Clinical, Hormonal, and Radiological Studies at Baseline, During and After Long Term GnRH Analog (Leuprolide) Treatment in Adolescent Hirsute Females with Increased Ovarian Androgen Production Due to Polycystic Ovary Syndrome
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To determine the site of primary pathogenesis in the hypothalamic-pituitary-ovarian (H-P-O) axes, which results in excess ovarian androgen secretion in polycystic ovary syndrome (PCOS), we investigated H-P-O axes function at baseline, during, and after long term H-P-O axes suppression in adolescent and young adult females with increased ovarian androgen production due to PCOS. Five hirsute females with menstrual disorders and PCOS, ranging from 12 to 22 yr of age, were evaluated for androstenedione (Δ4-A) and testosterone (T) levels, LHRH-stimulated LH and FSH levels, pelvic ultrasound, bone density, and hirsute score before, during (at 3, 6, and 12 to 15 months) and after (1 to 4 months) 8 to 15 months of combined leuprolide acetate and oral contraceptive replacement therapies. Before treatment, baseline serum Δ4-A (8.6 ± 1.7 nm/L) and T levels (3.3 ± 1.7 nm/L) in the PCOS females were highly elevated (p<0.001) compared to levels in the normal females (Δ4-A 4.7 ± 2.7 nm/L; T 1 ± 0.4 nm/L). LHRH-stimulated peak LH levels (85 ± 58 mIU/ml) in the PCOS females were elevated but not significantly from the levels of normal females in the follicular phase of the menstrual cycle (60 ± 10 mIU/ml). LHRH-stimulated FSH responses were similar between PCOS and normal females. The treatment with leuprolide acetate alone or with oral contraceptives in all patients resulted in suppression of elevated Δ4-A, T, and LHRH-stimulated LH and FSH levels beginning at 3 months to the end of treatment. Hirsute score and ovary size decreased during treatment. Following discontinuation of the treatment (1 to 4 months), serum T levels (2.4 ± 1.6 nm/L) in PCOS females rose promptly above the T levels of normal females. LHRH-stimulated LH levels (26 ± 21 mIU/ml), however, were below the follicular phase response of normal females. Lumbar bone density did not change appreciably in any patient. Conclusion: The combined GnRH analog and oral contraceptive treatment effectively suppressed gonadotropin and ovarian androgen secretion in young females with PCOS, which resulted in improved hirsute score without causing osteoporotic changes. The prompt and excess rise in serum T levels in the face of only partially restored LHRH-stimulated LH secretion after discontinuation of the treatment indicates the presence of an intra-ovarian or systemic factor rather than a hypothalamic-pituitary (gonadotropic) factor facilitating excess ovarian androgen secretion in PCOS.
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