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.

Many people who get pregnant easily but have experienced recurrent miscarriages may not realize that they may actually have an “infertility” problem. The rubric of infertility includes not only helping couples establish a pregnancy but also achieving a viable pregnancy, which will grow to full term. So the diagnosis and treatment of recurrent miscarriages is indeed an area that is managed by infertility experts.

Recurrent Miscarriages, also called recurrent pregnancy loss (RPL), is diagnosed after at least 2 or 3, or more, consecutive pregnancy losses in the first or early second trimester (less than 15 weeks gestation). It is one of the most common clinical problems in reproduction, yet a definite cause can be established in only about 50% of the cases, often leaving patients distraught and frustrated. Consequently, some patients will turn to alternative therapies of unproven benefit. Medically known causes and treatments are described in this article.

Egg Quality Factor
The normal biological aging process of the egg causes the egg to function less accurately during the fertilization process at the critical time of chromosomal duplication and pairing. The resulting chromosomally abnormal embryos have a lower chance of implanting in the uterine lining. If implantation does occur, these embryos have a higher chance of leading to a first trimester miscarriage. We test for egg quality by performing a blood test for the FSH and Estradiol hormones on menstrual cycle day 2 or 3. For some patients we may recommend a more extensive test called a Clomid Challenge Test.

Other Hormonal Factors
Other hormonal abnormalities that result in miscarriage must be very subtle because the cycle is normal enough to allow egg development, ovulation, fertilization, and implantation, yet the pregnancy is lost at a later time. The amount of progesterone produced by the follicle after ovulation and the effect of that progesterone on the lining of the uterus may be of importance. A low progesterone level or an inadequate maturation of the uterine lining is called a luteal phase defect.

Abnormalities of other metabolic hormones can cause a luteal phase defect. If the prolactin level is elevated, it is important to evaluate for prolactin-elevating drugs, hypothyroidism (check the TSH), and pituitary tumors. The prolactin level can be lowered to a normal range with medications.

Women who have polycystic ovary syndrome (PCOS) are at higher risk of miscarriages because of an intraovarian hormonal imbalance. If PCOS is suspected, checking for LH, androgens and insulin resistance can be helpful in discussing treatment with insulin-sensitizing agents (metformin).

Anatomical factors
The anatomical factors are a variety of structural abnormalities of the cervix and uterus that are found in about 15% of women with recurrent pregnancy loss. These factors are diagnosed by performing a hysterosalpingogram (HSG), mid-cycle ultrasound or saline hysterogram, with attention directed to the shape or contour of the uterine cavity.

Potential abnormalities that may be found and associated with recurrent miscarriages are polyps, fibroids, and uterine septums. These anatomical abnormalities can lead to an unfavorable uterine environment for the embryo at the time of implantation and early embryo development. These can lead to early pregnancy loss. All of these abnormalities can usually be corrected with minor surgery.

Chromosomal Factor
There are 2 types of chromosomal factors. One is a random event; the other is genetically inherited by the fetus. At least 60% of all miscarriages are chromosomally abnormal embryos that arose from sporadic, random genetic defects in the sperm or the egg. These are defects that would not have been detected by analysis of the couple’s chromosomes (karyotype). However, these defects become more common as the woman ages. The miscarriage risk increases from about 15% of pregnancies before age 35, to 35% by age 40 and to 50% by age 45. About 99% of the time a chromosomally abnormal embryo will be miscarried. Because perhaps 1% will continue to develop, amniocentesis or chorionic villus sampling, which determine the genetic makeup of the fetus, is suggested for women over 35. When the genetic makeup of the fertilized egg is very abnormal, no embryo forms. On ultrasound examination an empty sac or a “blighted ovum” is seen in the uterus.

Some patients have chromosomal abnormalities in each cell, including eggs and sperm, which place them at greater risk of making a larger proportion of abnormal embryos. The fetus then genetically inherits this abnormality. Every cell in our body other than eggs and sperm has 46 chromosomes arranged in 23 pairs. It is possible that between the two chromosomes of a designated pair there could be a mix-up in the sequence of genes that make up these chromosomes, but the total number of genes is still normal. This mix-up is called a “balanced translocation” and causes no symptoms, diseases, or abnormalities in the patient or partner. However, if this genetic rearrangement occurs in a sperm or egg, the embryo will be chromosomally abnormal, and a miscarriage will follow. Balanced translocations can be detected by performing a chromosomal analysis. Chromosomal analysis requires a blood sample from both partners. The white blood cells are cultured to produce an analysis, or karyotype, of the chromosome pairs. The karyotype will be abnormal in about 5% of cases of couples that have suffered from three or more miscarriages. It is difficult to say what the risk of repeated miscarriages will be with a balanced translocation, however a normal full term pregnancy is still possible.

Immunologic factors
The immune system protects our bodies against foreign micro-organisms by recognizing any cells that are different from our own and making antibodies that attack and destroy those cells. Some women with recurrent pregnancy loss have autoantibodies. These are antibodies in their blood vessels that are made to attack their own tissues (e.g., antiphospholipid (anticardiolipin), antinuclear, or antithyroid antibodies). Antiphospholipid antibodies, along with lupus anticoagulant, may interfere with the formation of a normal placenta early in pregnancy and increase the risk of abnormal blood clotting in the placenta later in the pregnancy. This compromised placenta will lead to compromised growth of the fetus and an eventual miscarriage. If one has a positive antibody test, the test should be repeated 6-8 weeks later. If both sets of tests are positive, the recommended treatment may include one “baby” aspirin tablet per day, and sometimes the addition of daily heparin.

Thrombophilia Factors
Various enzymes regulate effective flow and clotting of blood. If there is a deficiency in some of the clotting enzymes, then small blood vessels of the placenta may be at greater risk of forming clots. Clots of the placenta will compromise blood flow to the growing embryo, placing the pregnancy at greater risk of a miscarriage. There are now a number of clotting enzymes that are recommended to be tested for in patients with recurrent miscarriages. If specific combinations of these enzymes are found to be in an abnormal range, then recommended treatment is a “Baby” aspirin per day with the possible addition of heparin.

Most miscarriages are the result of a random genetic defect leading to abnormal chromosomes for that particular fetus. This random event is unlikely to recur. For patients who have had three consecutive first-trimester miscarriages, and normal results after full evaluation, the chance of the next pregnancy leading to the delivery of a child is approximately 65%. Therefore, despite having had three recurrent miscarriages, the odds are still in favor of the next pregnancy being a normal pregnancy. While it can be incredibly frustrating both for patient and physician, to face repetitive failed pregnancies, it is still important to understand that the odds are still in the patient’s favor of eventual success. This may require fertility treatment, from low-tech intervention such as Clomid to high tech intervention such as IVF with preimplantation genetic screening (PGS), but in general, success is in our favor. If you are, or know someone who is experiencing recurrent miscarriages, please discuss this with a fertility specialist who may be able to recommend treatment options.

– Isabelle Ryan MD

Q.
I’m confused. I heard that metformin is an alternative to clomid for women who have trouble ovulating, but isn’t metformin a drug to treat diabetes?

A.
Metformin (brand name: Glucophage) is indeed an FDA-approved drug for type 2 diabetes. It is also a promising new treatment in the portfolio of ovulation induction medications for women with polycystic ovary syndrome (PCOS).

Many women with PCOS suffer from insulin resistance (high blood insulin levels), a problem that is thought to possibly impede ovulation and elevate male hormone levels.

By way of background, PCOS is experienced by as many as 10 percent of women of reproductive age. An inability to ovulate normally and problems associated with an overproduction of male type hormone are typical findings in women diagnosed with PCOS. The “polycystic” aspect can be seen in the ovaries via ultrasound, which reveals a large multitude of tiny follicular cysts instead of a smaller group of well-defined emerging follicles preparing for ovulation.

Many women with PCOS respond well to clomiphene citrate (brand name: Clomid), which stimulates increased blood levels of FSH (follicle stimulating hormone) and LH (luteinizing hormone) to induce the growth of a follicle and eventual ovulation. Approximately 70% of patients treated with clomiphene citrate will ovulate and 40% will conceive, the majority within three to six ovulatory cycles.

A small fraction of patients who see no improvement from clomiphene treatment alone are good candidates for metformin, or a combination of clomiphene and metformin. Offering metformin provides such women with an alternative oral medication before being directed to the injectable stimulation medications. As an insulin-sensitizing medication, metformin decreases insulin levels, which is thought to help restore the normal ovarian hormone profile (reduces male hormone), thus allowing for spontaneous growth of a follicle and ovulation to occur. Alternatively, metformin enables the patient to become more sensitive to clomiphene. It is important to note that of those patients who do not ovulate on clomiphene alone, most benefit by the combination of metformin with clomiphene.

Metformin and other insulin-sensitizing medications may offer other benefits for women with PCOS, who are reported to be three times more prone to early pregnancy loss compared to ovulatory women. In several reports involving as yet small populations of PCOS patients, the use of these drugs appears to significantly reduce the rate of early miscarriage. One must approach this news with caution, however, until prospective controlled trials on this topic are conducted.

My story has a very happy ending. And I’ll start with the ending first. My husband and I have a beautiful girl who will turn two in September and are pregnant with our second child who is due late this year. We feel that this would not have been possible without the expertise of a fertility specialist and, specifically, Dr. Givens.

Four years ago my husband and I decided that we were finally ready to have children. We had been together for over ten years. When we decided to start to try to get pregnant and I stopped taking the pill, we anticipated it might take a few months for my period to start and my cycle to become regular. After many months, I had not had my period and was still not pregnant. Still, we optimistically had sex, thinking that I might get pregnant even without having my period. We had heard and read that it was possible. More months went by. I spoke to my gynecologist who said that it might take a while. Still more months went by.

After almost a year, I went back to my gynecologist to try to uncover what was going on. She advised that I could start taking Clomid to assist with the pregnancy. My understanding was that I would not be able to take Clomid indefinitely until I got pregnant, and I wanted to understand the underlying problem and diagnose it before I started taking drugs. Luckily for us, I had a family member who was able to advise us to seek help from a fertility specialist and even found out the names of the top specialists in San Francisco. I then found out that before I could see one, I would need to jump through a series of hoops. The first one was to try to get my doctor to identify the right tests I would need to take to get the referral to the specialists. After many phone calls to my doctor’s office and insurance company, I was finally able to identify and take the right tests. This took a couple of more months, after which I was diagnosed with polycystic ovarian syndrome.

The diagnosis was frightening to me at first. As it turned out, I had a mild case, and it did not interfere with my ability to get pregnant. Rather, Dr. Givens identified a very simple but elegant way to help me. She prescribed Clomid and monitored my ovulation. I was not able to detect ovulation with a home test, but Dr. Givens could see the egg maturing with ultrasounds. At the critical point, when I was about to ovulate, Dr. Givens prescribed a shot of HCG and said that my husband and I could have intercourse in the next 48 hours. It worked. This same approach worked with both pregnancies on the first cycle. We are fortunate to have found an excellent doctor and cannot underestimate the power of the expertise of Dr. Givens.

– LK (name withheld upon author’s request)

Once women with polycystic ovarian syndrome are successfully induced to ovulate with medications such as Clomid, it is likely that pregnancy will follow, if all else is normal. Sometimes Clomid alone will not work and ultrasound monitoring and appropriate timing of hCG injections will complete the ovulatory process. My patient, LK, is young and she only needed a little extra help to ovulate. She was very fortunate to conceive on the first try with both of her pregnancies. It is more typical that it may take 3-6 cycles of ovulation induction to achieve a pregnancy. Nonetheless, we are delighted that LK was able to have her family with a relatively low-tech approach.

– Carolyn Givens, MD