Hypothalamic Control of Female Reproduction
Summary and Keywords
Female reproduction is an interplay between the hypothalamus, pituitary, and ovaries. While the gonadotropin releasing hormone (GnRH) neuron in the hypothalamus regulates gonadal function through the pituitary, GnRH neuronal activity is also profoundly influenced by ovarian steroid hormones. GnRH is released from GnRH neurons in a pulsatile manner after integration of a diverse array of internal and external milieus. Since the discovery of the mammalian GnRH molecule, over a dozen GnRH forms have been identified in the animal kingdom, and large numbers of publications in various lab animal and human studies suggest that GnRH neurons are regulated by multiple neuromodulators in the brain, such as kisspeptin, neurokinin B, β-dynorphin, neuropeptide Y, GnIH, GABA, glutamate, and glial factors. A recent emerging concept is that steroids synthesized locally in the hypothalamus, namely, neuroestradiol and neuroprogesterone, also contribute to the regulation of GnRH neuronal activity, and hence female reproduction. Together with modulation by various inputs and ovarian steroid feedback, GnRH neurons are responsible for puberty, cyclic ovulation, and menopause.
A hallmark of female reproduction is the process of oogenesis, defined as the maturation of immature diploid sex cells (oogonium) into mature haploid cells (ovum). Oogenesis in viviparous mammals begins while the fetus is developing in the womb, is arrested at or near birth until it resumes at the initiation of puberty, continues through the ovarian cycle in adults culminating in ovulation of a mature ovum, and finishes the final maturational steps during fertilization. The timing and maturational processes largely depend on the breeding strategy of the species, but in all cases they are guided by folliculogenesis and steroidogenesis in the ovaries. It is the coordination of these essential functions in the ovary throughout an ovulatory cycle, with a concurrent uterine cycle, and sexual behavior that together comprise the female reproductive system.
The successful completion of oogenesis and coordination of these systems precariously rely on the proper function of a relatively small number of neurons distributed in the preoptic area (POA) and medial basal hypothalamus (MBH). These neurons, named gonadotropin releasing hormone (GnRH) neurons, release the decapeptide hormone, GnRH. Upon release of GnRH to the portal vasculature and diffusion into the anterior pituitary gland, GnRH binds to GnRH receptors on gonadotropes and subsequently stimulates the release of the gonadotropins (luteinizing hormone, LH, and follicle stimulating hormone, FSH), which are delivered into the general circulation. Upon reaching the ovaries, the gonadotropins control the functions of the ovaries: folliculogenesis, steroidogenesis, ovulation, and luteolysis. Estrogens and progestins synthesized and released from the ovaries, in turn, feed back to the hypothalamus and pituitary through the general circulation to regulate the release of GnRH and gonadotropins, resulting in the uterine (menstrual) cycle. Thus, the GnRH neuronal system is the master regulator of this hypothalamic-pituitary-ovarian axis responsible for female reproduction. Because the GnRH neuron is the key integrator, the composition and maturational pattern of the GnRH neuronal system and the regulatory mechanisms of GnRH release across the ovarian cycle are the focus of this review.
GnRH Neurosecretory System
In the late 1940s, a neurochemical substance in the hypothalamus was predicted to stimulate pituitary LH release. In female rabbits, a reflex ovulatory species, Harris (1948) observed that electrical stimulation of the medial basal hypothalamus induced ovulation without any coitus, and Sawyer et al. (1951) reported that reflex ovulation in rabbits was blocked by pentobarbital anesthesia. Everett and Sawyer (1950) also found that anesthesia with pentobarbital at 2–4 pm. on proestrous afternoon in female rats exhibiting regular 4-day estrus cycles delayed ovulation 24 hours. Harris further demonstrated that the dense fine capillary in the infundibulum transport the neurochemical substance to the anterior pituitary (see Harris, 1955). In 1971, a breakthrough occurred when two independent laboratories led by Andrew Schally and Roger Guillemin isolated and sequenced the mammalian form of the GnRH peptide (Matsuo et al., 1971, Amoss et al., 1971). Meanwhile, Knobil and colleagues, as well as others, revealed that LH (and presumably GnRH) is released episodically into circulation (Dierschke et al., 1970; Gay & Sheth, 1972) and pulsatility of LH release requires the medial basal hypothalamus (MBH, Blake & Sawyer, 1972; Krey et al., 1975; Plant et al., 1978). At about the same time, it was shown that GnRH neurons and their neuroterminals are distributed in the MBH as well as in the preoptic area (POA; Kordon et al., 1974; Barry et al., 1973). Subsequently, pulsatile release of GnRH from the hypothalamus was shown to be essential to stimulate LH release, as pulsatile infusion of synthetic GnRH, but not continuous infusion, maintains LH pulsatility (Belchetz et al., 1978). Importantly, simultaneous direct measurement of GnRH and LH release showed that a pulse of GnRH directly precedes a pulse of LH release (Clarke & Cummins, 1982; Levine et al., 1985). Based on these observations, Knobil (1980) proposed the concept of the GnRH pulse-generator in the MBH. In support of this concept, Kawakami et al. (1982) and Wilson et al. (1984) showed that periodical increases in the firing activity of neurons in the MBH are correlated with LH pulses. Furthermore, mutations in the genes coding for GnRH and its receptor, GnRH-R, cause idiopathic hypogonadotropic hypogonadism (IHH), characterized by delayed or absent puberty and infertility (de Roux et al., 1997; Bouligand et al., 2009); mutations in GnRH (Mason et al., 1986) or GnRH-R in mice also result in infertility (Wu et al., 2010), confirming the importance of GnRH neurons for reproduction. Over the 40 plus years since the isolation and sequencing of the GnRH peptide, substantial progress has been made in understanding the mechanisms responsible for the GnRH pulse generator.
Development and neuroanatomical features of the GnRH neurosecretory system
Development during the fetal period
Unlike most neurons in the brain and spinal cord, which originate from the neural plate, GnRH neurons originate from the olfactory placode during early gestation (Schwanzel-Fukuda & Pfaff, 1989; Wray et al., 1989; Ronnekleiv & Resko, 1990; Quanbeck et al., 1997). Although more recent studies show that a portion of olfactory epithelial (placode) cells originate from neural crest cells—a direct lineage of the neural plate (Whitlock et al., 2003; Forni et al., 2011)—olfactory epithelial cells yield GnRH neurons in mammalian species. After their differentiation, GnRH neurons migrate from the olfactory pit into the brain, namely, to the POA and MBH (Schwanzel Fukuda & Pfaff, 1989; Wray et al., 1989). Failure of GnRH neuronal migration into the hypothalamus in humans due to deficiency of the genes regulating GnRH neuronal migration also results in IHH, such as Kallmann syndrome (Crowley & Jameson, 1992). IHH is also seen in patients with inactivating mutations in genes necessary for regulation of GnRH release (de Roux et al., 1997; Seminara et al., 1998).
GnRH neurons undergo maturational changes during the fetal period, and GnRH neurons are functionally mature before birth (Ronnekleiv & Resko, 1990, also see Terasawa & Fernandez, 2001). Moreover, the negative feedback system by testosterone is already established in male monkey fetuses of embryonic days 179–180, demonstrated by measurements of LH and gonadal steroids in the umbilical cord (Resko et al., 1980; Ellinwood et al., 1982). Similarly, culture of fetal GnRH neurons derived from embryonic day 36 (Terasawa et al., 1993) for several weeks recapitulates fetal development in vivo (Ronnekleiv & Resko, 1990) and follows a similar epigenetic maturational process (Kurian et al., 2010). For example, functional maturation characterized by elevated levels of mRNA expression and pulse frequency of peptide release of GnRH neurons (Kurian et al., 2010) similar to those seen in adult females (Gearing & Terasawa, 1988) requires 3 weeks in vitro culture. As stated earlier, despite the unusual birthplace, GnRH neurons are distributed in the final adult location in the brain and are functionally well matured before birth (Terasawa & Fernandez, 2001).
The distribution pattern and activity of GnRH neurons in the brain are established well before birth. There are only a small number (~2000 in primates and ~800 in rodents) of GnRH perikarya diffusely distributed within the MBH and POA, intermingled among a large number of neurons and glia (Goldsmith et al., 1983, Silverman et al., 1977). Importantly, only a few GnRH neurons are necessary for positive and negative feedback effects of estradiol and cyclic ovulation in mice (Gibson et al., 1997; Herbison et al., 2008).
The morphology of GnRH neurons is unique. Their neuroprocesses are long, spanning several millimeters in length and containing many synaptic spines (Campbell et al., 2005), and they make many different types of connections, including axo-axonal, dendro-dendritic, and axo-somatic (Hrabovszky & Liposits, 2013). GnRH neurons also express many neurotransmitter/neuromodulator receptors (Todman et al., 2005). Unlike most neurons in the brain, however, their neuroprocesses have both dendritic and axonal characteristics (Herde et al., 2013). Based on their observations, Herbison and colleagues have proposed the term “dendron” to describe this unique morphology of GnRH neuroprocesses/projections (Iremonger & Herbison, 2015). Given the long processes of a GnRH neuron, regulation of GnRH release by other synaptic and nonsynaptic input takes place along the entirety of the neuron.
Cell bodies and neuroterminals of GnRH, kisspeptin, and dopamine neurons are present in the primate median eminence (Anthony et al., 1984; Ramaswamy et al., 2008; Goldsmith et al., 1990). GnRH neurons send the majority of their projections (neuroprocesses) to the median eminence and the pituitary stalk, where GnRH peptide is released to stimulate synthesis and secretion of pituitary gonadotropins. The primate has a long pituitary stalk. Neuroterminals of many neuropeptide neurons and neurotransmitter neurons, such as thyrotropin releasing hormone (TRH), corticotropin releasing hormone (CRH), and growth hormone releasing hormone (GHRH), somatostatin, and dopamine converge at the external zone of the median eminence (Wells & Murphy, 2003; Romero-Fernandez et al., 2014) and the pituitary stalk, and send signals to the anterior pituitary gland. Additionally, GnRH neurons interact with kisspeptin, neurokinin B (NKB), and substance P neuroprocesses at the median eminence and pituitary stalk (Borsay et al., 2014). Collectively, in addition to the synaptic input at the cell bodies, interactions of GnRH neurons at the median eminence are quite substantial.
GnRH neurons release GnRH peptide not only from the neuroterminal but also from other parts of the cell, including the soma and neuroprocesses (Fuenzalida et al., 2011). A similar concept has been previously reported in magnocellular neurosecretory neurons (Brown et al., 2007; Ludwig et al., 2005). The roles for GnRH release outside of the median eminence have been shown to be associated with lordosis behavior in female rats (Sakuma & Pfaff, 1980) and memory in fish (Okuyama et al., 2014). Nevertheless, using fast-scan cyclic voltammetry as an assessment tool for GnRH release, Moenter and colleagues show that GnRH release from perikarya of mouse GnRH neurons in the POA and their neuroterminals in the median eminence are differentially regulated by the neuropeptides kisspeptin, NKB, and GnIH (Gaskins et al., 2013; Glanowska & Moenter, 2015). Therefore, comprehensive identification of where inputs come from, which part of GnRH neurons receive input signals, and how input signals are transmitted to GnRH neurons (synaptic, simple diffusion, glial, etc.) should be accounted for when discussing the effects of a particular neural substrate on the GnRH system. Keeping this complexity in mind, in the next section, we will review what is known about the neural substrates responsible for GnRH pulse generation, bearing in mind the intrinsic features of GnRH neurons.
Neuronal Substrates Responsible for GnRH Pulsatility
The neural substrates of the GnRH pulse generator and the mechanism of pulsatile GnRH release have remained unknown for some time. This is in part due to the paucity in number and diffuse distribution within the MBH and POA of GnRH neurons (Goldsmith et al., 1983; Silverman et al., 1977). Accordingly, several model systems were established to test the hypothesis that GnRH neurons have an endogenous rhythmicity. However, the role of the synaptic input for pulsatile GnRH neurons cannot be excluded. In fact, recent advances in mouse genetics and other techniques have begun to address the molecular requirements necessary to stimulate gonadotropin release from the pituitary. For example optogenetic studies in mice have revealed the minimum requirements for an LH pulse (Campos & Herbison, 2014; Han et al., 2015).
There is evidence that GnRH neurons themselves have a capacity to release GnRH in a pulsatile manner independent of external signals. The support for this view lies in observations from GnRH neuronal cell culture systems, in which non-GnRH neurons or glia are absent. For example, immortalized GnRH neuronal cell lines exhibit burst firing, episodic calcium oscillations, and cyclic GnRH release (Mellon et al., 1990; Krsmanovic et al., 1992; Martinez de la Escalera et al., 1992; Wetsel et al., 1992; Bosma, 1993; Charles & Hales, 1995). Similarly, cultured monkey primary GnRH neurons derived from the embryonic olfactory placode exhibit periodical synchronization of calcium oscillations and release GnRH in a pulsatile manner, both at intervals of 50–60 min (Terasawa et al., 1999a, 1999b). The frequency of in vitro GnRH release (Terasawa et al., 1999b) is similar to frequencies reported in LH pulses (Knobil, 1980) and GnRH pulses in vivo (Gearing & Terasawa, 1988). Cultured GnRH neurons derived from the fetal placode of mouse, sheep, and rats have also shown various cyclic behaviors, including burst firing activity, periodical synchronization of calcium oscillations, and pulsatile GnRH release (Duittoz & Batailler, 2000, Funabashi et al., 2000; Constantin et al., 2009). Additional support is that GnRH neurons possess the ion channels necessary for burst firing behavior (Herbison, 2014) and several groups have mathematically modeled pulsatile burst behavior using the basic parameters measured from electrophysiological studies and synchronized calcium oscillations (Khadra & Li, 2006; Chen et al., 2013; Duan et al., 2011). Predicted results from mathematical modeling suggest that autocrine regulation by GnRH on GnRH neurons are sufficient and robust in generating GnRH pulses. Coordination among GnRH neurons may therefore be key for generation of GnRH pulses into the median eminence. For support of this view, a track tracing study shows that GnRH fibers in mice are closely associated with other GnRH fibers (Campbell et al., 2009) and GnRH treatment has predominantly stimulatory effects on neurons with GnRH-R in sliced hypothalamic preparations (Han et al., 2010). These observations indicate that GnRH neurons likely communicate with each other through direct cell–cell contact, although controversy exists as to whether GnRH neurons express GnRH-R (Wen et al., 2011).
Despite these significant findings in in vitro culture systems, there are notable shortcomings due to the inherent nature of the approaches. While immortalized GnRH cell cultures consist of a single cell type, it is unknown how immortalization changes the characteristics of the cells; thus, native GnRH neurons may not have the capacity to generate pulsatility. Conversely, although monkey GnRH neuronal cultures are devoid of other neurons and glia, they contain fibroblasts, epithelial cells, and other uncharacterized cells, which play a role in generating calcium oscillations (Richter et al., 2002), and it is possible that these other cells play a role in GnRH pulse-generation. Nevertheless, it appears that GnRH neurons may possess some capacity for pulse generation, although the current experimental technology to address this pulsatility question in vivo, especially in primates, is limited.
Synaptic/nonsynaptic input for GnRH pulse generation
Even though GnRH neurons likely possess an endogenous capacity to generate pulsatility, synaptic and nonsynaptic inputs influence pulsatility. This is an analogous situation with rodents and primates, in which endogenous activity rhythms are either longer or shorter than a 24-hour cycle, but the dark–light cycle entrains an exact 24-hour activity rhythm (Turek, 1994; Gillette & Tischkau, 1999). In the following section we will discuss some of the postulated synaptic input to GnRH pulse generation.
Kisspeptin-Neurokinin B- ß dynorphin (KNDy) expressing neurons
Peptidergic neurons, such as kisspeptin-containing neurons, are a major source of synaptic input to GnRH neurons. The role of kisspeptin and its receptor, GPR54, in regulating GnRH neural activity for pulsatile GnRH release and preovulatory surge has been extensively reported. Similar to GnRH and its receptor, mutations in the genes encoding kisspeptin and GPR54 cause IHH in humans (Seminara et al., 2003; de Roux et al., 2003; Silveira et al., 2010; Topaloglu et al., 2012). One key difference between GnRH-R and GPR54 mutations is that unlike patients with GnRH-R mutations, LH release from the pituitary gland in patients with GPR54 mutations is still responsive to exogenous GnRH treatment (Seminara et al., 2003), whereas in patients with GnRH-R mutations, kisspeptin treatment fails to induce LH release (Chan et al., 2014). This finding suggests that the effects of kisspeptin are upstream of GnRH neurons in the hypothalamus. More recently, similar mutations in the genes encoding for NKB, and its receptor, NK3-R, in regulation of pulsatile GnRH release have been discovered (Topaloglu et al., 2009; Guran et al., 2009; Gianetti et al., 2010). Subsequently, co-localization of kisspeptin and NKB in the same neurons in the arcuate nucleus has been shown (Rance, 2009). Although these studies show that kisspeptin and NKB are important for GnRH neuronal function, the specific mechanisms are still being debated.
A growing body of literature suggests that kisspeptin neurons expressed in the arcuate nucleus play an important role in generating GnRH pulsatile release. Initial work in the ewe by Goodman and colleagues (Goodman et al., 2007) suggests that although there are separate subsets of kisspeptin and NKB expressing neurons, a significant proportion of these neurons in the arcuate nucleus express both kisspeptin and NKB as well as the opioid peptide, ß-dynorphin; these neurons have been coined “KNDy” neurons (Lehman et al., 2010). Additionally, a high percentage of these neurons are thought to express steroid hormone receptors, such as estrogen receptors and progesterone receptors (Smith et al., 2005; Franceschini et al., 2006; Stephens et al., 2015), metabolic hormone receptors such as leptin receptors (Ratra & Elias, 2014), and the amino acid neurotransmitter GABA and glutamate (Cravo et al., 2011), positioning these neurons as an important regulatory node to GnRH neurons. Interestingly, expression of galanin in a subset of both AVPV and ARC kisspeptin neurons (Porteous et al., 2011; Kalló et al., 2012); reports of progesterone receptor expression in galanin neurons of AVPV and ARC region in guinea pig or kisspeptin neurons in mice (Warembourg & Jolivet, 1993; Molnár et al., 2016); and a recent report on galanin as a powerful inhibitor for kisspeptin-induced GnRH stimulation (Constantin & Wray, 2016) add another layer of complexity to the role of kisspeptin neurons in regulation of GnRH release.
It has been hypothesized that KNDy neurons are responsible for pulsatile GnRH release. This hypothesis is based on the fact that lesions of the arcuate nucleus region eliminate pulsatile LH release (Plant et al., 1978), multiple unit activity recorded from the arcuate nucleus is associated with LH pulses (Wilson et al., 1984; Silverman et al., 1986), and neurons in the arcuate nucleus express receptors for NKB and ß-dynorphin (Goodman et al., 2007; Navarro et al., 2009). Because GnRH neuron cell bodies express kisspeptin and NKB receptors and kisspeptin and NKB are both stimulatory to LH release, whereas ß-dynorphin is inhibitory to LH/GnRH release, the interplay between these three peptides within the arcuate nucleus results in pulsatile GnRH release via the final output from kisspeptin neurons (Goodman et al., 2007, 2014). A subsequent electrophysiological study with agonists and antagonists of kisspeptin, NKB, and ß-dynorphin and simultaneous LH measurement shows that pulses generated in the KNDy neurons appear to be the source of pulsatile GnRH release (Wakabayashi et al., 2010). A recent optogenetic approach in mice shows that photic activation of arcuate KNDy neurons stimulates pulsatile LH release and that kisspeptin release from KNDy neurons are essential for pulsatile LH release because the effects were absent in kisspeptin receptor null mice (Han et al., 2015). Nevertheless, the mechanism GnRH pulse-generation by the interplay between those three neuropeptides remains unclear.
Despite strong evidence supporting the role of KNDy neurons in GnRH pulsatility, this theory does not completely hold up across all species. For example, it has been reported that in IHH patients with GPR54 gene mutations, small LH pulses indicative of pulsatile GnRH release are seen, suggesting that GnRH neurons still release a small amount of GnRH peptide in the absence of kisspeptin input (Seminara et al., 2003). NPY release in the median eminence is also pulsatile, and the concordance of GnRH and NPY pulses (Woller et al., 1992) is greater than the concordance of GnRH and kisspeptin pulses (Keen et al., 2008). Finally, unlike sheep and rodents, where nearly 100 percent colocalization of kisspeptin, NKB, and ß-dynorphin is reported in the arcuate nucleus, in humans the colocalization of these three peptides in the arcuate neurons is much less (<33%; Hrabovszky et al., 2012). It has been postulated that there is a significant interaction among neuroprojections in the median eminence, as kisspeptin, NKB, and ß-dynorphin neurons in the arcuate nucleus send projections into the median eminence. Colocalization of these peptides in neurofibers in the median eminence is, however, rare in humans (Hrabovszky et al., 2012), but infusion of kisspeptin into the median eminence within monkeys, sheep, and mice stimulate GnRH release by a direct action at GnRH nerve terminals (Guerriero et al., 2012a; Keen et al., 2008; Ezzat et al., 2015; d’Anglemont de Tassigny et al., 2008). In addition, recent reports indicate that while the kisspeptin system in the median eminence appears to be part of the GnRH pulse-generating unit, upstream glutamate input is an important regulator of GnRH pulsatility (Garcia-Galiano et al., 2012; Ezzat et al., 2015). Collectively, the mechanism of GnRH pulse generation is multifactorial and far from a complete understanding.
Other potential input
Glutamate/GABA: Glutamate and gamma aminobutyric acid (GABA) are, respectively, the key excitatory and inhibitory neurotransmitters expressed widely throughout the brain. Receptors for glutamate include ionotropic N-methyl D-aspartate (NMDA) receptors (a tetramer of two NR1 subunits [8 types] and two NR2 subunits [4 types]), ionotropic kainic acid receptors (a tetramer of 5 different subunits), ionotropic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors (a tetramer of two dimer subunits [4 types]), and metabotropic glutamate receptors (1 thru 8; Iremonger et al., 2010). Receptors for GABA include ionotropic GABAA receptors (a pentamer of α [6 types], β [3 types], γ [3 types], σ, ε, π, θ [1 each]), ionotropic GABAC receptors (3 types, also known as GABAA ρ receptors), and metabotropic GABAB receptors (2 types) (Popova, 2015). In general, subunits for glutamate and GABA receptors can homo-oligoremize as well as hetero-oligoremize, creating a large number of receptors with different receptor properties. While the literature is relatively thorough with respect to receptor types, given the vast number of different receptor subunit combinations, there is room for growth in our understanding of the role specific subunits play in GnRH neuronal function.
The effects of glutamate on the GnRH system are predominantly mediated by NMDA receptors expressed in the POA, as well as kainic acid and AMPA receptors expressed in the arcuate nucleus (Brann, 1995). Metabotropic glutamate receptors in the POA and in the periventricular and dorsomedial nuclei of the hypothalamus also play a role (van den Pol, 1994). In monkeys, some of these effects may be through direct glutamatergic signaling to GnRH neurons as glutamatergic neurons directly synapse onto GnRH neurons (Goldsmith et al., 1994). Microarray analysis from single-cell GnRH neurons in mice indicate that GnRH neuronal subpopulations contain NMDA, AMPA, and/or metabotropic glutamate receptors (Todman et al., 2005). Immunocytochemistry studies show that NMDA, AMPA, and kainate receptors are expressed in rat GnRH neurons (reviewed in Iremonger et al., 2010). Additionally, co-localization of glutamate in large, dense core vesicles within GnRH neuroterminals has been reported (Yin et al., 2015). Regardless of direct or indirect signaling, infusion of AMPA (Ping et al., 1997; Christian et al., 2009) and NMDA stimulates GnRH and/or LH release in juvenile and/or adult animals (rat, Urbanski & Ojeda, 1990; Price et al., 1978 and monkey, Gay & Plant, 1987; Plant et al., 1989; Wilson & Knobil, 1982); and infusion of MK-801, an NMDA receptor blocker, in female rhesus monkeys partially suppresses GnRH release (Kasuya et al., 1999). Less is known about the metabotropic glutamate receptors. A few studies suggest that metabotropic glutamate receptors play a role either through regulation of GABA neurotransmission to GnRH neurons (Chu & Moenter, 2005) or through activation of a subset of GnRH neurons (Dumalska et al., 2008). Collectively, glutamatergic signaling is predominantly stimulatory to GnRH neurons.
In contrast, GABA neurotransmission both inhibits and stimulates GnRH neurons. For example, signaling through GABAA receptors causes either stimulatory or inhibitory effects on GnRH neurons depending on experimental conditions (Vijayan & McCann, 1978; Nikolarakis et al., 1988; Akema et al., 1990; Herbison & Dyer, 1991; Keen et al., 1999; Han et al., 2004; Kusano et al., 1995; DeFazio et al., 2002; Moenter & DeFazio, 2005). A few studies have noted that GABAA receptor subunit expression changes during postnatal development (Clarkson & Herbison, 2006) and these changes alter the function of GABA signaling to GnRH neurons (Wisden et al., 1992). The conflicting results may then be due to a difference of receptor subtype expression in different subpopulations of GnRH neurons. An important GABAA subunit is the δ subunit that has been shown to exert tonic inhibition in a high proportion of adult and juvenile GnRH neurons in mouse slice cultures (Bhattarai et al., 2011). Little is known about the other ionotropic GABAC receptors. At the same time, signaling through metabotropic GABAB receptors is inhibitory. Both GABAB receptors are expressed in GnRH neurons in the ewe (Sliwowska et al., 2006). In rodents, baclofen, the GABAB receptor agonist, hyperpolarizes mouse GnRH neurons (Zhang et al., 2009) and blocks the LH surge in rats when administered directly to the median eminence (Akema & Kimura, 1991). Interestingly, in female monkeys, infusion of 2-hydroxysaclofen, a GABAB receptor antagonist, into the median eminence did not cause any significant changes in GnRH release (Mitsushima et al., 1994), suggesting that there may be regional or species differences to GABAB receptor function.
NPY: Neuropeptide Y (NPY), localized in the arcuate nucleus (Think et al., 1993), plays an important role in appetite stimulation (Kalra & Kalra, 2003). The literature suggests that of the six NPY receptors (Y1, Y2, Y3, Y4, Y5, and Y6), the Y1 receptor plays a regulatory role in GnRH neurons as Y1 receptor agonists stimulate GnRH release in rat MBH explants (Kalra et al., 1991). In female pubertal monkeys, NPY infusion into the median eminence increases GnRH release regardless of the presence or absence of gonads (Woller & Terasawa, 1991; Gore et al., 1993). In contrast, NPY appears to be inhibitory in male monkeys because a Y1 antagonist stimulates LH release in male monkeys (El Majdoubi et al., 2000). NPY and Y1 receptor mouse knockout models, however, are not reproductively deficient (Erickson et al., 1997; Kushi et al., 1998). The different mechanisms underlying the sex and species differences of NPY treatments still remain to be resolved.
GnIH: Gonadotropin inhibitory hormone (GnIH) was discovered in birds in the early 2000s (Tsutsui et al., 2000) ,and a mammalian ortholog, RFamide-related peptide 3 (RFRP3), was discovered soon afterward (Kriegsfeld et al., 2006). GnIH neurons are found in the hypothalamus in rodents, sheep, and monkeys (Hinuma et al., 2000; Clarke et al., 2009; Ubuka et al., 2009) and project to GnRH neurons (Kriegsfeld et al., 2006; Ubuka et al., 2009) in which a subset expresses the GnIH receptor, GPR147 (Rizwan et al., 2012; Poling et al., 2012). Similarly, GnIH neurons project to a subset of kisspeptin neurons that also express GPR147 (Poling et al., 2013). Administration of GnIH to animals suppresses LH release, whereas administration of an antagonist stimulates LH release (Clarke et al., 2008; Anderson et al., 2009; Clarke, 2011). Additionally, in vitro administration of GnIH to neonatal mice also suppresses GnRH release as measured by fast-scan cyclic voltammetry (Glanowska et al., 2014). Recently, a GPR147 knockout mouse model demonstrated that the mice had high LH levels and larger litter sizes than WT controls (León et al., 2014) suggesting a modest, yet dispensable role for GnIH in reproductive function.
Glia: Glia also play an important regulatory role in GnRH neurons. In the MBH, astroglia make contacts with GnRH cell bodies and neuroprocesses and other interneurons such as GABA neurons, while in the median eminence tanycytes transmit signals and physically wrap around GnRH neuroterminals (de Seranno et al., 2010). Glia contain steroid receptors (Langub & Watson, 1992; Gudiño-Cabrera & Nieto-Sampedro, 1999) and are regulated by steroid hormones (Amateau & McCarthy, 2002). The interaction of GnRH neurons with glia changes throughout the ovulatory cycle. For example, during the late follicular stage, tanycytes recede from the GnRH neuroterminals and astroglia wrap around GABA neurons in the POA, conferring a more stimulatory state for the preovulatory surge (Cashion et al., 2003; Witkin & Silverman, 1985; Witkin et al., 1995; Garcia-Segura & McCarthy, 2004). Glial effects within the median eminence and MBH are mediated by secreted glial factors such as glutamate, various growth factors, and prostaglandin E2, as well as other substances (Ojeda et al., 2008; Clasadonte et al., 2011; Gearing & Terasawa, 1991, Garcia-Segura & McCarthy, 2004; Mong & Blutstein, 2006).
Steroid Action on the GnRH Neurosecretory System
Feedback regulation on GnRH neuronal circuitry is essential in females as the system changes dramatically across the ovulatory cycle, which in turn supplies the flexibility required to produce the different ovarian environments necessary for folliculogenesis, ovulation, and pregnancy. Predominantly, steroid hormones direct this temporal control of GnRH neurons, although circadian and nutritional inputs among others also play important roles. In the following discussion, we will focus on the feedback regulation of the GnRH system by the female steroid hormones, estrogens and progestins.
Periodical surge release of GnRH for ovulation
In mammals, females ovulate either periodically (cyclic ovulators) or in response to male coitus (reflex ovulators). The cyclic ovulators include humans and nonhuman primates, farm animals, and rodents. The reflex ovulators include rabbits and cats. In cyclic ovulators, feedback effects of estradiol and progesterone from the ovaries on GnRH release and pituitary LH release are essential. For example, removal of the ovaries results in an elevation of GnRH and LH levels over 2–4 weeks (Yamaji et al., 1972; Chongthammakun et al., 1993; Mizuno & Terasawa, 2005), whereas a small amount of estradiol replacement in ovariectomized females lowers GnRH and LH levels within a few hours, returning to pre-ovariectomy levels. This is known as estradiol negative feedback (Spies & Norman, 1975; Yamaji et al., 1972; Karsch et al., 1973, 1997; Chongthammakun & Terasawa, 1993). The negative feedback effects of estradiol underlie the low levels of LH and FSH throughout the ovarian cycle, except for a short period during the preovulatory surge when positive feedback effects of estradiol trigger the preovulatory GnRH, LH, and FSH surges. In order to study positive feedback, either a single large dose of estradiol replacement or a small dose resulting in an artificial follicular phase followed by an additional dose of estradiol treatment, which mimics the levels found in the late follicular phase, can be administered to ovariectomized animals to induce GnRH/LH surges with a latency of 24 hours, lasting 36 to 72 hours (Xia et al., 1992; Pau et al., 1993). Because estradiol directly stimulates or inhibits the activity of neurons in the hypothalamus and gonadotropes in the pituitary gland, the question of whether a GnRH surge is obligatory for the LH surge (deterministic view) or not obligatory (permissive view) has been a contentious subject for some time (Plant, 2012; Karsch et al., 1997). Specifically, according to the deterministic view, an estradiol-induced GnRH surge is necessary to drive the LH surge (Spies & Norman, 1975; Levine et al., 1985), whereas according to the permissive view, as long as the hypothalamus releases pulsatile GnRH, an increase in GnRH is unnecessary. In the latter case, the positive feedback action of estradiol on gonadotropes in the pituitary results in the LH surge (Hess et al., 1977; Knobil, 1980).
The necessity of neural input for an LH surge was originally shown in rats by Everett and Sawyer (Everett et al., 1949; Everett & Sawyer, 1950). These scientists found that treatment with a barbiturate between 2 and 4 p.m. during the proestrus cycle delays the expected ovulation for 24 hours. Similar effects by pharmacological treatments in sheep have also been reported (Radford, 1966; Jackson, 1975). Subsequently, direct measurement shows that a GnRH surge occurs in female rats, ewes, and monkeys (Sarkar et al., 1976; Moenter et al., 1993; Levine et al., 1985). Additional experiments with lesions and deafferentiation of the MBH indicate that GnRH pulse-generation and the GnRH surge are regulated by the MBH and POA, respectively, in these species (Halász et al., 1968; Blake et al., 1972). Upon discoveries of GnRH and kisspeptin, it is known that in rodents and sheep, (1) cell bodies of GnRH neurons are primarily in the POA and very sparse in the MBH (Barry et al., 1973; Silverman & Desnoyers, 1976; Lehman et al., 1986; Herbison, 2014) and (2) there are also two clearly discernible populations of kisspeptin neurons: one group in the arcuate nucleus in the MBH, which is responsible for GnRH pulse generation (KNDy neurons; Lehman et al., 2010), and the other group in the anteroventral periventricular nucleus (AVPV) in the POA, which is responsible for the GnRH surge (Smith et al., 2005; Herbison, 2008).
In contrast, the necessity of neural input for the LH surge is still unclear in primates, including humans. Although GnRH surges are present (Xia et al., 1992; Pau et al., 1993), LH release is not blocked by pharmacological treatment with phenobarbital or reserpine (Plant et al., 1978; Terasawa, unpublished observation). Moreover, estradiol can induce LH surges in monkeys with the pituitary isolated from the rest of the brain or with a completely lesioned MBH, as long as monkeys receive exogenous pulsatile GnRH infusion (Hess et al., 1977; Nakai et al., 1978). In a woman with Kallman syndrome who does not have GnRH neurons in the hypothalamus, it has been reported that pulsatile administration of GnRH increased circulating estradiol levels and resulted in an LH surge (Crowley & McArthur, 1980).
While the deterministic and permissive views illustrate clear species differences, several issues need be considered. First, regardless of species differences, the pituitary contribution to the LH surge is substantial. For example, in ewes there are direct estradiol actions on the pituitary (Clarke & Cummins, 1984), gonadotropes in ewes become more sensitive to GnRH prior to the LH surge (Reeves et al., 1971), and GnRH receptor expression in the pituitary increases by estradiol priming (Crowder & Nett, 1984; Wu et al., 1994). Second, a small number of GnRH neurons is sufficient for pulsatile release of LH and cyclic ovulation (Kokoris et al., 1988). This raises the possibility that the woman with Kallman syndrome described by Crowley and McArthur (1980) may have had quiescent GnRH neurons in the hypothalamus, which are activated by steroid treatments or GnRH infusion. Alternatively, these treatments may have generated new GnRH neurons. Third, in many studies, LH measurement is often used as a surrogate for GnRH release; however, LH release is not always an accurate measurement of neuroendocrine activity, as clearly shown by Moenter (2015). Finally, a recent study indicates that in gonadectomized female and male monkeys, kisspeptin neurons in the POA, but not the MBH, are activated at the timing of the LH surge (Watanabe et al., 2014), suggesting that the POA may also play a role in generating the GnRH surge in primates. Taken together, regardless of species, it is clear that at least a small amount of GnRH is released at the time of the preovulatory LH surge. In fact, Karsch et al. (1997) showed that only a small amount of GnRH is necessary to augment pituitary function, resulting in a gonadotropin surge, and the differences in the permissive versus deterministic viewpoints may not be as large as they appear.
Central inhibition prior to puberty
LH release (and presumably GnRH release) during the perinatal period is elevated and is often termed the perinatal surge (Terasawa & Kurian, 2012). There is a clear sex difference in the perinatal surge, with males having a larger surge than females (Plant, 2015). In rodents, the elevated levels of hormone release during this period play an important role in sexual differentiation of the hypothalamic-pituitary-gonadal (HPG) axis (McCarthy et al., 1992), whereas in primates, the HPG axis remains undifferentiated (Plant, 2015). Several weeks after birth, release of LH and GnRH decreases, entering into the juvenile period in primates, including humans. Because in primate species the decrease in LH/GnRH release is independent of the presence or absence of gonads and circulating gonadal steroid hormone levels, the LH/GnRH suppression during the juvenile period is attributed to a central inhibition (see Terasawa & Kurian, 2012). However, neural substrates of the central inhibition are still unclear. So far, GABA neurotransmission appears to play a prominent role. For example, in monkeys, prior to puberty, GABA release from the median eminence is elevated, and as puberty progresses, these GABA levels in pubertal female animals decrease (Mitsushima et al., 1994).
Inhibition of GABA synthesis from glutamate, via direct infusion of antisense oligonucleotide into the median eminence of prepubertal female monkeys, can stimulate early GnRH release (Mitsushima et al., 1996), and pulsatile infusion of bicuculline, a GABAA receptor blocker, into the MBH of prepubertal monkeys induces precocious puberty in female monkeys (Keen et al., 1999). Similarly, GABA may also block stimulatory input to GnRH as bicuculline increases release of the GnRH stimulator, kisspeptin, in prepubertal but not midpubertal female monkeys (Kurian et al., 2012). The role of NPY in male monkeys has also been suggested, based on the observation showing that during the neonatal period and after puberty onset when GnRH mRNA is elevated, NPY mRNA is low, whereas at the juvenile period when GnRH mRNA is low, NPY mRNA is elevated (El Majdoubi et al., 2000).
Initiation of puberty
Puberty is initiated by an increase in the frequency and amplitude of GnRH release from the hypothalamus (Watanabe & Terasawa, 1989), presumably due to a loss of central inhibition (Terasawa & Fernandez, 2001). In primates, during the juvenile/prepubertal period, only small intermittent pulses of GnRH peptide are released. As puberty progresses into early puberty (before first menstruation) and then midpuberty (between first menstruation and first ovulation), the amplitude and frequency of GnRH release gradually increase up to the patterns observed in adulthood (Figure 1; Watanabe & Terasawa 1989). Importantly, puberty onset and the initial pubertal increase in GnRH release are independent of circulating estradiol, as the pubertal increase in GnRH release occurs in ovariectomized monkeys and the timing is not affected by ovariectomy (Chongthammakun & Terasawa, 1993; Terasawa et al., 1984a). Nevertheless, after puberty onset, stimulatory inputs to GnRH neurons play a significant role in the pubertal progression. In fact, loss of function mutations in the genes encoding kisspeptin and its receptor GPR54 (Seminara et al., 2003; Silveira et al., 2010) or NKB and its receptor NK3R delays puberty in human patients (Topaloglu et al., 2009; Guran et al., 2009). Augmentation of the pubertal increase in GnRH release by stimulatory neuromodulators, such as glutamate, kisspeptin, and NKB, is twofold. First, levels of glutamate and kisspeptin rise during puberty in a similar manner to the pubertal increase in GnRH release (see Figure 1; Terasawa et al., 1999b; Keen et al., 2008; Guerriero et al., 2012b) and second, the sensitivity of GnRH neurons to stimulatory signals increases after puberty onset (Shahab et al., 2005; Guerriero et al., 2012a). The latter is evident through the effectiveness of agonists of glutamate, kisspeptin, and NKB during the progression of puberty (Claypool et al., 2000; Guerriero et al., 2012a; Garcia et al., 2015). For example, a higher dose of N-methyl D,L-aspartate (NMA), a glutamatergic N-methyl D-aspartate (NMDA) receptor agonist, is necessary to elicit GnRH release in prepubertal monkeys, whereas in pubertal monkeys a 10,000-fold lower dose is sufficient (Claypool et al., 2000). Similarly, infusion of the same dose of kisspeptin-10, a kisspeptin receptor agonist, into the median eminence in pubertal monkeys results in a much larger GnRH release than that in prepubertal monkeys (Guerriero et al., 2012a). The sensitivity of the GnRH neuronal system to stimulatory input is in part due to an increase in circulating estradiol (Guerriero et al., 2012b).
Especially in nonprimate species, steroid hormones play a role in regulating the progression of puberty. Negative feedback effects of ovarian steroids are present in the prepubertal period in sheep and rodents, and the onset of puberty is thought to be in part due to a decrease in response of GnRH neurons to the prepubertal negative feedback (Huffman et al., 1987; Dubois et al., 2016; see Foster & Hileman, 2014). Supporting this hypothesis is evidence that conditional ablation of estrogen receptor α (ERα) in kisspeptin neurons or NKB neurons results in precocious vaginal opening (Mayer et al., 2010; Greenwald-Yarnell et al., 2016). Prepubertal negative feedback of estradiol is also lost in the kisspeptin cell-specific knockout animals (Dubois et al., 2016). Similarly, ovariectomy in prepubertal and pubertal ewes results in an increased expression of kisspeptin and NKB in the brain (Nestor et al., 2012). Together, this suggests that estradiol feedback through these neurons are important for restraining pubertal development. In contrast, there is evidence in mice that kisspeptin expression in the AVPV-POA region depends on a pubertal increase in circulating estradiol (Clarkson et al., 2010). Kisspeptin is not expressed in the AVPV of mice after birth until sometime during postnatal day 10–15, at which point expression of kisspeptin increases with age. However, unlike in sheep, ovariectomy reduces and estradiol replacement rescues expression of kisspeptin in the AVPV; therefore, kisspeptin expression in the AVPV and presumably signaling during puberty are driven by estradiol (Clarkson et al., 2009). This suggests that in the mouse AVPV, kisspeptin neurons may perform distinct pubertal processes; whereas, kisspeptin/KNDy neurons in the arcuate nucleus may restrain puberty. A clear mechanism has yet to emerge.
The timing of puberty is significantly influenced by both genetic backgrounds and environmental factors (Terasawa & Kurian, 2012). Studies comparing monozygotic and dizygotic twins, as well as large-scale population studies (Eaves et al., 2004; Day et al., 2015), indicate that the age of menarche is associated with specific genes. It has also been shown that epigenetic factors, such as environmental contaminants and higher calorie intake, modify the age of puberty (Parent et al., 2015; Villamor & Jansen, 2016). Recently, advances have been made toward understanding genetic and epigenetic mechanisms underlying puberty onset. Using studies in rats, Ojeda and colleagues have suggested a role for the genes Oct-2, TTF1 and EAP, all of which regulate transcriptional processes and are associated with pubertal development (Ojeda et al., 1999; Heger et al., 2007; Mastronardi et al., 2006). Moreover, epigenetic modulation is important for puberty onset, as demonstrated by a study showing that inhibition of DNA methylation results in pubertal failure in female rats (Lomniczi et al., 2013). Further investigation into this DNA methylation mechanism revealed that members of the polycomb group (PcG) of transcriptional silencers repress kisspeptin expression in the prepubertal period and the genes of these PcG proteins are the targets of DNA methylation induced inactivation at puberty onset. As evidence for this mechanism, overexpression of one of these PcG proteins, EED, into the arcuate nucleus of prepubertal female rats represses kisspeptin expression, inhibits GnRH pulse frequency, and delays puberty (Lomniczi et al., 2013). More recently, Lomniczi, Ojeda, and colleagues have shown that the levels of several other transcriptional repressor molecules decrease in the hypothalamus of rats as well as monkeys when puberty progresses. These authors demonstrate that overexpression of two of these proteins, GATAD1 and ZNF573, in the arcuate nucleus of prepubertal rats also delays puberty (Lomniczi et al., 2015). It appears that transcriptional repression and epigenetic changes likely play a vital role in the progression of puberty.
Changes in the ubiquitin system may also play a role in puberty onset. In humans, inactivating mutations in the MKRN3 gene, coding for makorin ring finger protein 3 (MKRN3), result in precocious puberty (Abreu et al., 2013). Additionally, The levels of MKRN3 circulating in humans and expression in the mouse brain decrease at the time of puberty onset (Abreu et al., 2013; Busch et al., 2016; Varimo et al., 2016), placing MKRN3 at the right place and time to control puberty onset. Based on functional domains, MKRN3 may be an E3 ligase of the ubiquitin system, although its function is currently unknown. It is hypothesized that if MKRN3 is an E3 ligase, it may block the availability of stimulatory neuronal input such as kisspeptin or NKB through proteasomal destruction of peptides or their receptors. All together, the initiation of puberty appears to require developmental changes in the epigenetic pathways that regulate expression of neurotransmitters and GnRH neuronal function. Nevertheless, the mechanism of puberty onset still remains a mystery.
The perimenopausal transitional period is an important part of the aging process in women. This period is marked by an increase in prolonged and irregular menstrual cycles, which eventually result in menopause, or the cessation of menstrual cycles (clinical diagnosis is noted as one year after amenorrhea). The mechanisms guiding reproductive senescence differ by species. In rodent studies, deregulation of the hypothalamus appears to precede ovarian changes (Kermath & Gore, 2012). For example, LH surges induced by estradiol or estradiol plus progesterone in aged ovariectomized rats are much smaller than in ovariectomized young rats (see Wise, 1987), suggesting that a neuroendocrine change precedes a loss of ovarian function. These neuroendocrine changes are due to an increase in inhibitory input and a decrease in stimulatory input to GnRH neurons rather than to a loss of GnRH neuronal cell number (Neal-Perry et al., 2005, 2008), resulting in a decline of pulsatile GnRH and gonadotropin release (Kermath & Gore, 2012). In contrast, in primates, ovarian changes precede hypothalamic changes (Gore et al., 2004), although some hypothalamic changes do occur prior to the ovarian changes similar to rodents (Kermath & Gore, 2012). Unlike rodents, the progression of the reproductive system to menopause is a result of a decline in the number of viable oocytes and a deregulation of the ovarian processes of folliculogenesis, ovulation, and luteolysis necessary to continue the female reproductive cycle (Wise et al., 2002). This loss of ovarian function leads to a decrease in circulating estrogen and progestin levels and a loss of feedback effects to the hypothalamus and pituitary, culminating in an increase in pulsatile GnRH release (Gore et al., 2004) and increased levels of circulating LH and FSH (Fitzgerald et al., 1998).
Roles of estradiol and estrogen receptors in female reproductive function
Estradiol plays essential roles in the reproductive tissues of the ovaries, breast, uterus, and brain, but also important regulatory roles in bone, circulatory, adipose, and skin tissues. Not surprisingly, the absence of estrogen production due to mutations in CYP19A1, the gene that encodes aromatase, the enzyme responsible for conversion of estrogens from androgens, results in drastic reproductive consequences in girls and women. These patients display with genital virilization, pubertal failure, hypergonadotropic hypogonadism, and polycystic ovaries (Grumbach, 2011) and require estradiol replacement therapy for life. A similar phenotype has been described in female aromatase knockout mice (Simpson, 2000).
The effects of estradiol are mediated by several different estrogen receptors (ERs). There are two main types of ERs; classic ERs, notably, ERα and ERβ (Green et al., 1986; Kuiper et al., 1996), belonging to the nuclear steroid hormone superfamily of transcription factors; and nonclassical G-protein coupled ERs, such as G-protein coupled ER1 (GPER1, also called GPR30; Filardo et al., 2000) and the putative G-q membrane ER sensitive to the nonsteroidal compound STX (Qiu et al., 2003).
ERα is the primary ER responsible for the reproductive effects of estradiol. Recently, a single case of an ERα gene mutation in a woman was reported: She presented with a similar phenotype as aromatase deficiency, having absent puberty, polycystic ovaries, and mildly elevated levels of gonadotropes (Quaynor et al., 2013). Global ERα knockout mice display a similar phenotype, as they are also infertile, display absent ovarian cycles, have pubertal abnormalities, and polycystic ovaries (Lubahn et al., 1993; Dupont et al., 2000). ERα knockout animals display a lack of negative feedback and, if given estradiol, also fail to induce a gonadotropin surge (Couse et al., 2003). Neuron-specific knockout of ERα, using a CAMKIIα-Cre recombinase knockout strategy, revealed that ERα expressed specifically in neurons is critical for both positive feedback effects of estradiol (Wintermantel et al., 2006) and negative feedback effects (Cheong et al., 2014). Thus, ERα plays essential regulatory roles in the brain. However, despite these known estradiol actions in the hypothalamus, GnRH neurons do not express ERα (Sharifi et al., 2002; Herbison & Pape, 2001), and estradiol action through ERα to the GnRH system is mediated through interneurons: First, an earlier study with combined radioautography with immunocytochemistry showed that GnRH neurons fail to appreciably concentrate radioactive estradiol (Shivers et al., 1983). Second, ERα is consistently coexpressed by several types of neurons in the hypothalamus that synthesize kisspeptin, glutamate, GABA, NPY, proopiomelanocortin (POMC), and catecholamines (Stumpf & Jennes, 1984; Leranth et al., 1992; Smith et al., 2005; Franceschini et al., 2006).
Cell-specific knockout of ERα using Cre recombinase technology has unveiled a variety of ERα action through specific types of neurons. For example, kisspeptin cell-specific knockout of ERα reveals that ERα expression in kisspeptin/KNDy neurons is critical for positive feedback of LH secretion in adult mice (Dubois et al., 2015) and possibly some role in negative feedback (Greenwald-Yarnell et al., 2016). POMC-specific knockout of ERα demonstrates impaired negative feedback (Xu et al., 2011). GABA neuron-specific knockout of ERα resulted in impaired positive feedback effects but not negative feedback, whereas, ERα loss in glutamate neurons demonstrated impairment of both negative and positive feedback mechanisms (Cheong et al., 2015). However, cell type-specific knockout of ERα approach does not give perfect answers. For example, (1) ~70 percent of the kisspeptin neurons in the arcuate were targeted by the glutamate-specific knockout of ERα, and ~25 percent of the kisspeptin neurons in the POA were targeted by GABA-specific knockout of ERα (Cheong et al., 2015); and (2) POMC expressing precursor cells differentiate into adult POMC, AgRP, as well as kisspeptin neurons (Sanz et al., 2015), suggesting that developmental ERα knockout in POMC neurons could also affect kisspeptin neurons. Therefore, more sophisticated inducible or viral vector-mediated studies of ERα knockout in adult brains in multiple species are necessary to determine exactly which types of adult neuronal populations are involved in ERα-mediated estradiol control of GnRH neurons.
In addition to cell-specific knockouts, some investigators have explored the downstream cellular mechanisms of ERα activity using knockout, knockin strategies with mutant forms of ERα. Very early biochemical studies revealed that ERs mediate both “classic” transcription factor activity, as it was reported that estradiol localizes to the nucleus (Gorski et al., 1968; Jensen et al., 1968), and rapid “nonclassical” signaling mechanisms of estradiol (Szego & Davis, 1967). Accordingly, mice knocked in with ERα containing a nonfunctional DNA binding domain have been used to distinguish between classic estrogen response element (ERE) DNA binding activity of ERα from other nonclassic effects. This model has revealed that ERE DNA binding is necessary for positive feedback effects, whereas knockin of the nonclassical only ERα plays a partial role in negative feedback but was not able to rescue positive feedback effects (Glidewell-Kenney et al., 2007). Similarly, in order to determine membrane-initiated ERα activity from nuclear activity, mice knocked in with ERα only expressed at the cell membrane have been used. In this model, membrane signaling ERα mutants failed to rescue the global ERα knockout phenotype, suggesting that nuclear but not a membrane-initiated role for ERα is essential for negative and positive feedback (Pedram et al., 2009). Collectively, cellular activity that leads to either classical or nonclassical nuclear activity mediated by ERα plays important reproductive neuroendocrine roles in female mice.
Unlike ERα, ERβ has been reported to be expressed in a subset of GnRH neurons (Herbison & Pape, 2001; Hrabovszky et al., 2001, 2007; Sharifi et al., 2002; Skinner Dufourny, 2005; Kalló et al., 2001). In fact, ERβ-specific agonists stimulate electrical activity of GnRH neurons by patch clamp (Chu et al., 2009, Sun et al., 2010). However, much of the progress toward an understanding of the reproductive role of ERβ has been hindered by findings that (1) ERβ-specific antibodies are not reliable (Snyder et al., 2010), (2) ERβ has several predominant splice variants (Handa et al., 2012), and (3) unlike ERα knockout, the initial global ERβ knockout animals were not infertile, but rather subfertile (Krege et al., 1998), and it was later confirmed that these animals, which are widely used, contain splice variants (Antal et al., 2008). The new knockout animals generated using Cre recombinase technology to remove splice variants are infertile and are not able to ovulate (Antal et al., 2008). New data generated from neuron-specific deletion of ERβ and GnRH-specific deletion of ERβ indicate that ERβ may play a small, yet dispensable, role in negative feedback effects of estradiol on GnRH/LH release but not positive feedback effects (Cheong et al., 2015), suggesting that most of the phenotype seen in the global knockout is due to the effects of ERβ knockout in peripheral organs.
Nonclassical membrane estrogen receptors
Since the late 1990s, several nonclassical ERs have also been identified, including GPER1, ER-X, and G-q membrane ER sensitive to STX (Toran-Allerand et al., 2002; Filardo et al., 2000; Qiu et al., 2003). The most important characteristic features of nonclassical estrogen receptors, such as GPER1 and STX-sensitive membrane ER, are that they mediate rapid estradiol action (Terasawa & Kenealy, 2012). Like ERβ, GPER1 has been reported to be expressed in a subset of GnRH neurons (Noel et al., 2009; Naugle & Gore, 2014) and has stimulatory roles in monkey and mouse GnRH neurons themselves (Noel et al., 2009; Sun et al., 2010). Nevertheless, GPER1 knockout mice show no reproductive deficits (Otto et al., 2009). The G-q membrane ER sensitive to STX also stimulates GnRH neurons as well as POMC neurons (Qiu et al., 2003; Kenealy et al., 2011); however, the molecular identity of this receptor still remains to be discovered, curtailing any specific genetic studies. Presently, the role of non-ERα ERs in the regulation of GnRH neurons appears to be minor, although given the essential biological function of reproduction, it would not be surprising to find significant compensation by other ERs upon genetic or pharmacological inhibition of these receptors. Clearly, ERα is a key regulator of the neuroendocrine reproductive functions.
Roles of progesterone and its receptors in female reproductive function
Progesterone is the other major female hormone. Among others, it plays essential reproductive roles in ovulation, regulating the uterus during the luteal phase for implantation, maintenance of pregnancy, and breast development. Like estradiol, progesterone has both classic nuclear hormone receptors, progesterone receptor (PR, including two isoforms PR-A and PR-B; Misrahi et al., 1987; Gadkar-Sable et al., 2005), and nonclassical membrane progesterone receptors (Thomas & Pang, 2012), including progesterone receptor membrane component 1 (PGRMC1; Meyer et al., 1998). Many of the effects mediated by PR require estrogen priming, as the PR promotor contains an ERE binding site and is upregulated by estradiol in most reproductive tissues (Kraus et al., 1994; Blaustein et al., 1988). In monkeys, while estradiol initiates the preovulatory surge, progesterone amplifies the surge, producing a full LH surge effect (Terasawa et al., 1980, 1984b). These effects are blocked by RU486, the PR blocker (Collins & Hodgen, 1986) and are mediated in the hypothalamus through an NPY mediated mechanism (Yeoman & Terasawa, 1984; Woller & Terasawa, 1994; Mizuno et al., 2000). Another group showed that blockade of hypothalamic PRs blocks the estradiol-induced LH surge (Chappell & Levine, 2000). Global PR knockout female mice are infertile, do not ovulate, and have perturbed negative and positive feedback effects on LH release (Chappell et al., 1997). Additionally, estradiol-induced positive feedback but not negative feedback effects are disturbed in these PR knockout animals (Chappell et al., 1999). Kisspeptin cell-specific PR deletion results in fewer births and reduced litter sizes as well as impaired LH surges, suggesting that progesterone signaling specifically in kisspeptin neurons is important for surge generation of LH release and fertility (Stephens et al., 2015). Although little investigation of membrane PRs has been done with regard to reproductive neuroendocrinology, one study in GT1 cells suggests that there may be a role for membrane PRs in regulating some GnRH functions (Sleiter et al., 2009).
Emerging Concept: Regulatory Roles of Neurosteroids on the GnRH System
In addition to the ovaries, the brain is also a significant source of steroid hormones. In fact, progesterone, its precursor, and metabolites are well-recognized neurosteroids, which serve as potent allosteric regulators of GABAA receptor functions (Baulieu, 1998). Similarly, neuroestradiol has been shown to play an important role in behavior, learning and memory, and neuroprotection (Woolley, 2007; Suzuki et al., 2009; Hojo et al., 2008; Balthazart & Ball, 2006; Saldanha et al., 2011). Unlike most effects of steroids in the periphery, which are slow, neurosteroid effects in the brain are rapid and have synaptic neuromodulatory activity (Balthazart & Ball, 2006; Saldanha et al., 2011). For example, experiments conducted in GnRH primary cultures reveal rapid estradiol neuromodulation of GnRH neurons, including stimulation of electrical activity, calcium oscillations, and GnRH release within seconds to minutes (Figure 2; Kenealy & Terasawa, 2012; Abe & Terasawa, 2005; Abe et al., 2008; Noel et al., 2009). Yet, despite the known rapid actions of neurosteroids, their potential role in reproduction has received little attention. It is now known that neurosteroids do play roles in both rats and monkeys. Work by Micevych and colleagues in the rat demonstrates that neuroprogesterone synthesized in astrocytes plays an important role in augmenting the LH surge (Micevych et al., 2003; Micevych & Sinchak, 2008, 2011). In their studies, they infused a blocker for P450 side chain cleavage into the hypothalamus of rats during the proestrus afternoon, disrupting the initial cleavage of cholesterol to pregnenolone and therefore all de novo steroid production, and a blocker for 3βHSD, disrupting conversion of pregnenolone to progesterone and DHEA to androstenedione and therefore blocking de novo synthesis of all progestins, estrogens, and androgens excluding pregnenolone and DHEA. This interference attenuates the preovulatory surge in female rats (Micevych et al., 2003; Micevych & Sinchak, 2008). In combination with the data demonstrating a role for hypothalamic PRs in the surge (Chappell & Levine, 2000), these studies imply that neurosteroids, specifically neuroprogesterone, play an important role in the LH surge in the rat.
In nonhuman primates, three series of studies indicate that neuroestrogens appear to play important regulatory roles for reproduction. Studies by Resko, Roselli, and colleagues show that in male monkeys, estradiol is converted locally in the brain by aromatase from circulating testosterone and contributes to androgen negative feedback (Roselli & Resko, 2001). Similarly, work in our lab indicates a role for neuroestrogens in females. In female ovariectomized monkeys, (1) electrical stimulation of the MBH and median eminence region stimulates release of GnRH and neuroestradiol, (2) short or long infusions of estradiol benzoate into the median eminence rapidly stimulate GnRH and kisspeptin release, and (3) infusion of letrozole, an aromatase inhibitor, directly into the median eminence suppresses GnRH and neuroestradiol release (Figure 3; Kenealy et al., 2013, 2015). These stimulatory effects clearly differ from negative feedback effects of estradiol and are reminiscent of positive feedback effects of estradiol because 8-hour infusion of estradiol benzoate stimulates LH release, whereas subcutaneous injection of estradiol benzoate suppresses LH release (Kenealy et al., 2015).
Studies are now underway to test the hypothesis that neuroestradiol plays a role in the LH/GnRH surge in female monkeys, and preliminary data suggest that this hypothesis is correct (Kenealy et al., 2015; Terasawa, 2016). Recent investigation of the levels of neurosteroids released throughout pubertal progression in intact female monkeys has revealed yet another potential role for neuroestrogens in the female primate brain (Kenealy et al., 2016). While circulating levels of estrogens are low prior to puberty, neuroestrogens in the brain are elevated. As puberty progresses and the levels of GnRH, LH, and circulating steroid hormones increase, the levels of neuroestrogens in the brain decrease (Kenealy et al., 2016). Although a discrete role for neuroestrogens in pubertal progression is yet to be proven experimentally, this study provides an intriguing answer for why primates are not sensitive to circulating hormones during the juvenile period (Chongthammakun & Terasawa, 1993); neuroestrogens may play a role in the prepubertal central inhibition of the GnRH neuronal system, and as puberty progresses, there is a switch in neuroestradiol effects from inhibition to stimulation of the GnRH system. Although many questions remain (MacLusky, 2016), it appears that the current ovarian-centric role of steroid feedback may need to be modified to include a role for neurosteroids.
Information gathered from reproductive neuroendocrine research shows great potential for clinical application. In fact, birth control and effective infertility treatments are directly attributable to early findings from the field. Additionally, understanding of reproductive processes during the entire life span focusing on interactions between the nervous system and endocrine system would greatly benefit human health. For instance, abnormal levels of GnRH and gonadotropins in the brain are associated with Alzheimer’s disease, and understanding hormonal changes prior to menopause may provide new treatment options for this debilitating disease (Webber et al., 2007). Similarly, we have little knowledge regarding how pubertal changes in hormones modify neural circuitry formation for mature brain function. Understanding the mechanism of puberty onset and subsequent changes in gonadal steroid hormones, along with neural circuitry formation, would lead to treatment tools for psychiatric diseases associated with puberty, such as schizophrenia. Nonetheless, major questions remain, notably, what drives GnRH pulsatility; what are the neuronal substrates in central inhibition during the prepubertal/juvenile period; what is the mechanism initiating puberty, how do changes in reproductive hormones affect the aging process, and what precisely is neuroestradiol doing? The answers to these questions will provide exciting new avenues for better treatment options. There is little doubt that the recent discoveries in the field and advances in our basic research strategies will continue to expand our understanding of female reproduction.
This work was supported by National Institutes of Health Grant R01HD011355, HD015433 and R21HD077447. The work was also made possible by support for the Wisconsin National Primate Research Center by National Institutes of Health Grant 5P51OD011106.
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