SCIENCE PULSE    Metformin and PCOS

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⁾.

• 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.

               
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CONCEPTION HEALTH    An Inside Look at the Mind/Body Workshop

  As a patient undergoing fertility treatment, the many months of testing, uncertainty and waiting had begun to take its toll. Dividing my life into two week increments no longer had the same hope and anticipation that defined my first few months of trying to conceive. Seemingly harmless questions from friends and relatives, like “So…any good news to report?” had become annoying questions that received a snappy response.

Attending the Mind/Body workshop was a valuable experience on many levels. We began the day with a tasty breakfast and coffee while we introduced ourselves and spoke briefly about our own experiences trying to conceive. PFC instructors Peggy and Allison presented the research on the stress/infertility connection, and spoke about the isolating nature of infertility. Because the topic of infertility is not openly discussed in social situations, the person or couple going through treatment often lacks social support.

Next, we were introduced to relaxation techniques, which Allison and Peggy call “Minis” because they are short and easy to incorporate into daily life. We lay on yoga mats in a darkened room and slowly counted our breaths, letting go of the tension in our arms and legs. We were led through some basic tai chi moves, and then ended with a guided relaxation that put me immediately to sleep.

After a delicious lunch the discussion moved to the cognitive distortions that frequently emerge during stressful periods and cause people to magnify their problems. Peggy and Allison led us through some cognitive restructuring steps, which can help identify a true thought versus a magnified and distorted fear.

Questioning negative thought patterns is a difficult but extremely helpful way to take some of the blame off of myself and ease the level of stress I was feeling. Hearing that others had the exact same thought patterns as I did was also extremely reassuring and made me feel as though I was not alone in my challenging journey.

The next part of the day was my favorite. We learned a variety of yoga postures that can easily be done in a desk chair or in front of a computer. My co-workers may think I look funny, but I have been contorting myself at my desk ever since, and found that it truly does relieve the physical stress of staring at a computer all day, and provides me with a nice mental break before I start a new task.

After another guided relaxation session, which again left me in a deep sleep, we convened as a group to review the day. Peggy asked us to think about what brings us joy, and how we incorporate those things into our lives. As I looked around the room, most people were smiling as they wrote down the things that bring them joy – everything from pets, partners and family to bubble baths, traveling, and good food.

As we finished the day with questions, answers and good-byes I left feeling refreshed from my mini-naps and excited to have some tangible skills to utilize whenever I find myself too stressed to relax. From our very first discussions over breakfast to our final activity, I felt the isolation of my own stressed out perspective melting away. I’m grateful that I attended the Mind/Body workshop, both for the feeling of community and the concrete relaxation skills I came away with.

The Mind/Body Workshop was an invaluable experience. I came away feeling like I had:

• Gained tangible relaxation and yoga skills that I can use in my daily life.
• Decreased feelings of isolation and anxiety.
• Finished the day feeling calm, centered and ready for my journey to parenthood!

 Erika Linden

               
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FROM US TO YOU    FET Natural Cycle Success Rates

  Many IVF programs routinely schedule frozen embryo transfers (FET) to occur on specific days by putting their patients on estrogen and progesterone to prepare the uterine lining for implantation. This allows for a flexible schedule for the clinic and the patient, i.e. it allows the clinics to group FETs together and avoid weekend transfer procedures. However, the patient must remain on both estrogen and progesterone to support the pregnancy for up to 12 weeks.

More and more, clinics are starting to schedule FETs in natural cycles, timed to natural ovulation with minimal medications. This does mean that a transfer can occur any day of the week. Due to tradition and convenience, some clinics remain hesitant to switch to natural cycle FETs. Part of the problem is that there have been very few studies showing what the success rates were in natural vs. programmed FET cycles. The few studies that have been published have reported on a fairly limited number of cycles.

Pacific Fertility Center has always been a proponent of natural cycle FETs. Because we do about 400 FETs each year, we have been able to gather a large number of cycles to evaluate. Most of our patients we evaluated for this study were in natural cycles but some patients had to do programmed cycles because they did not ovulate regularly or because they had to travel some distance to come to PFC for their FET and needed to have the more precise scheduling that a programmed cycle affords.

In our study, we looked at 1,378 frozen embryo transfers done between 2000-2005. Of these, 934 were done in patients using embryos from their own eggs and 444 were done in patients using embryos from donor eggs. The bottom line is that there were no differences in delivered pregnancy rates within both groups of patients (own eggs and donor eggs) between those patients having a transfer timed to natural ovulation or those patients with estrogen-progesterone uterine preparation.

Because we feel that a natural cycle is less costly, requires no blood tests and (usually) fewer ultrasounds and injections, patients find this a desirable alternative to the more common, programmed FET. In addition to these patient-friendly reasons for choosing natural cycle FETs, we now feel PFC has solid data to justify this approach.

Preliminary results of this study were presented at an oral presentation at the Pacific Coast Reproductive Society meeting in Palm Springs this past April (see sidebar).

This study has just been submitted to Fertility and Sterility, the major reproductive endocrinology journal of the American Society for Reproductive Medicine. We expect full publication after the peer review process is completed.

 Carolyn Givens, MD

“Outcomes of Natural Cycles vs. Programmed Cycles for 1378 Frozen Embryo Transfers” Carolyn R. Givens, M.D.a, Leslie C. Markun,b Isabelle P. Ryan, M.D.,a Philip E. Chenette, M.D.,a Carl M. Herbert, M.D.,a and Eldon D. Schriock, M.D.a Submitted July 2007 to Fertility and Sterility.

  In April of this year, Dr. Carolyn Givens attended the annual meeting of the Pacific Coast Reproductive Society in Palm Springs, California. This is a meeting attended by approximately 200 infertility specialists, embryologists, nurses and other fertility professionals.

At the meeting, Pacific Fertility Center’s study entitled “Outcomes of Natural Cycles vs. Programmed Cycles for 1390 Frozen Embryo Transfers” was presented by Dr. Givens in an oral presentation in the scientific portion of the meeting program.

Following the presentation, Dr. Givens was awarded the Society’s Practicing Physician Award for the best scientific presentation by a physician in full time private practice. Congratulations to Dr. Givens!

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-- Best regards from all of us at Pacific Fertility Center.