PERIPHERAL ANDROGEN ACTION IN HIRSUTISM

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It has been suggested that measurements of serum 3 Alpha-androstanediol (3 Alpha-diol) reflect peripheral androgen production (PAP). Recently, we have shown that serum 3 Alpha-diol glucuronide (3 ALpha-diol G) is derived almost exclusively from extrasplanchnic sources and is a better marker of PAP than is unconjugated 3 Alpha-diol. In women with idiopathic hirsutism, we found that virtually all women had elevated levels of 3 Alpha-diol G despite normal levels of other androgens. In patients with polycystic ovary syndrome (PCO), we have shown that while all women exhibit elevated levels of androgens derived from glandular sources, the presence or absence of hirsutism may be explained by PAP as reflected by measurements of serum 3 Alpha-diol G. Nevertheless, the blood source of 3 Alpha-diol G has not been established. It is not known whether blood levels of DHT and 3 Alpha-diol G are in equilibrium or if they exist in separate pools. 3 Alpha-diol G is produced, in part, via 5 Alpha reductase (5 Alpha R) and probably reflect 5 Alpha R activity in peripheral tissues. Therefore, we will attempt to correlate serum 3 Alpha-diol G with in vitro 5 Alpha R activity in women. Spironolactone (S) is a receptor blocking agent which improves hirsutism in PCO. Whether S therapy changes serum 3 Alpha-diol G and if this correlates with the improvement in hirsutism should be investigated. In project #1 we propose to obtain blood and genital skin from 15 ovulatory premenopausal patients, from 15 hirsute (H) women with PCO and from 15 normal men. We will attempt to correlate measurements of serum DHT, 3 Alpha-diol G with in vitro DHT and 3 Alpha-diol production. In project #2, 3H-DHEA, 3H-Adione and 3H-DHT will be infused intravenously into 10 H-PCO women and 6 controls until steady state occurs. Conversion ratios between these precursor steroids and 3 alpha-diol G will be calculated. In addition, a 2-day dexamethasone suppression test and a 6-hour ACTH infusion will be carried out in order to help determine the source of serum 3 Alpha-diol G. In project #3, 30 H-PCO women will be treated with S and have the clinical assessment of hirsutism and hormonal measurements carried out before and after treatment at 3-month intervals for 18 months. Hair shaft diameters will be recorded and genital skin biopsies will be obtained after treatment in 10 patients. These studies will help establish the prevalence of PAP and increased 5 Alpha R activity in PCO, the clinical usefulness of measurements of 3 Alpha-diol G and its source(s) in blood. The clinical benefits of treatment with S in H-PCO women will be compared with the assessment of any changes in PAP as reflected by measuremets of 3 Alpha-diol and in 5 Alpha R activity.