GnRH agonists (GnRH-A) have been used for the treatment of hirsutism in women with ovarian hyperandrogenism. However, significant side-effects, including vasomotor symptoms and bone loss, have prevented the long term use of this therapy. In this study, we evaluated the effects of low dose (physiological) estrogen replacement on the side-effects and clinical and hormonal parameters of 22 hirsute women with ovarian hyperandrogenism when treated with a long-acting GnRH-A, Decapeptyl. Ten patients with Ferriman-Gallwey (FG) scores averaging 13.4 +/- 1.5 were randomly assigned to be treated with Decapeptyl alone (3.75 mg, im, every 28 days for 6 months), and 12 other patients with FG scores averaging 13.3 +/- 1 received Decapeptyl with estrogen (conjugated equine estrogens, 0.625 mg) for 21 days and medroxyprogesterone acetate (10 mg) for 10 days (days 12-21). After 6 months, LH was suppressed in both groups, whereas FSH was significantly reduced only in the group receiving GnRH-A with estrogen (2.5 +/- 4 vs. 4.8 +/- 0.6 IU/L; P < 0.01). Serum androgen levels were reduced in both groups, although the reduction of testosterone and unbound testosterone was greater in the group receiving hormonal replacement [1.73 +/- 0.3 vs. 2.57 +/- 0.4 nmol/L for testosterone (P < 0.05); 8.3 +/- 1 vs. 14.6 +/- 2.8 pmol/L for unbound testosterone (P < 0.05)]. The reduction in hirsutism scores was greater with hormonal replacement (FG scores, -4.1 +/- 0.3 vs. -2.5 +/- 0.3; P < 0.05), whereas the polycystic appearance of ovaries by ultrasound was decreased in both groups. Amenorrhea and vasomotor symptoms were observed only with GnRH-A alone. Serum osteocalcin rose significantly with GnRH-A alone, reflecting a change in bone turnover (0.49 +/- 0.05 to 0.64 +/- 0.09 nmol/L; P < 0.05), but was unchanged with hormonal replacement. Patients receiving hormonal replacement had treatment extended to 1 yr. A further improvement of hirsutism, with scores dropping into the normal range (4.9 +/- 0.7), as well as a normalization of ovarian morphology were evident at this time. In conclusion, low dose (physiological) estrogen replacement may enhance the effects of GnRH-A treatment, while preventing most of the side-effects encountered with GnRH-A alone. This may allow more prolonged treatment, which is necessary for hirsutism.
