Is There a New Treatment for PCOS?
Guest post by Rashmi Kudesia, MD MSc
In my experience working with and talking to women with polycystic ovary syndrome (PCOS), one of the most frustrating aspects is the lack of cure. In other words, though there are specific medications that might target irregular or absent ovulation, excess facial or body hair, acne, mood alterations and so on, there doesn’t really exist any one therapy that reliably addresses the constellation of symptoms in this syndrome. As such, there is always much interest when a new drug in the research and development phase holds promise for a broader positive impact in women with PCOS.
Just about a year ago, we reported on clinical trials of a drug that was shown in early trials to reduce circulating levels of luteinizing hormone (LH) and testosterone (http://pcosdiva.com/2016/01/new-pcos-treatment-undergoing-clinical-trials/). That drug was in the class of neurokinin 3 (NK3) receptor antagonists (NK3RA). The exciting aspect of that compound was that it seemed to downregulate LH selectively, not shutting down the whole reproductive axis (which would create a pseudo-menopausal state). This action was particularly relevant, because women with PCOS frequently have elevated LH levels, and LH stimulates androgen production.
A Possible New Treatment for PCOS
Though we don’t have much further to say about NK3RA trials, we are now also aware of another drug, Elagolix, which is under study for endometriosis and uterine fibroids. The pharmaceutical company behind this compound, Neurocrine (in collaboration with Abbvie), has also suggested a variety of other women’s health conditions that the drug could benefit, including PCOS. So let’s investigate the potential here.
Elagolix is also an antagonist, meaning it blocks certain enzyme function. In this case, it antagonizes the function of gonadotropin-releasing hormone (GnRH), the hormone released by the hypothalamus in the brain to stimulate the pituitary gland to release not only LH, but also follicle-stimulating hormone (FSH). So, unlike the NK3RA class, which selectively targets LH and its downstream hormones, GnRH antagonism would shut down the entire reproductive axis. This effect is not unlike medications we have on the market currently, such as leuprolide (Lupron), which also results in a shutdown of the reproductive axis.
This type of suppressive approach is particularly beneficial to conditions that worsen in the presence of ovarian estrogen (which is secreted by the growing ovarian follicles in response to FSH). Hence, it makes sense that the initial trials are for endometriosis and fibroids, both conditions that improve with reproductive axis suppression.
What impact could it have for women with PCOS?
Well, in general suppressive therapy comes with significant side effects – hot flashes, bone loss, etc. – so some form of “add-back therapy” is used, to add back protective ovarian steroid hormones (estrogen and progesterone) to prevent the unhealthy side effects of premature menopause. In the case of PCOS, it remains to seen what the benefits would be of suppression with add-back over just using a common add-back therapy like birth control pills.
One question I was asked to address was whether there could be healthier or more natural add-back options. In general, professional medical societies have been wary of the purported claims of “bio-identical” or compounded hormonal preparations, and there is not any scientific data to suggest that such hormones are better for most women needing them, and there can be much more variability (and less regulation) in how they are prepared. Regardless, young women with a uterus need both estrogen and progesterone supplementation to keep their heart, bones and uterine linings healthy, so however it is formulated, both hormones would need to be included. I don’t anticipate this approach being of particular assistance to PCOS women.
The second question I was asked was whether this suppression might also help quiet the adrenal production of androgens, particularly DHEAS. As many of you know, androgen hormones are made from both the ovary and the adrenal gland (a little gland that sits on top of the kidneys). Just like the ovary, the adrenal gland is stimulated by the hypothalamus and pituitary and is a parallel hormone axis to the reproductive. Though GnRH antagonism would reduce ovarian androgen production, multiple scientific studies have concluded that it does not suppress the adrenal axis. So for those women suffering from hyperandrogenic symptoms and a high DHEAS level, I do not believe that this approach would be of benefit.
In short, though Elagolix has potential benefit for women’s health, in that it’s an oral suppressive medication (making it potentially better than leuprolide, which is injectable), and may end up working well for women with hormonally-sensitive diseases, shutting down the reproductive axis does not to me seem (even with add-back therapy) a useful step in managing PCOS.
Of the drugs in development now, I would hypothesize that the NK3RA class, which targets the half of the reproductive axis especially overactive in PCOS women, is more likely to help. However, as both of these drugs move through trials, we will be staying tuned for results!
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.