In normally cycling women, changes in circulating oestradiol con centrations reflect follicular development during the follicular phase and corpus luteum function during the luteal phase. In general, oestrogens restrain gonadotropin secretion; and oestrogen deficiency (e.g. natural or surgical menopause) leads to a marked increase in gonadotropin secretion. Oestrogen restraint at the hypothalamus primarily reflects reductions in GnRH pulse amplitude rather than pulse frequency. GnRH pulse amplitude, but not GnRH pulse frequency, are increased in postmenopausal women and in ovariectomized post- pubertal female monkeys, and this is reversed with oestrogen replacement. Low- dose oestradiol administration does not substantively alter LH release in GnRH- deficient women treated with fixed- dose exogenous GnRH pulses.
Day- to- day changes in GnRH pulse frequency primarily reflect the imposition and removal of progesterone negative feedback. In the early luteal phase, the increase in progesterone secretion from the corpus luteum slows LH pulse frequency, and exogenous progesterone slows follicular phase LH pulse frequency. This effect of progesterone requires the permissive presence of oestradiol, likely through increased hypothalamic progesterone receptor expression. In contrast, androgens appear to reduce hypothalamic progesterone receptor expression and, thus, an tagonize progesterone’s ability to inhibit GnRH pulse frequency. At the gonadotrope, progesterone augments pituitary gonadotropin responses to GnRH.
Sex steroid feedback on GnRH secretion appears to be largely mediated by kisspeptin (KNDy) neurons (Figure 1). While GnRH neurons express few sex steroid receptors, kisspeptin and KNDy neurons colocalize with oestrogen, progesterone, and androgen receptors. Oestrogen or oestrogen plus progesterone re duces kisspeptin expression in the arcuate nucleus in monkeys, while kisspeptin expression in the infundibular (arcuate) nucleus is increased in sex steroid deficient monkeys and women. Similarly, postmenopausal women demonstrate fewer infundibular prodynorphin- expressing neurons compared to premenopausal women.
Fig1. Model of kisspeptin and KNDy signalling to GnRH neurons. Kisspeptin (KISS1) stimulates GnRH neurons. KnDy neurons also release neurokinin B (NKB), which stimulates KISS1 release; and dynorphin (Dyn), which inhibits KISS1 release. ERα, oestrogen receptor alpha; KISS1, kisspeptin; ME, median eminence; POA, preoptic area; PR, progesterone receptor. Adapted with permission from Skorupskaite K, George JT, Anderson RA. The kisspeptin- GnRH pathway in human reproductive health and disease. Hum Reprod Update 2014; 20:485– 500. (13). Copyright © 2014, Oxford University Press.
FSH secretion is also selectively impacted by inhibins, activins, and follistatin. Inhibins are heterodimer peptides that selectively inhibit FSH release from pituitary gonadotropes and con tribute to differential LH and FSH release across the menstrual cycle. Two inhibin isoforms contain identical α- subunits but different β- subunits (βA for inhibin A, βB for inhibin B). Inhibin B is primarily secreted by ovarian granulosa cells in response to FSH stimulation during the early follicular phase; while inhibin A is primarily secreted by the corpus luteum in response to LH stimulation during the luteal phase. Activins and follistatin are pituitary gonadotrope products that influence FSH secretion via autocrine- paracrine sig nalling. Activins stimulate production of FSH, while follistatin re duces FSH production by binding activin. Follistatin production varies as a function of GnRH pulse frequency and partly mediates the reduction in FSH production in response to high GnRH pulse frequencies.
