trend.

DHEA is a hormone secreted by the adrenal gland whose level in the body peak at early adulthood and then decline with age. As the most abundant steroid in the body, DHEA is chemically similar to testosterone and estrogen.

Because low DHEA levels brought on by aging also correlate with age-related diseases, DHEA supplements are openly marketed to prevent the effects of aging. Because a woman’s fertility declines with her age, it is no surprise that DHEA has been associated as a “promising” drug to offset age-related infertility. Yet there have been no scientific studies or evidence revealing that adjusting DHEA levels changes the development of age-related diseases. Nor has there been evidence that DHEA slows down the decline in fertility. Simply stated, there is no evidence that increasing DHEA slows down, stops, or reverses the aging process.

Some past rodent studies indicated DHEA was effective in controlling obesity, and prevented cancer, arteriosclerosis and diabetes. As a result, DHEA was quickly promoted as a miracle weight-loss drug. Yet no human studies have duplicated these results.

Nevertheless, DHEA has received considerable acclaim, with some authors touting it as a “superhormone” or “the youth and health hormone.” Articles on DHEA abound. In fact, DHEA received over 850 citations in a Medline search and 52 publications come up on an Amazon.com search.

A search of serious scientific research examining DHEA’s impact on fertility is scanty. There are less than a handful of scientific presentations or papers on the topic. Just last year a study (Fertil Steril. 2005; 84(3):756) conducted at the Albert Einstein College of Medicine announced: Increased oocyte production after treatment with dehydroepiandrosterone. This paper focused only on one 42 year old woman, whose number of oocytes retrieved increased after undergoing eight IVF cycles over the course of a year with DHEA supplementation. Not only did she take a DHEA dietary supplement, she also underwent acupuncture. Since she froze her embryos, it is not reported whether any of her eggs led to a successful pregnancy.

To date, no sound or controlled scientific studies have been designed to examine whether DHEA is able to reverse the results of aging on ovarian reserves.

A research paper was presented at the 2005 ASRM conference (O-101 by D. H. Barad and N. Gleicher). This retrospective cohort study examined 45 women previously diagnosed with decreased ovarian reserve who were treated with 25 mg DHEA for 4-48 weeks before undergoing ovulation induction for IVF. The study concludes that DHEA increased oocyte production and quality. Yet no pregnancy or live birth outcomes were reported. Both Drs. Barad and Gleicher are already offering “DHEA Therapy” in their practice.

Very little of the encouragement to self-administer DHEA is coming from the physician community, especially those who are initiating viable scientific research. Elizabeth Barrett-Connor, MD, professor and chair, department of family and preventive medicine at University of California, San Diego calls DHEA “a modern day snake oil”. Her initial research revealed that higher natural levels of DHEA in older men may help protect them against heart disease yet she recognizes the need for more studies.

Self-medicating by using DHEA supplements is a form of testosterone therapy. It is not likely to affect each individual in the same way due to variable existing androgen levels in the body and a lack of consensus on what are normal or benchmark levels. Increasing DHEA (and thus testosterone) may well lead to additional facial hair and possibly acne for women. Until more is known, taking DHEA is a risky gamble based on insubstantial evidence.

The hype about DHEA as a way to improve fertility will only continue as the public seeks information that they want to hear. An entire chapter is devoted to DHEA in an online book called “Mothers over 40”. If there were such an easy panacea to reverse the impacts of aging on infertility, the benefits would have been known much sooner.

– Eldon Schriock, MD

Pacific Fertility Center takes great pride in its pregnancy success rates resulting from oocyte donations to women who are unable to provide their own high-quality eggs. An oocyte donation procedure involves much more than screening and scheduling. Both the donor and the recipient’s bodies have to be “synchronized” carefully and deliberately, matching the donor’s oocytes to the recipient’s uterus, as if there were one body making the egg and growing the embryo. This article describes the synchronization steps that match the oocyte to the uterus.

After all parties have completed the required screening, the donor and recipient are typically started on low-dose oral contraceptive pills. While the menstrual cycles of donor and recipient may begin on different days, the pills cause the ensuing menstrual flows to match. Depending on how far apart their menstrual cycles occur, it can take up to two weeks for their respective cycles to be synchronized. Additionally, the pills help prevent the women from developing ovarian cysts, fluid sacs in the ovary, which can delay the start of the cycle.

After a minimum time of at least 14 days of the pill a medication called “Lupron” or “Synarel” is prescribed for both parties. These medications turn off the fertility hormones produced by the pituitary gland and, in essence, shut down the ovaries. Lupron is taken as a subcutaneous injection. Synarel is administered as a nasal spray. Once it is determined that both women’s pituitary glands are adequately suppressed, stimulation of the donor’s ovaries and the recipient’s endometrium may be initiated respectively. Both donor and recipient continue with Lupron injections or Synarel sprays to help prevent early ovulation.

As the donor is initiating stimulation of her ovaries, the recipient starts taking estrogen to prepare the endometrium or uterine lining. The lining is very thin after the menstrual flow. Estrogen stimulates the thickening and development of the lining in preparation for implantation of the future embryo. In a natural cycle, estrogen comes from the follicle developing in the ovary. Since the recipient’s ovaries are suppressed, the estrogen comes from medication. An ultrasound will determine the thickness of the uterine lining and some supplementation may be administered to ensure the best possible environment for implantation. She will have between 10 days and two weeks before the implantation.

High tech methods of administering estrogen have been developed. Pure estradiol is very similar to cholesterol, and is very poorly absorbed when taken orally. Injectable estradiol is closest to natural estrogen. It is most easily administered in an oil base, as estradiol valerate. Small amounts of estrogen can also be given through a patch, since estradiol can be absorbed through the skin. Vivelle and Estraderm are examples of estrogen patches. While oral estrogen is not easily absorbed, special manufacturing tricks can improve absorption. Estrace is a pill form in which the estradiol is specially manufactured in microcrystals that have a higher surface area to improve absorption through the intestinal tract.

The donor will begin intramuscular injections of fertility medications that gradually stimulate the growth of numerous follicles on her ovaries. This process is known as controlled ovarian hyperstimulation.

While the donor is administering the fertility medications, she begins to be monitored by routine blood tests that determine estradiol levels to monitor the development of the follicles.

At the same time, the recipient is being monitored by periodic estradiol levels and ultrasound evaluations for endometrial thickness.

After five to seven days of stimulation the donor’s follicles are measured. In a typical stimulation, both the left and right ovaries reveal multiple maturing follicles. Ideally the eggs mature at the same rate so they are all about the same size and have similar capacity to be fertilized.

When the physician determines the optimal timing of the egg retrieval, the donor will receive a final injection called hCG, which will mature the eggs for retrieval.

On the morning of egg retrieval, the male finally comes into play. Ideally a fresh collection of sperm by the recipient’s male partner or sperm donor is produced to fertilize the retrieved eggs. A masturbated sperm sample is enhanced by a highly specialized process prior to being placed with the eggs, generally involving washing of the sperm to remove the less viable ones.

Approximately 72 hours following ovum retrieval, selected embryo(s) are transferred to the recipient’s uterus. If there are embryos of sufficient quality remaining, they may be cryopreserved for subsequent transfers.

The embryo transfer procedure into the recipient usually requires no anesthesia. A catheter is inserted through the cervix into the uterus, and the embryos are gently and carefully placed into the uterine cavity. The recipient is maintained in a recumbent position for approximately five minutes and then discharged. The recipient will need to take daily progesterone hormone injections in order to sustain an optimal environment for the embryo implantation. This post-implantation or post embryo transfer time is called the luteal phase. Ideally, the embryo begins developing and implants in the lining of the uterus.

Approximately two weeks after the embryo transfer a pregnancy test is performed. If the pregnancy test is negative, all hormonal treatments are discontinued and menstruation will usually ensue within two weeks. If the Beta-hCG titer is rising, as determined by a second test, this indicates that implantation has taken place. Hormone injections will then be continued until 12 weeks of gestation at which time the placenta will supply all the hormones necessary to sustain the pregnancy. In the interim, ultrasound examination(s) will be performed to definitively diagnose pregnancy between 5 to 6 weeks after the embryo transfer.

The donor by this time will begin to return to her regular cycle, and will most likely have her period about 10 days after retrieval.

– Philip E. Chenette, MD

Pacific Fertility Center is pleased to be involved in a six month study that will provide research data comparing two different methods of delivering enhanced progesterone to women after in vitro fertilization. Progesterone is a hormone that is produced by the ovaries after ovulation. Progesterone support is important for initiating implantation and supporting the embryo through the first months of growth.

Some women benefit from direct delivery of progesterone to enhance the implantation process.

The current protocol for direct progesterone application is via vaginal suppositories. Endometrin is an effervescent tablet that is inserted vaginally and absorbed locally to provide progesterone to the developing uterine lining and to provide support of pregnancy. The study aims to demonstrate the equivalence in maintaining pregnancy of the new medication to an existing FDA approved medication.

PFC is currently recruiting up to 25 women experiencing infertility to take part in this clinical research study.

The participants must be non-smokers between the ages of 18 and 42, with two functioning ovaries and a Body Mass Index of 34 or below. Additional screening will be conducted to determine if a patient is eligible to participate. Women who qualify and undergo an IVF treatment cycle will receive free medications and a reduction in IVF fees. Individuals interested in participating are invited to contact Dr. Philip Chenette at (415) 834-3000, or (888)-834-3095.

– Philip Chenette, MD

One of the most common questions from patients about to embark on any fertility treatment plan is “What are the side effects of the medications I will be taking?” This is a most appropriate question to which I’d like to provide an in-depth answer.

When discussing any medication, it is important to keep in mind some concepts when discussing “side effects.” Side effects are really those symptoms, usually minor, most commonly suffered by a significant proportion of patients taking the medication. Typically, this would include nausea or headaches.

There are also “adverse effects.” These are more serious events, usually rare and often unpredictable. Examples would be a stroke or a heart attack. An example of a less severe adverse effect would be ovarian hyperstimulation syndrome. If a drug has been found to have a significant incidence of severe adverse effects, it is not likely to pass FDA approval. If the adverse effect is extremely rare, it may not be discovered until very large numbers of patients have taken the drug and the medication may be pulled from the market after approval (e.g. Bextra).

Separate from side effects and adverse effects, are “long term effects.” These are generally serious adverse effects not discovered until well after the drug therapy is undertaken. An example of this is the effect on the uteri of daughters of mothers who took the drug DES during pregnancy. When patients ask us about the safety of fertility drugs, they are usually referring to adverse or long-term effects as much as concerns about side effects.

When reading the FDA-approved package labeling for almost all medications, fertility drugs included, it’s important to be aware that any possible adverse effect anyone has ever experienced on the drug will be reported. Unfortunately, this almost renders this information useless because there are virtually no drugs that someone somewhere has taken without something happening at the same time. It is often impossible to prove whether or not that medical event was related to taking the drug or not.

None of the medications that are in use for fertility treatment are known to have such serious adverse effects that the FDA has even considered withdrawing its approval.

Overall, we believe fertility medications to be very safe, usually associated with only very mild side effects, relatively rare and treatable adverse effects (mostly commonly ovarian hyperstimulation) and no known significant long term effects.

Below is a list of some of the most common side effects our patients mention, as well as some of the more common adverse effects. It is by no means an authoritative or exhaustive list.

THE MOST COMMON SYMPTOMS AND SIDE EFFECTS:

Clomiphene (Clomid, Serophene®)
• FDA: FDA-approved for ovulation induction in anovulatory women, but widely used for unexplained infertility in women who do ovulate regularly on their own.
• Most common side effects: Hot flashes, night sweats, dizziness, mood swings
• Adverse reactions: ovarian hyperstimulation, abdominal pain or bloating, temporary visual disturbances.
• Long term effects: Possible increased incidence of noninvasive (“borderline”) ovarian tumors – not proven to be causative. Most recent studies find no link with invasive ovarian cancer.

GnRH agonists (Lupron, Synarel)
• FDA: Although Lupron and Synarel are not FDA-approved for IVF use, they are widely used in the U.S. to prevent premature ovulation in IVF cycles.
• Most common side effects: Mild headache
• Adverse reactions: Patients with unrecognized pituitary tumors can experience a type of pituitary “stroke” when on Lupron. This is very rare but potentially serious.
• Long term effects: bone loss in long-term users, not significant for the short courses used for IVF.

Gonadotropins (Follistim, Gonal-f, Repronex, Menopur)
• FDA: FDA-approved for super-ovulation and in IVF to recruit multiple eggs.
• Most common side effects: Tiredness, local injection site skin reactions such as pain and redness (especially Repronex), abdominal fullness, bloating. Contrary to popular belief, we rarely hear our patients complaining of mood swings on gonadotropins.
• Adverse reactions: Ovarian hyperstimulation, multiple pregnancies (twins or more).
• Long term effects: Some concern was raised in the early 1990′s about whether these drugs could increase a woman’s risk of ovarian cancer. Most recent studies are reassuring that there is not an increased risk. These studies are ongoing because this class of drugs has only been in wide use for about 25 years.

GnRH Antagonists (Ganirelix, Cetrotide)
• FDA: FDA-approved for use in IVF to prevent premature ovulation.
• Most common side effects: None that we have seen.
• Adverse reactions: Earlier (pre-FDA approval) versions of these medications were sometimes associated with severe allergic reactions but we have not seen any yet in our practice.
• Long term effects: bone loss in long-term users, not significant for the short courses used for IVF.

hCG (Novarel, Pregnyl)
• FDA: FDA-approved for ovulation induction. Commonly used in clomiphene, gonadotropin and IVF cycles to time insemination or egg retrieval.
• Most common side effects: Some increased discomfort, rarely outright pain, at the time of ovulation.
• Adverse reactions: If a patient has multiple follicles on gonadotropins, hCG can be the final kick to the ovaries to tip someone over into hyperstimulation syndrome. This is not seen in natural cycles or in most patients on clomiphene.
• Long term effects: None known.

Progesterone (Prometrium, Progesterone suppositories, Progesterone in oil)
• FDA: Only Prometrium is FDA approved and it is approved for use in menopause in conjunction with estrogen hormone replacement. It is pure oral micronized progesterone. Progesterone suppositories and Progesterone in oil are usually compounded by individual specialty pharmacies (pharmacies that specialize in distributing fertility drugs). Most progesterone packaging advises not to use in pregnancy but these drugs are the exact same progesterone produced by the human ovary in the luteal phase and in early pregnancy so are widely used in fertility treatment.
• Most common side effects: Mostly very minor things like breast tenderness or mild bloating. For patients on progesterone in oil, local pain and redness at injection sites is common.
• Adverse effects: Local vaginal reactions such as irritation or itching from suppositories. Severe local skin reactions to progesterone in oil are fairly rare.
• Long term effects: Questions have been raised as to whether high doses of progesterone in early pregnancy may be associated with urinary tract abnormalities in the fetuses of the mothers taking progesterone. There has never been any such association proven.

– Carolyn Givens, MD