Adrenal Hyperplasia Among Young Patients With Polycystic Ovarian Syndrome

Polycystic ovarian syndrome (PCOS) is a heterogeneous group of disorders presenting with hyperandrogenism in adolescents and young women. The etiology of this condition remains unknown, despite its many identified links to insulin resistance, hypertension and metabolic syndrome, as well as its potential connection to the various forms of congenital adrenal hyperplasia (CAH).

The adrenal glands are the only source in the body of adrenocortical steroids. In normal physiology, the pituitary hormone ACTH regulates the secretion of glucocorticoids, while the secretion of mineralocorticoids is controlled by the renin-angiotensin system. In addition to these two steroids, the adrenal gland secretes lesser amounts of intermediate metabolites of these steroids, as well as the sex-steroids DHEA, DHEAS, androstenedione, testosterone, estrogen, and estrone. Dysregulated secretion of any of these hormones can be caused by the development of hyperplasia of the adrenocortical tissue, which may be mild and lead to specific clinical syndromes depending on the identity of the secreted hormones. Bilateral adrenocortical hyperplasia (BAH) is now an increasingly diagnosed cause of adrenal dysfunction.

We propose that there is a subgroup of patients with PCOS who actually have non-CAH primary forms of BAH. To investigate this possibility, we propose to study the hypothalamic-pituitary-adrenal axis (HPAA) over the next 2 years in 120 young girls and women (ages 16 to 25 years) that we will compare to 30 age- and race-matched normal females. Patients will be recruited primarily (although not exclusively) from a busy New York City clinic run by the Pediatric Endocrine Division at the Infants and Children's Hospital of Brooklyn at Maimonides and SUNY Downstate. All patients will undergo standard testing of the HPAA including oral low- and high-dose dexamethasone (DEX)-suppression testing (Liddle s test). Paradoxical rise of cortisol and/or other steroid metabolites in response to DEX is considered a sensitive test for the diagnosis of BAH. Patients with such responses will be molecularly investigated for the known causes of BAH (GNAS, PRKAR1A, PDE11A, PDE8B and other mutations).

The first goal of this study is to identify any possible contributions of the BAH phenotypes and genotypes to the pathophysiology of PCOS, a yet unknown factor in the etiology of this multifaceted disorder. The second goal is to perform a comparative analysis of the expression of large sets of genes in cells of these patients using gene arrays and other genetic analyses. This study will generate important information about the molecular pathways that are affected in this subgroup of patients with PCOS. Thirdly, this study will also allow for the collection of DNA from affected and non-affected relatives of the patients to perform genetic studies and identify causative genetic defects. Finally, the study is expected to lead to new diagnostic and therapeutic methods for at least certain forms of PCOS.