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result(s) for
"hormone secretion"
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Novel role for anti-Müllerian hormone in the regulation of GnRH neuron excitability and hormone secretion
Anti-Müllerian hormone (AMH) plays crucial roles in sexual differentiation and gonadal functions. However, the possible extragonadal effects of AMH on the hypothalamic–pituitary–gonadal axis remain unexplored. Here we demonstrate that a significant subset of GnRH neurons both in mice and humans express the AMH receptor, and that AMH potently activates the GnRH neuron firing in mice. Combining
in vivo
and
in vitro
experiments, we show that AMH increases GnRH-dependent LH pulsatility and secretion, supporting a central action of AMH on GnRH neurons. Increased LH pulsatility is an important pathophysiological feature in many cases of polycystic ovary syndrome (PCOS), the most common cause of female infertility, in which circulating AMH levels are also often elevated. However, the origin of this dysregulation remains unknown. Our findings raise the intriguing hypothesis that AMH-dependent regulation of GnRH release could be involved in the pathophysiology of fertility and could hold therapeutic potential for treating PCOS.
Anti-Müllerian hormone (AMH) plays a role in sexual differentiation and gonadal function, but extra-gonadal effects of AMH are not known. Here Cimino
et al
. show that AMH activates a subset of gonadotrophin-releasing hormone (GnRH)-releasing neurons, contributing to luteinizing hormone secretion from the pituitary gland.
Journal Article
Functional anterior pituitary generated in self-organizing culture of human embryonic stem cells
Anterior pituitary is critical for endocrine systems. Its hormonal responses to positive and negative regulators are indispensable for homeostasis. For this reason, generating human anterior pituitary tissue that retains regulatory hormonal control
in vitro
is an important step for the development of cell transplantation therapy for pituitary diseases. Here we achieve this by recapitulating mouse pituitary development using human embryonic stem cells. We find that anterior pituitary self-forms
in vitro
following the co-induction of hypothalamic and oral ectoderm. The juxtaposition of these tissues facilitated the formation of pituitary placode, which subsequently differentiated into pituitary hormone-producing cells. They responded normally to both releasing and feedback signals. In addition, after transplantation into hypopituitary mice, the
in vitro
-generated corticotrophs rescued physical activity levels and survival of the hosts. Thus, we report a useful methodology for the production of regulator-responsive human pituitary tissue that may benefit future studies in regenerative medicine.
It is difficult to generate functional human anterior pituitary tissues
in vitro
. Here, Ozone
et al.
generate human anterior pituitary from embryonic stem cells by recapitulating
in vivo
development, and demonstrate this tissue secretes hormones and rescues hypopituitarism when grafted into mice.
Journal Article
Optogenetic activation of GnRH neurons reveals minimal requirements for pulsatile luteinizing hormone secretion
The mechanisms responsible for generating the pulsatile release of gonadotropins from the pituitary gland are unknown. We develop here a methodology in mice for controlling the activity of the gonadotropin-releasing hormone (GnRH) neurons in vivo to establish the minimal parameters of activation required to evoke a pulse of luteinizing hormone (LH) secretion. Injections of Cre-dependent channelrhodopsin (ChR2)-bearing adeno-associated virus into the median eminence of adult GnRH-Cre mice resulted in the selective expression of ChR2 in hypophysiotropic GnRH neurons. Acute brain slice experiments demonstrated that ChR2-expressing GnRH neurons could be driven to fire with high spike fidelity with blue-light stimulation frequencies up to 40 Hz for periods of seconds and up to 10 Hz for minutes. Anesthetized, ovariectomized mice had optical fibers implanted in the vicinity of GnRH neurons within the rostral preoptic area. Optogenetic activation of GnRH neurons for 30-s to 5-min time periods over a range of different frequencies revealed that 10 Hz stimulation for 2 min was the minimum required to generate a pulse-like increment of LH. The same result was found for optical activation of GnRH projections in the median eminence. Increases in LH secretion were compared with endogenous LH pulse parameters measured from ovariectomized mice. Driving GnRH neurons to exhibit simultaneous burst firing was ineffective at altering LH secretion. These observations provide an insight into how GnRH neurons generate pulsatile LH secretion in vivo.
Significance The mammalian reproductive system is critically dependent upon pulsatile hormone release patterned and driven by a small population of gonadotropin-releasing hormone (GnRH) neurons. The scattered distribution of GnRH neurons within the brain has made it extremely difficult to investigate the nature and properties of these cells in any selective manner in vivo. We report here a procedure that enables selective, high-fidelity activation of the GnRH neurons that control gonadotropin secretion in ovariectomized mice. Using this approach, we have been able to define minimal parameters of activation required to generate pulsatile gonadotropin secretion in the blood. This provides critical information for understanding and manipulating the genesis of gonadotropin pulsatility in reproductive biology.
Journal Article
Timing and completion of puberty in female mice depend on estrogen receptor α-signaling in kisspeptin neurons
Puberty onset is initiated by activation of neurons that secrete gonadotropin-releasing hormone (GnRH). The timing and progression of puberty may depend upon temporal coordination of two opposing central mechanisms—a restraint of GnRH secretion before puberty onset, followed by enhanced stimulation of GnRH release to complete reproductive maturation during puberty. Neuronal estrogen receptor α (ERα) has been implicated in both controls; however, the underlying neural circuits are not well understood. Here we test whether these mechanisms are mediated by neurons that express kisspeptin, a neuropeptide that modulates GnRH neurosecretion. Strikingly, conditional ablation of ERα in kisspeptin neurons results in a dramatic advancement of puberty onset in female mice. Furthermore, subsequent pubertal maturation is arrested in these animals, as they fail to acquire normal ovulatory cyclicity. We show that the temporal coordination of juvenile restraint and subsequent pubertal activation is likely mediated by ERα in two separate kisspeptin neuronal populations in the hypothalamus.
Journal Article
Kisspeptin directly stimulates gonadotropin-releasing hormone release via G protein-coupled receptor 54
We have recently described a molecular gatekeeper of the hypothalamic-pituitary-gonadal axis with the observation that G protein-coupled receptor 54 (GPR54) is required in mice and men for the pubertal onset of pulsatile luteinizing hormone (LH) and follicle-stimulating hormone (FSH) secretion to occur. In the present study, we investigate the possible central mode of action of GPR54 and kisspeptin ligand. First, we show that GPR54 transcripts are colocalized with gonadotropin-releasing hormone (GnRH) neurons in the mouse hypothalamus, suggesting that kisspeptin, the GPR54 ligand, may act directly on these neurons. Next, we show that GnRH neurons seem anatomically normal in gpr54-/-mice, and that they show projections to the median eminence, which demonstrates that the hypogonadism in gpr54-/-mice is not due to an abnormal migration of GnRH neurons (as occurs with KAL1 mutations), but that it is more likely due to a lack of GnRH release or absence of GnRH neuron stimulation. We also show that levels of kisspeptin injected i.p., which stimulate robust LH and FSH release in wild-type mice, have no effect in gpr54-/-mice, and therefore that kisspeptin acts directly and uniquely by means of GPR54 signaling for this function. Finally, we demonstrate by direct measurement, that the central administration of kisspeptin intracerebroventricularly in sheep produces a dramatic release of GnRH into the cerebrospinal fluid, with a parallel rise in serum LH, demonstrating that a key action of kisspeptin on the hypothalamo-pituitary-gonadal axis occurs directly at the level of GnRH release. The localization and GnRH release effects of kisspeptin thus define GPR54 as a major control point in the reproductive axis and suggest kisspeptin to be a neurohormonal effector.
Journal Article
Massage increases oxytocin and reduces adrenocorticotropin hormone in humans
Human beings are highly social creatures who often touch each other during social interactions. Although the physiologic effects of touch are not understood fully, it appears to sustain social bonds and to increase cooperative behaviors. Oxytocin (OT) is a hormone known to facilitate social bonding, and touch may affect OT release. Previous studies seeking to relate massage and oxytocin in humans have been inconsistent in their findings.
This study examined the effect of massage on oxytocin and also measured its effect on other physiologic factors, including adrenocorticotropin hormone (ACTH), nitric oxide (NO), and beta-endorphin (BE).
The research team advertised that the trial would study relaxation and assigned participants randomly to the intervention or the control group. A lab administrator assigned a random numeric code to participants to mask their identities.
The study took place at the University of California Los Angeles (UCLA), Los Angeles, CA.
Ninety-five people from UCLA gave written informed consent for participation in the study, with the team paying them to participate. The intervention group included 65 participants and the control group 30 participants.
For the intervention (massage) group, the research team drew participants' blood and followed the blood draw with 15 minutes of moderate-pressure massage of the upper back. The control (rest) group rested quietly for 15 minutes after the blood draw. A second blood draw followed for both groups.
The research team assayed OT, ACTH, NO, and BE. The team used four survey instruments to examine the relationship between personality factors and the physiologic measures of interest. The team analyzed data using SPSS 15.0 for Windows.
Massage was associated with an increase in OT and reductions in ACTH, NO, and BE. Comparing the effects of massage for the massage group with those for the rest group, the research team found significant differences between groups for changes in OT, ACTH, NO, and BE.
This study is the first using a large sample of mixed gender that demonstrates that massage increases OT and decreases ACTH, NO, and BE. These findings may help explain the mechanisms through which social connections reduce morbidity and mortality.
Journal Article
Effects of betaine on performance and body composition: a review of recent findings and potential mechanisms
Betaine is a methyl derivative of glycine first isolated from sugar beets. Betaine consumed from food sources and through dietary supplements presents similar bioavailability and is metabolized to di-methylglycine and sarcosine in the liver. The ergogenic and clinical effects of betaine have been investigated with doses ranging from 500 to 9,000 mg/day. Some studies using animal models and human subjects suggest that betaine supplementation could promote adiposity reductions and/or lean mass gains. Moreover, previous investigations report positive effects of betaine on sports performance in both endurance- and resistance-type exercise, despite some conflicting results. The mechanisms underlying these effects are poorly understood, but could involve the stimulation of lipolysis and inhibition of lipogenesis via gene expression and subsequent activity of lipolytic-/lipogenic-related proteins, stimulation of autocrine/endocrine IGF-1 release and insulin receptor signaling pathways, stimulation of growth hormone secretion, increased creatine synthesis, increases in protein synthesis via intracellular hyper-hydration, as well as exerting psychological effects such as attenuating sensations of fatigue. However, the exact mechanisms behind betaine action and the long-term effects of supplementation on humans remain to be elucidated. This review aims to describe evidence for the use of betaine as an ergogenic and esthetic aid, and discuss the potential mechanisms underlying these effects.
Journal Article
Redirecting intracellular trafficking and the secretion pattern of FSH dramatically enhances ovarian function in mice
FSH and luteinizing hormone (LH) are secreted constitutively or in pulses, respectively, from pituitary gonadotropes in many vertebrates, and regulate ovarian function. The molecular basis for this evolutionarily conserved gonadotropin-specific secretion pattern is not understood. Here, we show that the carboxyterminal heptapeptide in LH is a gonadotropin-sorting determinant in vivo that directs pulsatile secretion. FSH containing this heptapeptide enters the regulated pathway in gonadotropes of transgenic mice, and is released in response to gonadotropin-releasing hormone, similar to LH. FSH released from the LH secretory pathway rescued ovarian defects in Fshb -null mice as efficiently as constitutively secreted FSH. Interestingly, the rerouted FSH enhanced ovarian follicle survival, caused a dramatic increase in number of ovulations, and prolonged female reproductive lifespan. Furthermore, the rerouted FSH vastly improved the in vivo fertilization competency of eggs, their subsequent development in vitro and when transplanted, the ability to produce offspring. Our study demonstrates the feasibility to fine-tune the target tissue responses by modifying the intracellular trafficking and secretory fate of a pituitary trophic hormone. The approach to interconvert the secretory fate of proteins in vivo has pathophysiological significance, and could explain the etiology of several hormone hyperstimulation and resistance syndromes.
Journal Article
Kisspeptin Signaling Is Required for the Luteinizing Hormone Response in Anestrous Ewes following the Introduction of Males
The introduction of a novel male stimulates the hypothalamic-pituitary-gonadal axis of female sheep during seasonal anestrus, leading to the resumption of follicle maturation and ovulation. How this pheromone cue activates pulsatile secretion of gonadotropin releasing hormone (GnRH)/luteinizing hormone (LH) is unknown. We hypothesised that pheromones activate kisspeptin neurons, the product of which is critical for the stimulation of GnRH neurons and fertility. During the non-breeding season, female sheep were exposed to novel males and blood samples collected for analysis of plasma LH profiles. Females without exposure to males served as controls. In addition, one hour before male exposure, a kisspeptin antagonist (P-271) or vehicle was infused into the lateral ventricle and continued for the entire period of male exposure. Introduction of a male led to elevated mean LH levels, due to increased LH pulse amplitude and pulse frequency in females, when compared to females not exposed to a male. Infusion of P-271 abolished this effect of male exposure. Brains were collected after the male effect stimulus and we observed an increase in the percentage of kisspeptin neurons co-expressing Fos, by immunohistochemistry. In addition, the per-cell expression of Kiss1 mRNA was increased in the rostral and mid (but not the caudal) arcuate nucleus (ARC) after male exposure in both aCSF and P-271 treated ewes, but the per-cell content of neurokinin B mRNA was decreased. There was also a generalized increase in Fos positive cells in the rostral and mid ARC as well as the ventromedial hypothalamus of females exposed to males. We conclude that introduction of male sheep to seasonally anestrous female sheep activates kisspeptin neurons and other cells in the hypothalamus, leading to increased GnRH/LH secretion.
Journal Article