David Ehrmann, MD

The overall aim of our research is to gain insight into the pathogenesis of polycystic ovary syndrome (PCOS) and its associated metabolic disorders. Our studies have centered on investigation of: 1. ovarian steroidogenic dysfunction in PCOS; 2. the pathogenesis of impaired glucose tolerance and type 2 diabetes in PCOS, with a specific focus on insulin secretory abnormalities; 3. causal relationships between PCOS, obstructive sleep apnea, and the metabolic syndrome.

Our initial research led to characterization of ovarian steroidogenic abnormalities in women with PCOS. In response to a test-dose of a gonadotropin releasing hormone (GnRH) agonist, women with PCOS had significantly greater increases in levels of luteinizing hormone (LH) and significantly lesser increases in follicle-stimulating hormone (FSH) responses than did normal women. Women with PCOS also exhibited a greater response of the ovarian steroid 17-hydroxyprogesterone when compared to normal women. This ovarian response suggested an increase in the activity of the ovarian steroid-forming enzyme P450c17. Based upon these results, a new model of PCOS was proposed.

Insulin resistance is a key component in the PCOS phenotype. While it seemed initially that this insulin resistance could be accounted for on the basis of the obesity that often accompanies PCOS, the magnitude of insulin resistance had been shown to be greater in PCOS than in controls matched for total or fat-free body mass. The degree of insulin resistance is often profound and had been assumed to underlie the high prevalence of type 2 diabetes in PCOS. We postulated that insulin secretory defects could play an important role in the propensity to develop diabetes in PCOS and tested this in a series of studies. We found that a substantial proportion of non-diabetic women with PCOS subjects had insufficient b-cell responses for their degree of insulin resistance. Specifically, women with PCOS who had a first-degree relative with type 2 diabetes were significantly more likely to demonstrate alterations in b-cell function when compared to a matched group of PCOS subjects without a family history of type 2 diabetes. To follow-up on this observation, we sought to determine if pancreatic b-cell dysfunction is heritable in families of women with PCOS and found strong evidence for this. Analysis of genetic, metabolic, and hormonal information obtained in approximately 700 women with PCOS and 350 of their first-degree relatives allowed us to determine that by age 40 years, approximately 35% of women with PCOS will have impaired glucose tolerance (IGT) and nearly 10% will have type 2 diabetes mellitus. We have also reported that variation in a number of genes (e.g., PPARg, IRS-1, IRS-2, calpain-10, PPP1R3) has significant impact upon glucose tolerance in women with PCOS and their first-degree relatives.

Most recently we have embarked upon a series of studies to examine “environmental” influences on the PCOS phenotype. It has recently been reported that obstructive sleep apnea is up to 40 times more common in PCOS than in weight-matched control women. Because the risk imparted by obesity does not appear to be sufficient to fully account for this high prevalence of obstructive sleep apnea in PCOS, gender-based differences in sleep architecture and hyperandrogenemia, among others, are likely to play important roles in this population. Our NIH-funded studies are designed to determine the direction of causality between sleep loss resulting from obstructive sleep apnea and the hormonal alterations that characterize PCOS. In particular, we are focused upon the features of the metabolic syndrome that are extremely common in PCOS: glucose intolerance, hypertension, dyslipidemia, coronary, and other vascular diseases. We have devised protocols to test two alternative hypotheses: 1. sleep disturbances are caused by the hormonal alterations (hyperandrogenemia and hyperinsulinemia) of PCOS; 2. sleep disturbances cause the hormonal, metabolic and cardiovascular alterations seen in women with PCOS. Because a relationship between obstructive sleep apnea, insulin resistance and elevated testosterone levels has also been observed in men and in women without PCOS, insights gained from these studies may provide a greater understanding of these relationships in other populations.