Alterations in sex steroids and gonadotropins in post-menopausal women subsequent to long-term mifepristone administration

Long-term administration of progesterone antagonists (PAs) and progesterone receptor modulators (PRMs) has been proposed as a novel hormonal therapy f or various hormone dependent maladies. We studied the long-term endocrine e ffects of mifepristone on the kinetics of estradiol (E-2) and its precursor s, and on gonadotropin levels in five postmenopausal women treated for unre sectable meningioma with mifepristone [200 mg/day] for at least 15 months. Serum samples were analyzed for LH, FSH and SHBG with fluoroimmunoassay; an drostenedione (A), testosterone (T), estrone (E-1) and E-2 were measured wi th radioimmunoassay (RIA). Serum levels of mifepristone were measured using both RIA and high performance-liquid chromatoraphy (HPLC). Serum levels (m ean +/- SD) of LH and FSH were suppressed from pretreatment values of 32 +/ - 16 and 65 +/- 30 IU/l to 13 +/- 7 and 33 +/- 16 IU/l at 6 months (P < 0.0 5), respectively. Serum (mean +/- SD) A, T, E-1, and E-2 were increased fro m initial values of 6.9 +/- 0.9 nmol/l, 1.2 +/- 0.3 nmol/l, 77 +/- 25 pmol/ l, and 29 +/- 14 pmol/l to 6 month values of 13.1 +/- 5.6 nmol/l, 1.8 +/- 0 .6 nmol/l, 178 +/- 60 pmol/l, and 45 +/- 22 pmol/l (n.s.). The correlation coefficients between the levels of A, T, E-1, and E-2 were statistically si gnificant, whereas the ratios of T/A, E-1/A, E-2/E-1, and E-2/T remained un changed. The levels of SHBG remained stable, and ranged from 48 +/- 10 to 6 5 +/- 9 nmol/l (mean +/- SD). Thus, prolonged mifepristone treatment margin ally increased the serum levels of A, T, E-1 and E-2. These effects of mife pristone are likely due to its antiglucocorticoid effect and thus increased secretion of adrenal A. Serum levels of LH and FSH declined. The serum lev els of gonadotropins and those of T, E-1 and E-2 were inversely, yet signif icantly, correlated. Therefore the decrease in LH and FSH might reflect the slightly increased levels of T, E-1 and E-2. However, the lack of change i n SHBG and the low E-2 levels suggest that enhanced systemic estrogen effec ts are unlikely during long-term mifepristone treatment. (C) 2000 Elsevier Science Inc. All rights reserved.