Letrozole v. Clomiphene in Women with PCOS

Guest post by Rashmi Kudesia, MD MSc

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. Kudesia is a board-certified Reproductive Endocrinology and Infertility specialist, practicing at Houston IVF in Houston, Texas. She joined Houston IVF in 2018 after practicing in New York City, where she was named a “New York Super Doctors Rising Star” in 2016 and 2017.

After completing her Baccalaureate degree in Biology & Medicine magna cum laude from Brown University, she received her M.D. with honors from the Duke University School of Medicine, where she was selected into a clinical research training program co-sponsored by the National Institutes of Health. Her residency training in Obstetrics & Gynecology at the New York Hospital-Weill Cornell Medical Center was followed by subspecialty training in Reproductive Endocrinology and Infertility (REI) at the Albert Einstein College of Medicine-Montefiore Medical Center, alongside a Masters’ of Science degree in Clinical Research Methods. She subsequently served as a Clinical Assistant Professor at the Icahn School of Medicine at Mount Sinai, as well as the Research Rotational Director for the REI fellowship, and Medical Director of the Brooklyn office of the Reproductive Medicine Associates of New York.

Dr. Kudesia is a Fellow of the American College of Obstetricians and Gynecologists, and an active member of the American Society for Reproductive Medicine (ASRM), Society for Reproductive Endocrinology and Infertility, Androgen Excess & Polycystic Ovary Syndrome Society, and American Medical Association (AMA). She has served in multiple local and national leadership roles in organized medicine, including her current positions as Secretary of the ASRM Women’s Council Executive Board and the ASRM delegate to the AMA Young Physicians’ Section.

Dr. Kudesia has also presented scientific research at national and international conferences, and has received multiple awards and grants for her work. She has published peer-reviewed articles and book chapters, including in leading journals such as Fertility & Sterility and the American Journal of Obstetrics & Gynecology, as well as editing a theme issue on reproductive medicine for the American Medical Association Journal of Ethics. Her current areas of focus include improving in vitro fertilization cycle prognosis, polycystic ovary syndrome, LGBT fertility, and fertility awareness, counseling, and access to care. She actively promotes women’s health and wellness on social media via Twitter, Facebook, and Instagram.