madman
Super Moderator
The KiNG of reproduction: kisspeptin/ nNOS interactions shaping hypothalamic GnRH release (2021)
Virginia Delli, Mauro S.B. Silva, Vincent Prévot, Konstantina Chachlaki
Abstract
Gonadotropin-releasing hormone (GnRH) is the master regulator of the hypothalamic-pituitary-gonadal (HPG) axis, and therefore of fertility and reproduction. The release pattern of GnRH by the hypothalamus includes both pulses and surges. However, despite a considerable body of evidence in support of a determinant role for kisspeptin, the mechanisms regulating GnRH pulse and surge remain a topic of debate. In this review, we challenge the view of kisspeptin as an absolute “monarch”, and instead, present the idea of a Kisspeptin-nNOS-GnRH or “KiNG” network that is responsible for generating the “GnRH pulse” and “GnRH surge”. In particular, the neuromodulator nitric oxide (NO) has opposite effects to kisspeptin on GnRH secretion in many respects, acting as the Yin to kisspeptin’s Yang and creating a dynamic system in which kisspeptin provides the “ON” signal, promoting GnRH release, while NO mediates the “OFF” signal, acting as a tonic brake on GnRH secretion. This interplay between an activator and an inhibitor, which is in turn fine-tuned by the gonadal steroid environment, thus leads to the generation of GnRH pulses and surges and is crucial for the proper development and function of the reproductive axis.
1 Introduction
ὁρμῶν (hormôn), “to set in motion, to excite, to stimulate”. Since its introduction by Ernest Starling in 1905 (Starling, 1905), this Greek word has been used to describe the chemical messengers used as a means of communication between different organs in an animal. When the term was introduced, practically nothing was known about the nature or the action of these messengers, which were believed to be produced by only a few specialized organs of the endocrine system (i.e. the glands). We have come a long way since then, with many conceptual changes occurring over the years, the most important of which is possibly the acknowledgment that the nervous and endocrine systems work together to transmit physiological information. The discipline of “Neuroendocrinology” was launched by Geoffrey Harris with his publication in 1955, which not only provided the first proof that the endocrine system could be controlled by the central nervous system (CNS), but also laid the foundations for the notion of the hypothalamic-pituitary-gonadal axis (HPG) (Harris, 1955). In the past two decades, we have come to acknowledge that the field of Neuroendocrinology extends far beyond the traditional neuron-endocrine pathways to encompass the production of hormones by non-traditional cells and tissues, with new and often non-catalytic roles in the regulation of an organism’s development, physiological homeostasis, reproductive capacity, and behavior.
The three components of the HPG axis – the hypothalamus, pituitary gland, and gonads (i.e. the testes and ovaries) – closely interact and depend on each other to allow the complex dialogue between the CNS and the periphery that is indispensable for reproductive function. The hypothalamus is undeniably the single most important brain region integrating vegetative and endocrine signals and controls diverse processes including cardiovascular function, sleep, metabolism, stress, thermoregulation, water and electrolyte balance, growth, and reproduction. Within the hypothalamus, specialized neuronal populations sense moment-to-moment changes in circulating levels of hormones and nutrients, to regulate the neuroendocrine function (Elmquist et al., 2005). Among these hypothalamic neuronal populations are the neurons producing gonadotropin-releasing hormone (GnRH), the main orchestrators of reproductive function, which act as integrators of various signals coming from both the central and the peripheral nervous system.
In spite of their crucial role, GnRH neurons are an extremely small population of cells across mammalian species, counting only 1,000−3,000 neurons in the rodent brain. The GnRH neuronal soma is primarily distributed in the preoptic hypothalamic area (POA) extending their nerve terminals to the pericapillary space of the median eminence (ME), located in the more mediobasal area of the hypothalamus (MBH), releasing the GnRH decapeptide in an episodic manner in both sexes (Sarkar et al., 1976; Moenter et al., 1991; Sarkar & Minami, 1995, Terasawa et al, 1999). Indeed, both immortalized GnRH-secreting GT1 cells and primary GnRH neurons release GnRH in a pulsatile manner, at species-specific intervals (for review see Terasawa, 2019). GnRH is then carried through the pituitary portal circulation for delivery to the anterior pituitary, where it stimulates gonadotropes to synthesize and secrete the gonadotropins, luteinizing hormone (LH), and follicle-stimulating hormone (FSH). These gonadotropins then act on the gonads (i.e. the testes and ovaries) to promote gonadal development and the secretion of sex steroids, which in turn provide positive or negative feedback back to the brain to regulate GnRH release (Prevot, 2015). The pulsatile pattern of GnRH secretion is reflected in the pulsatile secretion of LH during the negative feedback action of sex steroids, while GnRH surge, taking place during the positive feedback action of sex steroids, results in a crucial peak of LH release, triggering ovulation in females (Nett et 79 al., 1974).
Thus, the correct release of LH and FSH depends on the regulation of the frequency and timing of GnRH secretion by sex steroids as well as other neuronal and non-neuronal factors. In turn, the proper development of GnRH neurons, GnRH expression, and GnRH signaling are all essential for the normal functioning of the mammalian HPG axis (Cattanach 84 et al., 1977; Mason et al., 1986; Schwanzel-Fukuda et al., 1989). Justified by the authority of the GnRH system over the regulation of key physiological events, the network surrounding GnRH neurons, ensuring the controlled and timely regulation of their response is complex and multidimensional. To date, kisspeptin neurons have so far been considered the master excitatory driving force behind GnRH/LH release during both positive and negative feedback phases (Navarro et al., 2009; Pielecka-Fortuna et al., 2010; Clarkson et al., 2017).
*In this review, based primarily on research carried out in rodents, we challenge the views of kisspeptin neurons as the sole regulators or supreme “monarchs” of the GnRH network, controlling both GnRH pulse and surge generation. We also explore the implication of the much-overlooked population of neuronal nitric oxide synthase (nNOS) neurons, producing the diffusible messenger nitric oxide (NO), in the control of the GnRH system. Finally, we will discuss how the tripartite Kisspeptin, nNOS, GnRH (KiNG) network could be essential for the regulation of LH pulsatility and LH surge.
2 Milestones during the developmental maturation of the GnRH network in the mouse
2.1 Kisspeptin: the “Yang” of the GnRH network
2.2 NO: the “Yin” of the GnRH network
3 The involvement of ovarian steroid hormones in the GnRH pulse and the GnRH surge generators
3.1 The divergent role of estrogen on the AVPV and ARH kisspeptin populations
3.2 The impact of estrogen on nNOS enzymatic activity
4 The tripartite KiNG network: Could NO be the yin to kisspeptin’s yang?
4.1 The mechanism underlying the ability of nNOS cells to promote the synchronized activity of GnRH neurons
4.2 Interaction of nNOS and kisspeptin neurons as part of the “GnRH pulse” generator
4.3 Interaction of nNOS and kisspeptin neurons as part of the “GnRH surge” generator
4.4 Insights into the involvement of the KiNG interactions controlling reproduction in sheep and primates
5 Concluding remarks and perspectives
Overall, it appears at present that even though kisspeptin neurons undoubtedly play a key role in GnRH secretion, they are not the sole arbiters or “monarchs” of the activation and the function of the HPG axis and that NO, by acting as a brake on GnRH neurons, not only leads to their pulsatility but actually primes them for further stimulation, allowing kisspeptin to instigate the surge in neuropeptide release. Further studies are required to determine how NO and kisspeptin, by acting as the Yin and Yang of the GnRH axis, maintain reproductive homeostasis and the survival and propagation of the species.
Virginia Delli, Mauro S.B. Silva, Vincent Prévot, Konstantina Chachlaki
Abstract
Gonadotropin-releasing hormone (GnRH) is the master regulator of the hypothalamic-pituitary-gonadal (HPG) axis, and therefore of fertility and reproduction. The release pattern of GnRH by the hypothalamus includes both pulses and surges. However, despite a considerable body of evidence in support of a determinant role for kisspeptin, the mechanisms regulating GnRH pulse and surge remain a topic of debate. In this review, we challenge the view of kisspeptin as an absolute “monarch”, and instead, present the idea of a Kisspeptin-nNOS-GnRH or “KiNG” network that is responsible for generating the “GnRH pulse” and “GnRH surge”. In particular, the neuromodulator nitric oxide (NO) has opposite effects to kisspeptin on GnRH secretion in many respects, acting as the Yin to kisspeptin’s Yang and creating a dynamic system in which kisspeptin provides the “ON” signal, promoting GnRH release, while NO mediates the “OFF” signal, acting as a tonic brake on GnRH secretion. This interplay between an activator and an inhibitor, which is in turn fine-tuned by the gonadal steroid environment, thus leads to the generation of GnRH pulses and surges and is crucial for the proper development and function of the reproductive axis.
1 Introduction
ὁρμῶν (hormôn), “to set in motion, to excite, to stimulate”. Since its introduction by Ernest Starling in 1905 (Starling, 1905), this Greek word has been used to describe the chemical messengers used as a means of communication between different organs in an animal. When the term was introduced, practically nothing was known about the nature or the action of these messengers, which were believed to be produced by only a few specialized organs of the endocrine system (i.e. the glands). We have come a long way since then, with many conceptual changes occurring over the years, the most important of which is possibly the acknowledgment that the nervous and endocrine systems work together to transmit physiological information. The discipline of “Neuroendocrinology” was launched by Geoffrey Harris with his publication in 1955, which not only provided the first proof that the endocrine system could be controlled by the central nervous system (CNS), but also laid the foundations for the notion of the hypothalamic-pituitary-gonadal axis (HPG) (Harris, 1955). In the past two decades, we have come to acknowledge that the field of Neuroendocrinology extends far beyond the traditional neuron-endocrine pathways to encompass the production of hormones by non-traditional cells and tissues, with new and often non-catalytic roles in the regulation of an organism’s development, physiological homeostasis, reproductive capacity, and behavior.
The three components of the HPG axis – the hypothalamus, pituitary gland, and gonads (i.e. the testes and ovaries) – closely interact and depend on each other to allow the complex dialogue between the CNS and the periphery that is indispensable for reproductive function. The hypothalamus is undeniably the single most important brain region integrating vegetative and endocrine signals and controls diverse processes including cardiovascular function, sleep, metabolism, stress, thermoregulation, water and electrolyte balance, growth, and reproduction. Within the hypothalamus, specialized neuronal populations sense moment-to-moment changes in circulating levels of hormones and nutrients, to regulate the neuroendocrine function (Elmquist et al., 2005). Among these hypothalamic neuronal populations are the neurons producing gonadotropin-releasing hormone (GnRH), the main orchestrators of reproductive function, which act as integrators of various signals coming from both the central and the peripheral nervous system.
In spite of their crucial role, GnRH neurons are an extremely small population of cells across mammalian species, counting only 1,000−3,000 neurons in the rodent brain. The GnRH neuronal soma is primarily distributed in the preoptic hypothalamic area (POA) extending their nerve terminals to the pericapillary space of the median eminence (ME), located in the more mediobasal area of the hypothalamus (MBH), releasing the GnRH decapeptide in an episodic manner in both sexes (Sarkar et al., 1976; Moenter et al., 1991; Sarkar & Minami, 1995, Terasawa et al, 1999). Indeed, both immortalized GnRH-secreting GT1 cells and primary GnRH neurons release GnRH in a pulsatile manner, at species-specific intervals (for review see Terasawa, 2019). GnRH is then carried through the pituitary portal circulation for delivery to the anterior pituitary, where it stimulates gonadotropes to synthesize and secrete the gonadotropins, luteinizing hormone (LH), and follicle-stimulating hormone (FSH). These gonadotropins then act on the gonads (i.e. the testes and ovaries) to promote gonadal development and the secretion of sex steroids, which in turn provide positive or negative feedback back to the brain to regulate GnRH release (Prevot, 2015). The pulsatile pattern of GnRH secretion is reflected in the pulsatile secretion of LH during the negative feedback action of sex steroids, while GnRH surge, taking place during the positive feedback action of sex steroids, results in a crucial peak of LH release, triggering ovulation in females (Nett et 79 al., 1974).
Thus, the correct release of LH and FSH depends on the regulation of the frequency and timing of GnRH secretion by sex steroids as well as other neuronal and non-neuronal factors. In turn, the proper development of GnRH neurons, GnRH expression, and GnRH signaling are all essential for the normal functioning of the mammalian HPG axis (Cattanach 84 et al., 1977; Mason et al., 1986; Schwanzel-Fukuda et al., 1989). Justified by the authority of the GnRH system over the regulation of key physiological events, the network surrounding GnRH neurons, ensuring the controlled and timely regulation of their response is complex and multidimensional. To date, kisspeptin neurons have so far been considered the master excitatory driving force behind GnRH/LH release during both positive and negative feedback phases (Navarro et al., 2009; Pielecka-Fortuna et al., 2010; Clarkson et al., 2017).
*In this review, based primarily on research carried out in rodents, we challenge the views of kisspeptin neurons as the sole regulators or supreme “monarchs” of the GnRH network, controlling both GnRH pulse and surge generation. We also explore the implication of the much-overlooked population of neuronal nitric oxide synthase (nNOS) neurons, producing the diffusible messenger nitric oxide (NO), in the control of the GnRH system. Finally, we will discuss how the tripartite Kisspeptin, nNOS, GnRH (KiNG) network could be essential for the regulation of LH pulsatility and LH surge.
2 Milestones during the developmental maturation of the GnRH network in the mouse
2.1 Kisspeptin: the “Yang” of the GnRH network
2.2 NO: the “Yin” of the GnRH network
3 The involvement of ovarian steroid hormones in the GnRH pulse and the GnRH surge generators
3.1 The divergent role of estrogen on the AVPV and ARH kisspeptin populations
3.2 The impact of estrogen on nNOS enzymatic activity
4 The tripartite KiNG network: Could NO be the yin to kisspeptin’s yang?
4.1 The mechanism underlying the ability of nNOS cells to promote the synchronized activity of GnRH neurons
4.2 Interaction of nNOS and kisspeptin neurons as part of the “GnRH pulse” generator
4.3 Interaction of nNOS and kisspeptin neurons as part of the “GnRH surge” generator
4.4 Insights into the involvement of the KiNG interactions controlling reproduction in sheep and primates
5 Concluding remarks and perspectives
Overall, it appears at present that even though kisspeptin neurons undoubtedly play a key role in GnRH secretion, they are not the sole arbiters or “monarchs” of the activation and the function of the HPG axis and that NO, by acting as a brake on GnRH neurons, not only leads to their pulsatility but actually primes them for further stimulation, allowing kisspeptin to instigate the surge in neuropeptide release. Further studies are required to determine how NO and kisspeptin, by acting as the Yin and Yang of the GnRH axis, maintain reproductive homeostasis and the survival and propagation of the species.
