Reproductive Endocrinologist and Infertility Specialist, RMA of New York
There are many frustrating aspects to both having and studying polycystic ovary syndrome (PCOS). One might argue, however, that the fact that so little is still fully understood about what causes PCOS and links various components of the syndrome, is among the most aggravating! Last month, however, a group of French researchers published a paper summarizing a series of experiments that might jumpstart a new line of investigation and understanding in this area.
The team focused their studies around uncovering novel roles of Anti-Müllerian hormone (AMH). It is well known that PCOS women tend to have higher AMH levels, fittingly so since the hormone is made by cells in the ovarian follicles, of which PCOS women tend to have more; it is also understood that higher AMH levels often correspond with more severe PCOS. However, the team wondered if AMH might also act in other parts of the body. Specifically, they hypothesized that AMH might stimulate cells in a particular part of the brain, the hypothalamus, that makes gonadotropin-releasing hormone (GnRH). GnRH stimulates the production of two other hormones, follicle-stimulating hormone (FSH) and luteinizing hormone (LH), and elevated LH levels or LH:FSH ratios are commonly seen in PCOS. LH in particular is responsible for the high androgens, or male hormones, often seen in PCOS. Essentially, the team questioned whether the high AMH levels seen in PCOS might help to explain the altered secretion of GnRH and LH.
Let us review their findings in detail. First of all, it is important to realize that these experiments were conducted on mice. Though they used a good mouse model that is highly replicative of human PCOS, no animal model is 100% representative, and so further research would be needed to demonstrate similar findings in human trials. So, let’s get going. The first step in investigating this hypothesis was to look for AMH receptors in nerve cells, or neurons, of the hypothalamus. Indeed, they discovered that AMH receptors were present, and in GnRH-specific neurons. By looking at mouse embryos in various stages of development, they also found that this receptor became much more prevalent after the time at which those neurons matured. The next step was to figure out where and how AMH was acting on the GnRH neuron. Through a series of detailed experiments isolating different portions of the neurons and exposing them to AMH and other key ingredients, they concluded that AMH stimulates the neurons’ overall excitability and secretion of GnRH.
Next, they injected AMH directly into the brain and measured LH levels (increased LH levels would be analogous to the elevated LH levels seen in PCOS women, and also reflect elevated GnRH activity). Indeed, by injecting AMH, LH levels went up, an effect that could be blocked if they simultaneously administered a medication that blocks GnRH action. Finally, they utilized a specific PCOS model; the embryo is exposed prenatally to high levels of androgens resulting in a mouse that demonstrates LH patterns and irregular cycles similar to human PCOS. In this set of experiments, they found that the PCOS-type mice didn’t have higher AMH levels than the non-PCOS, but, in the PCOS-type mice only, higher AMH levels were correlated with higher LH levels.
So, in summary, this complex set of mouse experiments demonstrates that there are AMH receptors in the GnRH neurons of the hypothalamus, that AMH stimulates GnRH and LH expression, and that in PCOS-type mice, higher AMH levels may generate higher LH levels. If these findings were true in humans, they might help to explain why PCOS women demonstrate higher LH levels and could identify elevated AMH as one of the early changes that kicks off the chain of hormonal events causing the development of PCOS. Indeed, a few human studies have looked at daughters of PCOS women and shown that though their FSH and LH levels are still normal, they show higher AMH levels. This finding may support the theory that ovaries with many follicles, producing high AMH levels, may be how PCOS starts. If a theory like this were proven, the knowledge would offer new potential targets for medications geared at treating, or even preventing, PCOS progression. But much more work will be needed to prove or disprove this idea, so stay tuned!
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).