Endocrinology: The effect of flutamide on pulsatile gonadotrophin secretion in hyperandrogenaemic women

Abstract

The pulsatile gonadotrophin secretion in hyperandrogenaemic women was examined, following short-term androgen antagonism induced by flutamide, a specific androgen receptor blocker. Flutamide was administered to seven hyperandrogenaemic women and five normal cycling women, at a dose of 250 mg on the evening of day 1, followed by daily doses of 750 mg for 6 days. Blood samples were collected at 10 min intervals for 8 h before (day 1) and during treatment (days 2 and 6). Gonadotrophin and prolactin concentrations were measured in all samples while sex hormone concentrations were analysed in selected samples. Flutamide administration to hyperandrogenaemic women was followed by a decrease in luteinizing hormone (LH) pulse amplitude (P < 0.05), associated with an apparent decline in mean LH concentrations. Follicle stimulating hormone (FSH) showed a significant fall after 6 days of treatment (P < 0.05). Total testosterone, free testosterone, androstenedione and dihydroepiandrosterone sulphate were significantly decreased during flutamide administration, while sex-hormone-binding globulin and oestradiol were not affected. Normal women showed no significant changes in the above mentioned parameters. These results demonstrate that short-term androgen receptor blockade with flutamide reduces gonadotrophin secretion and androgen concentration in hyperandrogenaemic women. Since flutamide is devoid of intrinsic hormonal activity, it is suggested that the observed hormonal changes are secondary to the androgen blockade.

Neuroendocrine Effects of Androgens in Adult Polycystic Ovary Syndrome and Female Puberty

“…Androgen infusions did not alter LH pulse frequency in women with PCOS, 31 and shortterm ( 1 month) treatment with the androgen receptor blocker flutamide did not alter basal LH pulse patterns in women with PCOS or normal controls. 32,33 However, an indirect effect of HA is suggested by the ability of flutamide to restore sensitivity of the GnRH pulse generator to suppression by E2 and P (Fig. 1).…”

Increase in daily LH secretion in response to short-term calorie restriction in obese women with PCOS

“…However, several studies have suggested that androgens exert a paradoxical effect on gonadotropin secretion in women with PCOS. In particular, (sub)chronic blockade of androgen receptors by flutamide appears to blunt LH pulsatility in PCOS (10,39), which supports the thesis that hyperandrogenemia impairs estrogen and progesterone negative feedback restraint of LH release in these patients (17,34) and in experimental animal models of the syndrome (14). In this scenario, a reduction of testosterone concentrations would be expected to reduce pulsatile LH secretion in women with PCOS by enhancing hypothalamic feedback sensitivity to estrogens/progesterone.…”

Neuroendocrine Dysfunction in PCOS: A Critique of Recent Reviews

“…Indeed, flutamide administration to hyperandrogenic women is followed by a decrease in LH pulse amplitude associated with an apparent decline in mean LH concentrations. [29][30][31] Androstenedione concentrations significantly decrease during flutamide administration, while sex-hormone-binding globulin and estradiol are not affected. 31 On the other hand, reduction in estradiol alone via treatment with aromatase inhibitors does not alter LH significantly and in fact increases LH pulse amplitude and frequency slightly in association with increased androgens.…”

“…[29][30][31] Androstenedione concentrations significantly decrease during flutamide administration, while sex-hormone-binding globulin and estradiol are not affected. 31 On the other hand, reduction in estradiol alone via treatment with aromatase inhibitors does not alter LH significantly and in fact increases LH pulse amplitude and frequency slightly in association with increased androgens. 32 Furthermore, in patients with androgen secreting ovarian neoplasms, LH is high but returns to normal after tumor removal.…”