ADRENAL ANDROGEN EXCESS--HYPERANDROGENIC OLIGO-OVULATION

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.