Guest post by Rashmi Kudesia, MD MSc
Reproductive Endocrinologist and Infertility Specialist, RMA of New York
For women with polycystic ovary syndrome (PCOS), complete management involves addressing all potential symptoms, including not only the irregular ovulation, but also the metabolic and hormonal dysregulation, mental health and quality of life. In some regards, working on the reproductive piece can actually seem one of the simplest! For those women that do not ovulate, or release an egg, regularly, the most common initial approach is to use oral medications, called ovulation induction agents, to essentially help the ovary grow a mature egg. However, there seems to remain a low level of awareness in the general community regarding the best approach to ovulation induction in women with PCOS. Here, we will review the landmark trial that compared letrozole versus clomiphene, published in the New England Journal of Medicine in July 2014.
Before we dive into this trial, we should first review, as this paper does, the history of ovulation induction in PCOS women. Historically, many providers prescribed metformin, an insulin sensitizer, or clomiphene citrate (or Clomid), which is in the class of selective estrogen-receptor modulators, for ovulation induction. Both of these medications made good sense as to why they would assist with ovulation, as PCOS is inherently an insulin-resistant state. Metformin may also assist with weight loss, which could also promote improved ovulation. In contrast, clomiphene works by impacting the estrogen receptor such that, in simple terms, the brain senses a low level of estrogen, and in response tries to stimulate the ovary a bit harder. This extra hormonal push is what helps the PCOS ovary to grow a dominant follicle (the fluid-filled sac in which the egg grows). Prior research has clearly demonstrated that metformin alone or a metformin-clomiphene combination is no better than clomiphene alone. Though this finding has been out for about a decade, I still see women coming into the office on metformin alone for ovulation induction!
So, let’s now move on to the current study. Letrozole is an aromatase inhibitor, blocking estrogen production, and its mechanism of ovulation induction is similar to clomiphene in that in response to a perceived low level of estrogen, the brain releases more hormone to induce follicular growth. Though there were many perceived potential benefits to letrozole, particularly a lower multiple-pregnancy rate, better side-effect profile and improved stimulation of the uterine lining, there were also concerns about safety. As such, this trial was designed to directly address whether letrozole or clomiphene would be better as an infertility treatment, and whether there would be a difference in safety profile.
The study was extremely well-designed trial, and its design was published back in 2012 to allow for it to be well-publicized and open for critique. Since the instructions for the two medications are the same, it was very easy to have them manufactured to look identical, resulting in what we call a “double-blinded” study – where it is unknown to the researchers and participants which drug they are taking. Infertile women aged 18-40 meeting Rotterdam diagnostic criteria, with a normal uterus and at least one open tube, and a partner with a normal semen analysis, were eligible to participate. After delivery, participants had the option to have their infant examined by a qualified pediatrician or geneticist to evaluate for any anomalies.
In terms of the results, 750 women participated. Live birth, the main outcome, was noted in 27.5% of women taking letrozole and 19.1% of those on clomiphene. This difference was confirmed to be statistically meaningful, and resulted in 44% higher live birth rate in the letrozole group. Letrozole was also associated with a higher ovulation rate and higher singleton pregnancy rate. The complication and birth defect rates were low in both groups, and not found to be different from one another. In terms of the side effect profile, clomiphene was more likely to cause hot flushes while letrozole was more likely to result in fatigue and dizziness. Women on clomiphene had a greater reduction in their androgen levels and in perceived hair growth.
Overall, then, the findings indicated that women on letrozole had higher ovulation, conception, pregnancy and live birth rates than those on clomiphene, without a highly meaningful difference in risk or side effect profile. As such, for many women with PCOS looking to conceive, letrozole should really be the first-line drug of choice for ovulation induction. Women should feel comfortable to ask their provider if this is a good choice for them, and/or seek a reproductive specialist who is well-versed in the routine management of ovulation induction cycles, and can monitor them closely throughout their cycle. In addition, I would encourage all women diagnosed with PCOS to make sure they understand the lifestyle choices that we can all make, but seem to be particularly important for women with PCOS, to ensure a healthy pregnancy and the best possible lifelong health!
Dr. Rashmi Kudesia is a reproductive endocrinologist and infertility specialist who leads RMA of New York’s Brooklyn office. Dr. Kudesia specializes in treating couples who are trying to build their families.
Dr. Kudesia earned her medical degree from Duke University. She completed her residency in obstetrics and gynecology at New York Presbyterian Hospital/Weill Cornell Medical College. She completed her fellowship training in Reproductive Endocrinology and Infertility as well as a Masters of Science in Clinical Research Methods at Albert Einstein College of Medicine.
Dr. Kudesia has received numerous grants and awards for her academic accomplishments and medical research. She was awarded a Global Women’s Health certificate by Mount Sinai School of Medicine in 2011, and was nominated into the Duke Engel Society, which recognizes intellectual development, service and clinical excellence. Dr. Kudesia is the recipient of the Joan F. Giambalvo Scholarship Research Grant from the AMA Foundation in 2013, as well as multiple in-training research grants. Dr. Kudesia served as a Theme Issue Editor for the American Medical Association’s Journal of Ethics’ issue on Innovation in Reproductive Care, and has held multiple regional and national leadership positions within organized medicine.
Dr. Kudesia is an accomplished lecturer and author and has written numerous scientific research articles and manuscripts in leading medical journals. She has presented many of her research findings at national meetings, including the American Society for Reproductive Medicine (ASRM).