Adrenal androgen (AA) production is frequently abnormal in women with hyperandrogenic oligoovulation (HO). A number of investigators, including ourselves, have noted that AA excess may result from a generalized adrenocortical hyper-reactivity to adrenocorticotropic hormone (ACTH) or pituitary overresponse to corticotropin releasing hormone (CRH). This adrenocortical dysfunction may represent an acquired defect secondary to excessive ovarian secretion of androgens, such as testosterone. Alternatively, the dysfunction may represent an inherited abnormality, such as heterozygosity for 21-hydroxylase (21-OH) deficiency. Regardless of the etiology, the significance of AA excess in the maintenance of ovulatory dysfunction in HO is unclear.
The Specific Aims of the proposal include: 1) to establish the sensitivity and responsivity to ACTH and CRH in HO patients with and without adrenocortical dysfunction; 2) to establish the role of ovarian factors in the development/maintenance of adrenocortical dysfunction; 3) to establish the role of mild inherited defects in adrenal 21-OH function in the development of HO; 4) and to establish the role of AA excess in the maintenance of ovulatory dysfunction in HO patients, while elucidating endocrine markers for a favorable response to corticosteroid suppression. To achieve Specific Aim 1 the adrenocortical sensitivity and responsivity to incremental doses of ACTH, and to ovine CRH, will be determined in 10 HO patients with and 10 without adrenocortical hyperreactivity, and in 10 control women.
For Specific Aim 2 ten HO patients with and 10 without adrenocortical dysfunction will undergo three months of ovarian suppression using a long-acting GnRH-a, and alterations in basal androgen profiles, response to ovine CRH and ACTH, and glucose tolerance will be assessed.
For Specific Aim 3 at least 30 females who are obligate heterozygotes for 21-OH deficiency will be studied for the presence of HO. To achieve Specific Aim 4 at least forty consecutive patients presenting with HO will be treated with three months of dexamethasone (0.5 mg/day), and their clinical response correlated with various adrenocortical markers. These studies will shed light on the etiology and role of adrenocortical of HO.
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