Abstract
Estrogen produced by ovarian follicles plays a key role in the central mechanisms controlling reproduction via regulation of gonadotropin-releasing hormone (GnRH) release by its negative and positive feedback actions in female mammals. It has been well accepted that estrogen receptor α (ERα) mediates both estrogen feedback actions, but precise targets had remained as a mystery for decades. Ever since the discovery of kisspeptin neurons as afferent ERα-expressing neurons to govern GnRH neurons, the mechanisms mediating estrogen feedback are gradually being unraveled. The present article overviews the role of kisspeptin neurons in the arcuate nucleus (ARC), which are considered to drive pulsatile GnRH/gonadotropin release and folliculogenesis, in mediating the estrogen negative feedback action, and the role of kisspeptin neurons located in the anteroventral periventricular nucleus-periventricular nucleus (AVPV-PeN), which are thought to drive GnRH/luteinizing hormone (LH) surge and consequent ovulation, in mediating the estrogen positive feedback action. This implication has been confirmed by the studies showing that estrogen-bound ERα down- and up-regulates kisspeptin gene (Kiss1) expression in the ARC and AVPV-PeN kisspeptin neurons, respectively. The article also provides the molecular and epigenetic mechanisms regulating Kiss1 expression in kisspeptin neurons by estrogen. Further, afferent ERα-expressing neurons that may regulate kisspeptin release are discussed.
Highlights
It has been well accepted that estrogen produced by the ovary plays an indispensable role in the female reproductive system via its feedback actions on gonadotropin-releasing hormone (GnRH) release in mammals
A previous study demonstrated that estrogen receptor α (ERα) knock-in/knockout (KIKO) mice, in which a mutant ERα (E207A/G208A) lacks the binding ability for the estrogen response element (ERE) but is capable of interacting with other transcriptional partners [29,30], showed the negative, but not the positive, feedback action of estrogen on luteinizing hormone (LH) release [31]. These findings suggest that the negative feedback action of estrogen on GnRH pulses is likely mediated via some gene(s) controlled by the ERE-independent estrogen–ERα signaling and that the estrogen positive feedback action is likely mediated via some gene(s) controlled by the ERE-dependent estrogen–ERα signaling
LH pulses in OVX rats in 1983; Nagatani et al [40] showed that estrogen micro-implants in the arcuate nucleus (ARC) suppressed LH pulses in both fasted and re-fed OVX rats, while the estrogen implants in either the paraventricular nucleus (PVN) or brainstem A2 region suppressed LH pulses in only fasted rats in 1994. These findings suggested that the negative feedback action of estrogen may be mediated by ERα-expressing neurons located in the ARC under the normal nutritional condition and by multiple ERα-expressing neurons located in the ARC, PVN, and brainstem A2 region under the malnutritional condition
Summary
It has been well accepted that estrogen produced by the ovary plays an indispensable role in the female reproductive system via its feedback actions on gonadotropin-releasing hormone (GnRH) release in mammals. Estrogen production and release gradually increase along with the follicular development, and consequent high levels of circulating estrogen derived from mature follicles ( known as Graafian follicles), in turn, induce a large release of hypothalamic GnRH and pituitary LH (GnRH/LH surge). This is the so-called “positive feedback action of estrogen” on GnRH release, and the LH surge evokes ovulation. Estrogen replacement at a physiological level (not a preovulatory level) suppressed tonic pulsatile LH release in ovariectomized (OVX) rhesus monkeys [8] These findings suggest that estrogen secreted from the ovary is a major humoral factor that exerts its negative feedback action on the tonic pulsatile LH release. It is plausible that estrogen regulates the activity of GnRH pulse and surge generators via the negative and positive feedback actions, respectively
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