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Differential Roles of Hypothalamic AVPV and Arcuate Kisspeptin Neurons in Estradiol Feedback Regulation of Female Reproduction

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Differential Roles of Hypothalamic AVPV and Arcuate Kisspeptin Neurons in Estradiol Feedback Regulation of Female Reproduction At the Cutting Edge Neuroendocrinology 2020;110:172–184 Received: July 10, 2019 DOI: 10.1159/000503006 Accepted after revision: August 28, 2019 Published online: August 30, 2019 Differential Roles of Hypothalamic AVPV and Arcuate Kisspeptin Neurons in Estradiol Feedback Regulation of Female Reproduction a a–c Luhong Wang Suzanne M. Moenter a b Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, USA; Department c of Internal Medicine, University of Michigan, Ann Arbor, MI, USA; Department of Obstetrics and Gynecology, University of Michigan, Ann Arbor, MI, USA Keywords dian eminence and release GnRH near the primary capil- Ovulation · CRISPR · Estradiol · Reproduction · Kisspeptin · laries of the hypophyseal portal vasculature, which carry Anteroventral periventricular nucleus · Arcuate this decapeptide to the pituitary where it activates the synthesis and secretion of the gonadotropins luteinizing hormone (LH) and follicle-stimulating hormone (FSH) Abstract [1, 3]. GnRH is released in an episodic, or pulsatile, man- Mammalian reproductive function includes puberty onset ner that is critical for pituitary function [4–6]. High and completion, reproductive cyclicity, steroidogenesis, ga- GnRH pulse frequency favors LH synthesis and release, metogenesis, fertilization, pregnancy, and lactation; all are whereas low GnRH pulse frequency preferentially pro- indispensable to perpetuate species. Reproductive cycles motes FSH [7–9]. FSH and LH regulate gametogenesis are critical for providing the hormonal milieu needed for fol- and steroidogenesis [10]. The sex steroids, including es- licular development and maturation of eggs, but cycles, in tradiol, progesterone, and testosterone, feed back to the and of themselves, do not guarantee ovulation will occur. brain to regulate GnRH release, and on the pituitary to Here, we review the roles in female reproductive neuroen- regulate the responsiveness of gonadotropes to GnRH docrine function of two hypothalamic populations that pro- [11–16]. In males and during most of the female repro- duce the neuropeptide kisspeptin, demonstrating distinct ductive cycle, sex steroids suppress GnRH neuron activ- roles in maintaining cycles and ovulation. ity and release via negative feedback [17–22]. During the © 2019 S. Karger AG, Basel preovulatory stage of the female cycle (late follicular phase or proestrus in rodents), a sustained elevation in estradiol causes a switch of estradiol action from negative The Reproductive Axis and Estradiol Feedback to positive feedback, thus inducing elevated GnRH neu- ronal activity and causing a preovulatory surge of GnRH, Gonadotropin-releasing hormone (GnRH) neurons and subsequent LH, release [6, 23–25]. The LH surge trig- integrate central, peripheral, and external cues to gener- gers ovulation. There is some debate in higher primates ate the central output that regulates fertility [1, 2]. GnRH about the necessity of the GnRH surge for ovulation, as neurons reside primarily in the preoptic area (POA) and an LH surge can occur without a change in episodic re- anterior hypothalamus. These neurons project to the me- lease in women [26], and an unchanging frequency of © 2019 S. Karger AG, Basel Suzanne M. Moenter Department of Molecular and Integrative Physiology, University of Michigan 7725 Med Sci II, 1137 E Catherine St E-Mail [email protected] Ann Arbor, MI 48109-5622 (USA) www.karger.com/nen E-Mail smoenter @ umich.edu GnRH pulse administration can induce cycles in mon- ceptor α (ERα) and ER β [43–45], as well as membrane- keys in which endogenous GnRH was ablated [4]. In this associated receptors (GPR30 and mER) [46–48]. In ro- regard, it is worth noting that in monkeys, GnRH surges dents and humans, the two nuclear receptors are encoded have been observed along with the preovulatory or estra- by Esr1 (human ESR1) and Esr2 (human ESR2), respec- diol-induced LH surge [27, 28]. In rodents and sheep, a tively. Both ERα and ERβ typically act as ligand-activated surge release of GnRH is required for the LH surge [25, transcription factors [49], by either binding directly to 29, 30]. The investigation of estradiol feedback regulation estrogen response elements or interacting with other pro- of the hypothalamus has focused mainly on ovarian estra- teins to alter gene expression [50, 51]. ERα and ERβ can diol as it is the predominant signal to generate the switch also modulate nongenomic membrane-associated signal- between negative and positive feedback. For a recent re- ing cascades [47, 52–55]. Genomic and nongenomic ac- view on the possible role of local neurosteroids in these tions of ERs are evident for many reproductive processes processes, the reader is directed to Terasawa et al. [31]. [50, 56]. For example, signaling via the estrogen response With the help of the advanced genetic and other tech- element is needed for estradiol-induced changes in GnRH nical tools available, much of the work to understand neuron firing rate [57], whereas nonclassical signaling central control of fertility has been done in rodents, spe- also plays a role in this response at the pituitary [58]. Mice cifically laboratory mice. To study systemic estradiol reg- with global knockout of ERα or ERβ show distinct repro- ulation, both stages of the estrous cycle characterized by ductive deficits. ERαKO mice are infertile and have dis- negative (diestrus) and positive (proestrus) feedback and rupted reproductive tracts including hypoplastic uteri hormone manipulation have been used [32, 33]. With re- and large hemorrhagic cysts and absence of corpora lutea gard to the latter, one paradigm utilizes ovariectomy in the ovaries [59]. In contrast, ERβKO mice are fertile (OVX) with low estradiol replacement (OVX+E, negative but have fewer and smaller litters [59, 60]. Further, feedback), followed by a subsequent estrogen injection ERαKO, but not ERβKO, female mice exhibit atypically several days later to induce positive feedback (OVX+E+E); elevated serum LH in ovary-intact mice compared to this is referred as the estradiol rise model [34]. Another their littermate controls. Likely related to this, estradiol paradigm utilizes OVX with or without a constant high replacement in OVX ERαKO females does not reduce LH physiological level of estradiol [17]. This daily surge mod- [61]. A neuron-specific ERα KO mouse model shares el exhibits a diurnal switch in estradiol feedback, with LH similarly impaired negative feedback as the ERαKO mice levels lower in estradiol-treated than OVX mice due to as well as disrupted positive feedback marked by an ab- estradiol negative feedback in the morning (OVX+E AM) sence of estradiol-induced LH surge release [62]. Togeth- and higher in estradiol-treated mice in the afternoon due er, these observations suggest that estradiol negative and to positive feedback (OVX+E PM). As with LH in vivo, positive feedback rely on estrogen signaling via ERα. Al- GFP-identified GnRH neurons in brain slices prepared though tightly regulated by estradiol, GnRH neurons do from this model exhibit low firing rates and release fre- not express detectable levels of ERα; their response is thus quency in OVX+E AM mice and high firing rates and at least in part attributable to estradiol action through up- release frequency in OVX+E PM mice [17, 18]. Fast syn- stream ERα-expressing neurons [63, 64]. The upstream aptic transmission to and intrinsic membrane properties neurons that have by far been the subject of the most in- and ionic conductances of GnRH neurons are both al- vestigation for its role in estradiol feedback over the past tered by estradiol in this model [35–40]. Similar changes 15 years are kisspeptin neurons. occur between positive feedback during the cycle [33, 41]. Recent studies further demonstrated that GnRH neurons integrate fast synaptic and intrinsic changes to increase Kisspeptin Signaling firing rates during positive feedback [42]. The discovery of the link between KISS1 (produce kis- speptin) and KISS1R (produce kisspeptin receptors) Estrogen Receptors Involved in Systemic Estradiol genes and puberty and fertility comes from human stud- Feedback ies. Patients carrying mutations in either of these genes exhibit idiopathic hypothalamic hypogonadism, im- The physiological responses to systemic estradiol in paired pubertal maturation, and low-amplitude LH puls- regulating reproductive functions are primarily mediated es [65, 66]. Transgenic mice that lack Kiss1 or Kiss1r ex- by two known subtypes of nuclear receptors, estrogen re- hibit a similar hypothalamic hypogonadism phenotype Brain Sites for Estradiol Feedback Neuroendocrinology 2020;110:172–184 173 DOI: 10.1159/000503006 [66, 67]. Kisspeptin is expressed in several organs includ- keys, goats, sheep, and rodents [91–94]. In rats, sheep, ing gonads, pancreas, colon, pituitary, and brain [68, 69]. and goats, only a small percent of GnRH neurons are in In mouse hypothalamus, kisspeptin expression is restrict- the MBH, suggesting that other neurons in the MBH are ed to two regions: the arcuate nucleus and the anteroven- involved in generating MUA peaks and perhaps pulse tral periventricular nucleus (AVPV) [70]. Both popula- generation. tions express ERα, ∼99% in the arcuate and ∼70% in the Identification of a role of kisspeptin in fertility refo- AVPV [71]. Arcuate kisspeptin expression is similar in cused attention on the arcuate region, as arcuate kiss- both sexes, whereas AVPV kisspeptin expression is more peptin neurons exhibit two characteristics needed for ste- extensive
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