Kisspeptin-10 stimulation of gonadotrophin secretion in women is modulated by sex steroid feedback

Abstract

Does sex-steroid feedback influence gonadotrophin responses to kisspeptin-10? Gonadotrophin response to kisspeptin-10 is enhanced in sex-steroid deficient post-menopausal women and suppressed in women taking pharmacological doses of exogenous estrogen and progestogen. Kisspeptin, a novel hypothalamic neuropeptide, stimulates gonadotrophin secretion by stimulating GnRH secretion and has been shown in animal models to play a pivotal role in mediating sex steroid feedback. As estrogen feedback occurs at both the hypothalamus and the pituitary levels, we hypothesized that the stimulatory effect of kisspeptin-10 in women would be dependent on prevailing sex steroid milieu. An experimental study of a novel neuropeptide in women-10 in the early follicular phase, 6 post-menopausal and 8 taking sex-steroid contraceptives (combined pill, n = 4; progestogen implants, n = 4) with suppressed LH secretion. Gonadotrophin secretion was followed for 60 min after kisspeptin administration. The gonadotrophin response to intravenous kisspeptin-10 (0.3 µg/kg) in women in the early follicular phase was compared with that in the presence of low endogenous sex steroids/high gonadotrophin secretion (post-menopausal women) and in women taking sex-steroid contraceptives (combined pill, n = 4; progestogen implants, n = 4) with suppressed LH secretion. Area under the curve (AUC) of gonadotrophin secretion sampled at 15 min intervals over 60 min before and after kisspeptin-10 was analysed. Kisspeptin-10 stimulated LH secretion in follicular (ΔAUC 2.3 ± 0.8 IU/l h, P = 0.009), post-menopausal (5.3 ± 0.9 IU/l h P 0.002) and progestogen (2.6 ± 0.8 IU/l h P 0.05) groups but not in women taking combined pill (0.9 ± 0.4 IU/l h P 0.13). FSH secretion was significantly increased only in post-menopausal women (ΔAUC 2.6 ± 0.8 IU/l h P = 0.03) with changes of <0.5 IU/l h observed in the other three groups. Both LH and FSH responses in post-menopausal women were significantly larger than the other groups (one-way ANOVA analysis of ΔAUC; LH (P = 0.012) and FSH (P = 0.001)]. This study only assessed acute responses to an intravenous bolus of kisspeptin-10 administration, and the impact of continuous exposure to kisspeptin-10 on LH pulse frequency in women remains to be studied to fully understand the translational potential. Gonadotrophin secretion in women is stimulated by kisspeptin-10. These results suggest that the pituitary gonadotrope is a functionally important locus of estrogen feedback in women and also inform potential translational applications of kisspeptin in reproductive endocrine disorders. Medical Research Council (UK). None.