Yoshihisa Uenoyama1 , Naoko Inoue1 , Nahoko Ieda1 , Vutha Pheng2 , Kei-ichiro Maeda3 and Hiroko Tsukamura1
Graduate School of Bioagricultural Sciences, Nagoya University, Chikusa-ku, Furo-cho, Nagoya Aichi, 464-8601, Japan
Asian Satellite Campus-Cambodia, Nagoya University, Phnom Penh, Cambodia
Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo 113-8657, Japan
Yoshihisa Uenoyama (Corresponding author)
EstrogenFollicle-stimulating hormoneGnRHGPR54KisspeptinLuteinizing hormoneMetastinNeurokinin BPubertyReproduction
It is well accepted that the hypothalamus plays a pinnacle role in the hierarchical control of the gonadal axis through the anterior lobe of the pituitary gland in mammals. The concept of hypothalamic regulation of the gonadal axis dates back to the late 1940s, when Geoffrey Harris and colleagues  predicted the presence of neurohumoral substances, which control the pituitary gland. By this time, two gonadotropins , i.e., follicle-stimulating hormone (FSH) and luteinizing hormone (LH) , had already been isolated from the pituitary gland . Intensive studies have been performed to isolate the predicted substance(s) controlling FSH and/or LH release. In the early 1970s, a decapeptide, which stimulates both FSH and LH release , was isolated from porcine and ovine hypothalami by two groups, led by Andrew Schally  and Roger Guillemin , respectively. The discovery of the gonadotropin-releasing hormone (GnRH) facilitated the studies on the involvement of hypothalamic neurotransmitters and neuropeptides in GnRH/gonadotropin release system during the last three decades of the twentieth century. It has become increasingly clear that the activity of GnRH neurons is under a complex influence of afferent inputs, which mediates the feedback action of gonadal steroids, timing of sexual maturation at puberty, drives estrous/menstrual cycles, and arrests gonadal activity under the adversity such as lactation, malnutrition, and diseases [6–11].
At the turn of the twenty-first century, discoveries via inactivating mutations of novel neuropeptide signaling , i.e., kisspeptin-GPR54 signaling, in humans suffering the hypogonadotropic hypogonadism, provided a breakthrough in our understanding of the hypothalamic mechanism controlling GnRH/gonadotropin release at the onset of puberty. This review focuses on our current understanding of how the hypothalamus regulates pubertal maturation of gonadal axis in mammals via GnRH/gonadotropin release.
Tonic GnRH/Gonadotropin Release Controls Pubertal Maturation of Gonadal Activity
There are two modes of GnRH/gonadotropin release in mammals. Males exhibit only tonic GnRH/gonadotropin release, whereas females exhibit both tonic and surge-mode GnRH/gonadotropin release . The tonic GnRH/gonadotropin release is characterized by its pulsatile nature, which was originally detected by a combination of frequent blood sampling and radioimmunoassay for LH in primates , and controls follicular development and maintenance of corpus luteum in females, and spermatogenesis in males, along with the steroidogenesis in both sexes. The surge-mode GnRH/gonadotropin release is observed at the mid-menstrual cycle in primates [13, 14] and the end of the follicular phase in other animals [15, 16] to trigger ovulation and the corpus luteum formation.
Sexual maturation at the puberty onset seems to be timed by an increase in tonic GnRH/gonadotropin release in several mammals examined to date [17–21]. Experimentally, a pioneer study by Ernst Knobil and colleagues demonstrated that intermittent GnRH stimulation to the pituitary at a physiological frequency observed in adulthood induced puberty onset in immature female rhesus monkeys and that its withdrawal reverted to the immature state . This finding strongly suggests that an increase in tonic GnRH/gonadotropin release is the first step in the pubertal onset. Knobil and colleagues also established a method for electrophysiological recording of multiple unit neuronal activity (MUA) that is synchronized with LH pulses  and suggested that the neuronal activity recorded in the mediobasal hypothalamus could be derived from the so-called GnRH pulse generator. The periodic increase in electrical activity, called MUA volleys , is considered as a manifestation of GnRH release and seems to be suppressed in prepubertal animals. The onset of puberty, therefore, is considered to be dependent on the activation of the GnRH pulse generator.
KNDy Neurons as a Master Regulator of Tonic GnRH/Gonadotropin Release
An intrinsic source of the GnRH pulse generator had been deemed as a great enigma of the GnRH/gonadotropin-releasing system before the discovery of kisspeptin (first named metastin ). To date, the most plausible interpretation is that kisspeptin neurons localized in the hypothalamic arcuate nucleus (ARC) (also known as KNDy neurons as described below) serve as a master regulator of tonic GnRH/gonadotropin release in mammals. A critical role of kisspeptin in puberty onset has emerged from clinical studies for familial hypogonadotropic hypogonadism, characterized by pubertal failure due to gonadotropin deficiency. Two years after the deorphanization of GPR54 as a receptor for kisspeptin in 2001 [24, 25], two studies demonstrated that inactivating mutations of GPR54 gene caused pubertal failure in humans [26, 27]. Subsequently, the phenotype of humans with inactivating mutations of the GPR54 gene was recapitulated in humans bearing inactivating mutations of the KISS1 gene (coding kisspeptin)  and in rodent models carrying targeted mutations of Kiss1 or Gpr54 loci [27, 29–33]. In particular, Kiss1 knockout rats showed a severe hypogonadotropic hypogonadal phenotype, suggesting an indispensable role of kisspeptin in pubertal maturation of gonadal axis in both sexes . Because Gpr54 gene expression in GnRH neurons is evident in rodents [29, 34], kisspeptin is thought to directly control GnRH release and thus gonadotropin release. Indeed, increasing evidence indicates that kisspeptin stimulates gonadotropin release via GnRH neurons in several mammals [34–36].
Clinical studies for hypogonadotropic hypogonadism also demonstrated a critical role of neurokinin B (NKB) , a member of tachykinin family, in hypothalamic regulation of puberty onset. Inactivating mutations of TAC3 (coding NKB) or its cognate TACR3 (coding tachykinin NK3 receptor) gene were found in humans suffering from the hypogonadotropic hypogonadism [37–40]. It should be noted that kisspeptin, NKB, and an endogenous opioid, dynorphin A, are co-localized in a cohort of ARC neurons in mammalian species [41–43], and thus the cohort of neurons has now become known as the KNDy neurons for the names of three neuropeptides, such as kisspeptin, NKB, and dynorphin A. Our previous studies demonstrated that the neuronal activity accompanied with LH pulses is successfully detected in the area near the cluster of KNDy neurons in goats [43, 44], suggesting that KNDy neurons are an intrinsic source of the GnRH pulse generator. Based on the results currently available [43–45], we envision that NKB and dynorphin A regulate the intermittent discharge of KNDy neurons in an autocrine and/or paracrine manner, resulting in pulsatile GnRH/gonadotropin release. Indeed, our recent study indicates the involvement of NKB and dynorphin A in pubertal maturation of GnRH/gonadotropin release , i.e., chronic administration of tachykinin NK3 receptor agonist or kappa-opioid receptor antagonist facilitated puberty onset along with the induction of tonic LH release in female rats. This result suggests that a lack of NKB signaling and relatively high dynorphin A tone may play a key role in suppression of the intermittent discharge of KNDy neurons, which drive pulsatile GnRH/gonadotropin release. In other words, it is likely that an increase in NKB stimulation and/or decrease in the inhibitory tone of dynorphin A (#1 in Fig. 1.1) drives intermittent discharge of KNDy neurons and hence GnRH/gonadotropin release (#2 in Fig. 1.1), resulting in puberty onset along with follicular development in the ovary (#3 in Fig. 1.1). Double-labeled immunoelectron microscopic studies indicate that an action site of kisspeptin seems GnRH neuronal terminals in the median eminence, where kisspeptin exerts stimulatory influence on GnRH neurons via volume transmission [47, 48]. Direct evidence for pubertal increase in kisspeptin release was proposed from a previous study, in which Keen et al.  showed a pubertal increase in both kisspeptin and GnRH release and coordinated release of pulsatile kisspeptin and GnRH at the median eminence in rhesus monkeys.
Schematic illustration showing the possible hypothalamic mechanism regulating pubertal increase in GnRH/gonadotropin release in female mammals. KNDy neurons localized in the hypothalamic arcuate nucleus (ARC) play a key role in pubertal increase in GnRH/gonadotropin release in mammals. At the onset of puberty, an increase in neurokinin B stimulation and/or decrease in the inhibitory tone of dynorphin A (#1) may drive the intermittent discharge of KNDy neurons in an autocrine/paracrine manner. Kisspeptin stimulates tonic GnRH release at the median eminence and thus gonadotropin secretion (#2), which times puberty onset along with the follicular development in females (#3)
Estrogen-Dependent and Estrogen-Independent Prepubertal Restraint of GnRH/Gonadotropin-Releasing System
The GnRH/gonadotropin-releasing system seems to be already matured before the onset of puberty. Indeed, ARC Kiss1 gene expression and pulsatile LH release immediately increased after ovariectomy in prepubertal rats [50, 51]. Estrogen replacement restores the prepubertal restraint of the ARC Kiss1 gene expression and LH pulses in female rats [50, 51], suggesting that the prepubertal suppression of the tonic GnRH/gonadotropin-releasing system is dependent on a circulating estrogen derived from the immature ovaries. A possible mechanism involved in the prepubertal restraint of tonic GnRH/gonadotropin-releasing system is illustrated in Fig. 1.2. Based on the results currently available [50, 51], we envisage that estrogen derived from the immature ovaries (#1 in Fig. 1.2) may play a key role in prepubertal suppression of ARC Kiss1 gene expression (#2 in Fig. 1.2), resulting in a restraint of tonic GnRH/gonadotropin release during the prepubertal period (#3 in Fig. 1.2). Since kisspeptin neuron-specific estrogen receptor α (ERα) knockout mice show precocious puberty onset along with a higher ARC Kiss1 gene expression than wild-type mice , estrogen-dependent prepubertal restraint of Kiss1 gene expression and LH pulses would be directly mediated by ERα in ARC KNDy neurons. Similarly, in males, the prepubertal suppression of the tonic GnRH/gonadotropin-releasing system seems dependent on a circulating testosterone derived from the immature testes, because castration increases plasma LH levels in prepubertal male rats .
Schematic illustration showing a possible mechanism regulating the pubertal restraint of the GnRH/gonadotropin release system in female mammals. During the prepubertal period, estrogen derived from the immature gonads (#1) strongly suppresses ARC Kiss1 gene expression in KNDy neurons (#2) and hence GnRH/gonadotropin release (#3). Estrogen may exert an inhibitory influence on ARC Kiss1 gene expression via direct or indirect pathways (#1). Estrogen-responsive neurons in the medial preoptic area (mPOA) may exert an inhibitory influence on GnRH/gonadotropin release via suppression of ARC Kiss1 gene expression (#4)
In addition to the direct inhibitory effect on ARC Kiss1 gene expression, estrogen may indirectly inhibit Kiss1 gene expression and/or GnRH/gonadotropin-releasing system during the prepubertal period. Our recent study showed that site-specific micro-implants of estradiol in the medial preoptic area (mPOA) or ARC restored suppression of LH pulses in prepubertal ovariectomized rats . This suggests that estrogen-responsive neurons, at least, in the mPOA and ARC, are involved in the estrogen-dependent prepubertal restraint of GnRH/gonadotropin-releasing system in female rats. Given the critical role of kisspeptin and NKB in pubertal maturation in humans and rodents, KNDy neurons could be a first candidate for the estrogen-responsive neurons in the ARC. Additionally, estrogen-responsive neurons in the mPOA may exert an inhibitory influence on ARC Kiss1 gene expression (#4 in Fig. 1.2).
The inhibitory influence of estrogen on ARC Kiss1 gene expression and GnRH/gonadotropin release appears to decrease during the pubertal transition, resulting in upregulation of ARC Kiss1 gene expression and GnRH/gonadotropin release . This scenario is consistent with the classical gonadostat hypothesis  that changes in hypothalamic sensitivity to negative feedback action of estrogen are associated with pubertal maturation of the GnRH/gonadotropin-releasing system in rodents. We envisage that pubertal decrease in the responsiveness to estrogen in ARC KNDy neurons plays a role in pubertal increase in Kiss1 gene expression. It is unlikely that changes in responsiveness to estrogen negative feedback action during the pubertal transition are simply caused by a change in the expression of ERα, because our previous study showed that the number of ERα-expressing cells and Esr1 gene (encoding ERα) expression in the POA and ARC was comparable between pre- and postpubertal periods in female rats . Further studies are warranted to address this issue.
It should be noted that the central mechanism controlling the prepubertal restraint of GnRH/gonadotropin-releasing system in primates appears to differ from other species such as rodents and sheep [10, 11]. In monkeys, gonadectomy induces an increase in gonadotropin release during the neonatal period and after the onset of puberty, but not during the prepubertal period . This indicates that both steroid-dependent and steroid-independent pathways are responsible for restraint of GnRH/gonadotropin-releasing system. Terasawa and Fernandez  suggest that the steroid-independent inhibition may be due to the abundant synaptogenesis in primate brain than other species and that the decrease in the number of synapse to the adult levels could lead to pubertal increase in GnRH/gonadotropin release via removal of inhibitory inputs in primates. The characteristic steroid-independent restraint period of GnRH/gonadotropin-releasing system in primates is called the juvenile period . In humans, the juvenile hiatus in GnRH/gonadotropin secretion is seen between the ages of 4–9 years , even in girls suffering from Turner syndrome with gonadal dysgenesis  and boys with testicular defects , both which exhibit elevated plasma gonadotropin levels in infantile and peripubertal period.
Cues Relieving Prepubertal Restraint of GnRH/Gonadotropin-Releasing System
It is well demonstrated that the timing of puberty onset is dependent on body weight rather than chronological age . Epidemiologic studies showed that age of menarche in girls declined from 17 years old in the nineteenth century to 13 years old in the twentieth century in developed countries . This secular trend can be understood in terms of the faster somatic growth in humans in the twentieth century . Thus, nutritional cues are likely to contribute to the regulation of pubertal maturation of GnRH/gonadotropin-releasing system. Energy storage in the body fat has been considered to be a possible determinant for the onset of puberty for a long time [59, 60]. Leptin, the first hormone discovered from fat tissue [61, 62], was then considered as a signal that relays the attainment of energy storage to the brain, because leptin-deficient mice do not show puberty and exogenous leptin restores fertility . In fact, the leptin receptor is expressed in several hypothalamic and extra-hypothalamic nuclei including ARC . Recently, KNDy neurons were found to express leptin receptors . Mice with a leptin deficiency showed decreased ARC Kiss1 gene expression , suggesting that leptin seems to be a nutritional cue relieving the prepubertal restraint of GnRH/gonadotropin-releasing system. Leptin, however, could be a prerequisite of normal puberty, because the increase in leptin secretion is not necessarily synchronized with the onset of puberty .
In addition to nutrition, the photoperiod tightly regulates the timing of puberty onset in seasonal breeders such as sheep and Syrian hamsters. Foster et al.  clearly showed that the onset of puberty is postponed to the next breeding season in lambs, which achieved critical body size in late winter. Earlier studies showed that Kiss1 gene expression is higher in the breeding season than in the nonbreeding season in sheep and Syrian hamsters [66, 67]. Taken together, KNDy neurons may integrate multiple external cues, such as nutrition or photoperiod, to control pubertal maturation of the GnRH/gonadotropin-releasing system.
Conclusions and Unanswered Questions
Studies during the last few decades have provided a new framework for the understanding of pubertal maturation of hypothalamic regulation of gonadal axis in mammals. It is now well accepted that KNDy neurons are responsible for the regulation of pubertal increase and GnRH/gonadotropin release in mammals. But, there are still some important unanswered questions. Little is known about the cellular and molecular mechanisms controlling the prepubertal restraint of and pubertal increase in kisspeptin biosynthesis, which is tightly controlled by steroid-dependent and steroid-independent mechanism. In particular, mechanisms underlying the relationship between nutritional statuses and relieving the prepubertal restraint of kisspeptin biosynthesis are still unanswered questions. Further studies, therefore, are needed to fully elucidate the pubertal maturation of hypothalamic mechanism regulating gonadal axis in mammals.
We wish to thank Dr Nicola Skoulding for editorial assistance. The present study was supported in part by a grant from the Science and Technology Research Promotion Program for Agriculture, Forestry, Fisheries, and Food Industry, Grants-in-Aid 26252046 (to HT), 24380157 (to KM), from the Japan Society for the Promotion of Science, and from the Ito Foundation (to YU).
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