David Ehrmann, M.D.

Pathogenesis and Therapy of Hyperandrogenic States and Genetics of Insulin Secretion and Action in Polycystic Ovary Syndrome (PCOS)

Research Summary

Pathogenesis and Therapy of Hyperandrogenic States

Our clinical research studies have been designed to define the mechanisms of ovarian and/or adrenal androgen excess in women presenting with menstrual disturbances, hirsutism, acne and obesity. We have found that women with well-defined PCOS have a characteristic pattern of ovarian steroid secretion in response to the endogenous gonadotropin secretion induced by administration of a gonadotropin releasing hormone agonist. This response, a supranormal elevation of 17-hydroxyprogesterone, suggests abnormal regulation of androgen formation by ovarian 17-hydroxylase and 17, 20-lyase activities and appears to be a unique means for the detection of the functional ovarian hyperandrogenism of polycystic ovary syndrome. In addition, a similar abnormality of ovarian and adrenal steroidogenesis has been elucidated. This abnormality appears to be due to abnormal regulation of the androgen-forming enzyme, cytochrome P450c17.

Additional clinical studies have been carried out in hirsute women with suspected adrenal deficiency of the enzyme 3b -hydroxysteroid dehydrogenase (3b -HSD). This enzyme is common to the adrenal and ovary and women with a putative deficiency should manifest an abnormal ovarian steroidogenic response to nafarelin. The ovarian steroidogenic response to nafarelin in these women did not support the diagnosis of 3b -HSD deficiency. Rather, they were consistent in most cases with polycystic ovary syndrome due to increased activity of cytochrome P450c17.

We have also obtained data which suggest that perinatal exposure of the neuroendocrine axis to excess levels of androgen may program the neuroendocrine system to secrete excessive LH at puberty, thus resulting in ovarian hyperandrogenism. We found that women with congenital adrenal virilization have elevated LH levels at baseline and in response to a test dose of GnRH agonist. These abnormalities are not reversed by glucocorticoid therapy. This "masculinization" of gonadotropin secretion in women appears to depend on the duration and intensity of perinatal androgen exposure.

Finally, we have undertaken studies designed to assess the impact of modulation of insulin resistance on measures of insulin secretion, glucose tolerance, ovarian steroidogenesis, and fibrinolytic capacity. We have studied both metformin and troglitazone. In the case of troglitazone, but not metformin, there is improvement in glucose tolerance, insulin secretion, ovarian androgen excess and inhibition of fibrinolysis.

Genetics of Insulin Secretion and Action in PCOS

We have undertaken studies designed to examine the role of defects in insulin secretion as well as familial factors to the predisposition to NIDDM seen in PCOS. Our current studies are designed to address the following:

• To determine if beta cell secretory dysfunction is more prevalent among insulin resistant women with PCOS compared to similarly insulin resistant controls
• To determine if first-degree relatives of women with PCOS are at increased risk of a) impaired glucose tolerance or NIDDM; b) insulin resistance; c) beta cell secretory dysfunction
• To a) characterize the transmission of beta cell function and insulin sensitivity in families of women with PCOS; b) determine whether the transmission of insulin sensitivity is independent of the transmission of beta cell function; c) characterize the extent to which beta cell dysfunction contributes to the risk imparted by insulin resistance to the development of NIDDM.

Selected Papers

Hara M, Alcoser SY, Qaadir A, Beiswenger KK, Cox NJ, Ehrmann DA (2002). Insulin resistance is attenuated in PCOS women with the Pro12Ala polymorphism in the peroxisome proliferator-activated receptor-y gene (PPARG). J Clin Endocrinol Metab. 87: 772-775.

Ehrmann DA, Schwarz PEH, Hara M, Tang X, Horikawa Y, Imperial J, Bell GI, Cox NJ (2002). Relationship of calpain-10 genotype to phenotypic features of PCOS. J Clin Endocrinol Metab. 87: 1669-1673.

Ehrmann DA, Breda E, Cavaghan MK, Bajramovic S, Imperial J, Toffolo G, Cobelli C, Polonsky K (2002). Insulin secretory responses to rising and falling glucose levels are delayed in subjects with impaired glucose tolerance. Diabetologia. 45: 509-517.

Ehrmann DA, Tang X, Yoshiuchi I, Cox NJ, Bell GI (2002). Relationship of insulin receptor substrate-1 and -2 genotypes to phenotypic features of polycystic ovary syndrome. J Clin Endocrinol Metab. 87: 4297-4300.

Azziz R, Ehrmann DA, Legro RS, Fereshetian AG, O'Keefe M, Ghazzi MN, PCOS/Troglitazone Study Group (2003). Troglitazone decreases adrenal androgen levels in women with PCOS. Fertil Steril. 79: 932-937.

Ehrmann DA, Breda E, Corcoran MC, Cavaghan MK, Imperial J, Toffolo G, Cobelli C, Polonsky KS (2003). Impaired ß-Cell compensation to dexamethasone-induced hyperglycemia in women with polycystic ovary syndrome. Am J Physiol Endocrinol Metab. (E-pub 2003 Dec 09).

Legro RS, Azziz R, Ehrmann DA, Fereshetian AG, O'Keefe M, Ghazzi MN (2003). Lack of response of dyslipidemia in women with polycystic ovary syndrome to improvement in insulin sensitivity with troglitazone. J Clin Endocrinol Metab. 88: 5137-5144.

Alcoser SY, Hara M, Bell GI, Ehrmann DA. (2004). Association of the ARE polymorphism in PPP1R3 with hormonal and metabolic features of polycystic ovary syndrome. J Clin Endocrinol Metab 89: 2973-2976.