Inhibition Of Gonadotropin-releasing Hormone Research Articles

Chronic inflammation decreases arcuate kisspeptin expression in male sheep

Lipopolysaccharide (LPS) from Gram-negative bacteria induces an immune response and impairs reproduction through suppression of gonadotropin releasing hormone (GnRH), subsequently luteinizing hormone (LH) secretion. While there is evidence that acute inflammation inhibits kisspeptin, little is known about the impact of chronic inflammation on this key reproductive neuropeptide in livestock species. Thus, we sought to examine a central mechanism whereby LPS suppresses LH secretion in sheep. Twenty wethers were randomly assigned to one of five treatment groups: control (CON; n=4), single acute IV LPS dose (SAD; n=4), daily acute IV LPS dose (DAD; n=4), daily increasing IV LPS dose (DID; n=4), and chronic subcutaneous LPS dose (CSD; n=4). On Days 1 and 7, blood samples were collected every 12 minutes for 360 minutes using jugular venipuncture. Following blood collection on Day 7, all animals were euthanized, brain tissue was perfused with 4% paraformaldehyde, and hypothalamic blocks were removed and processed for immunohistochemistry. On Day 1, LH pulse frequency was significantly lower (p=0.02) in SAD (0.25 ± 0.1 pulses/hour), DAD (0.25 ± 0.1 pulses/hour), DID (0.35 ± 0.1 pulses/hour), and CSD (0.40 ± 0.1 pulses/hour) compared to CON (0.70 ±0.1 pulses/hour). On Day 7, only DID animals (0.35 ± 0.1 pulses/hour) had significantly lower (p=0.049) LH pulse frequency compared to controls (0.85 ± 0.1 pulse/hour). Furthermore, only DID animals (33.3 ± 10.9 cells/section/animal) had significantly fewer (p=0.001) kisspeptin-immunopositive cells compared to controls (82.6 ± 13.6 cells/section/animal). Taken together, we suggest that daily increasing doses of LPS is a powerful inhibitor of kisspeptin neurons in young male sheep and a physiologically relevant model to examine the impact of chronic inflammation on the reproductive axis in livestock.

405 The Effects of Disease-Induced Inflammation on Reproductive Neuroendocrinology: Evidence from Sheep

Abstract Reproduction is dictated by the cohesive functioning of the organs of the hypothalamic-pituitary-gonadal (HPG) axis. As the name suggests, reproduction starts within the hypothalamus through the production and pulsatile secretion of gonadotropin releasing hormone (GnRH) followed by subsequent secretion of luteinizing hormone (LH) from the anterior pituitary and then steroidogenesis and gametogenesis in the gonads. Additionally, the HPG axis is tightly regulated by internal and external cues and, over the last twenty years, kisspeptin has been identified as a key modulator for reproduction through its stimulatory actions on GnRH neurons to secrete GnRH and subsequently LH. Growing evidence indicates that these kisspeptin expressing neurons are negatively affected by stressors (e.g., inflammation, social stress, metabolic stress) resulting in impaired reproduction. Inflammation caused by lipopolysaccharide (LPS, endotoxin), a component of the cell membrane of Gram-negative bacteria (e.g., Escherichia coli), is of particular interest due to its relationship with common livestock ailments, such as mastitis and metritis, and its suppression of GnRH and LH secretions. However, there is limited information about the influence disease-induced inflammation has on kisspeptin expressing neurons. In rats, acute endotoxin inflammation will cause about a 50% decrease in the number of kisspeptin immunopositive cells in the arcuate nucleus along with a suppression in LH secretion. In ewes, an acute dose will decrease the proportion of activated kisspeptin neurons in the ARC and POA. However, the mechanisms by which inflammation affects reproduction are not completely understood, especially in domestic livestock. Through a series of experiments, we aim to elucidate these mechanisms and effects of endotoxinemia in both an acute and a chronic model. To accomplish these goals, we administered endotoxin acutely to ewes. Overall, the suppression of LH secretion at the level of hypothalamus is possible, however, more research is required to further elucidate the mechanism. To evaluate a chronic model of systemic inflammation, we evaluated routes of endotoxin administration by randomly assigning twenty two castrated male sheep into one of five groups - control (CON), single acute IV dose (SAD; 400 ng/kg BW LPS) administered on Day 1, daily acute IV dose (DAD; 400 ng/kg BW LPS), daily increasing IV dose (DID; starting with 400 ng/kg BW LPS and increasing 20% each day), or steady subcutaneous dose (SSD; 20 µg/kg BW LPS over 24 hours), all administered during a one-week study period. Chronic inflammation, induced by a daily rising dose of IV administered LPS, suppresses LH secretion through effects on kisspeptin protein expression in the middle arcuate nucleus of the hypothalamus of sheep. Taken together, systemic inflammation associated with infection and disease likely impairs reproduction in part through suppression of kisspeptin-expressing neurons.

Disruption of Intranasal GnRH Neuronal Migration Route into the Brain Induced by Proinflammatory Cytokine IL-6: Ex Vivo and In Vivo Rodent Models

Maternal immune activation results in altered levels of cytokines in the maternal–fetal system, which has a negative impact on fetal development, including the gonadotropin-releasing hormone (GnRH) system, which is crucial for the reproduction. Suppression of GnRH–neuron migration may be associated with cytokine imbalances, and primarily with proinflammatory cytokine interleukin (IL)-6. This study aimed to determine the effects of IL-6 and monoclonal antibody to IL-6 or IL-6R or polyclonal IgG on the formation of migration route of GnRH–neurons in ex vivo and in vivo rodent models on day 11.5 of embryonic development. The increased level of IL-6 in mouse nasal explants suppressed peripherin-positive fiber outgrowth, while this led to an increase in the number of GnRH–neurons in the nose and olfactory bulbs and a decrease in their number in the fetal brain. This effect is likely to be realized via IL-6 receptors along the olfactory nerves. The suppressive effect of IL-6 was diminished by monoclonal antibodies to IL-6 or its receptors and by IgG.

Transcriptomic response to GnRH down regulation by RNA interference in clam Ruditapes philippinarum, suggest possible role in reproductive function

Gonadotropin-releasing hormone (GnRH) plays a key role in the control of the reproductive axis in vertebrates, however, little is known about its function in reproductive endocrine regulation in molluscs. In the present study, RNA-seq was used to construct transcriptomes of Ruditapes philippinarum testis and ovaries of control and GnRH suppressed individuals using RNA interference. GnRH suppression caused 112 and 169 enriched KEGG pathways in testis and ovary, with 92 pathways in common in both comparisons. The most enriched KEGG pathways occurred in the “Oxidative phosphorylation”, “Dorso-ventral axis formation”, “Thyroid hormone synthesis” and “Oxytocin signaling pathway” etc. A total of 1838 genes in testis and 358 genes in ovaries were detected differentially expressed in GnRH suppressed clams. Among the differentially expressed genes, a suit of genes related to regulation of steroid hormones synthesis and gonadal development, were found in both ovary and testis with RNAi of GnRH. These results suggest that GnRH may play an important role in reproductive function in bivalves. This study provides a preliminary basis for studying the function and regulatory mechanism of GnRH in bivalves.

Levels of prolactin and testosterone and associated sexual dysfunction and breast abnormalities in men with schizophrenia treated with antipsychotic medications

Sexual dysfunction is one of the most bothersome adverse drug effects seen in men and women taking antipsychotic medications and negatively impacts medication adherence. Antipsychotic medications are associated with hyperprolactinemia, which is known to contribute to sexual and hormonal side effects in men. However, testosterone also plays a key factor in male sexual function and may be affected by abnormal prolactin levels through gonadotropin-releasing hormone inhibition. This study was a pilot study undertaken to assess the prevalence of elevations in prolactin levels, related reductions in testosterone levels, associated symptoms of sexual dysfunction and breast abnormalities in male participants, and related distress to these symptoms in men taking prolactin-elevating antipsychotic medications. The study was conducted as a cross-sectional study. Our results showed a notably high prevalence of sexual side effects in this population, with gynecomastia occurring in 50% and penile-related symptoms in 73%. Additionally, we found elevated prolactin levels in 68% and low testosterone levels in 55% of our participants. This study was limited in its power due to a small sample size of 22 men and the lack of a control group. Still, even in our relatively small sample, we see a trend of hyperprolactinemia being associated with low testosterone and a significant correlation of low testosterone levels with penile-related symptoms. This suggests that testosterone plays a major role in the sexual side effects reported by men taking antipsychotics, although larger studies are needed to further categorize this relationship.

Undernutrition reduces kisspeptin and neurokinin B expression in castrated male sheep.

SummaryUndernutrition impairs reproductive success through suppression of gonadotropin-releasing hormone (GnRH), and subsequently luteinizing hormone (LH), secretion. Given that kisspeptin and neurokinin B (NKB) neurons in the arcuate nucleus (ARC) of the hypothalamus are thought to play key stimulatory roles in the generation of GnRH/LH pulses, we hypothesized that feed restriction would reduce the ARC mRNA abundance and protein expression of kisspeptin and NKB in young, male sheep. Fourteen wethers (castrated male sheep five months of age) were either fed to maintain (FM; n = 6) pre-study body weight or feed-restricted (FR; n = 8) to lose 20% of pre-study body weight over 13 weeks. Throughout the study, weekly blood samples were collected and assessed for LH concentration using RIA. At Week 13 of the experiment, animals were killed, heads were perfused with 4% paraformaldehyde, and brain tissue containing the hypothalamus was collected, sectioned, and processed for detection of mRNA (RNAscope) and protein (immunohistochemistry) for kisspeptin and NKB. Mean LH was significantly lower and LH inter-pulse interval was significantly higher in FR wethers compared to FM wethers at the end of the experiment (Week 13). RNAscope analysis revealed significantly fewer cells expressing mRNA for kisspeptin and NKB in FR wethers compared to FM controls, and immunohistochemical analysis revealed significantly fewer immunopositive kisspeptin and NKB cells in FR wethers compared to FM wethers. Taken together, this data supports the idea that long-term feed restriction regulates GnRH/LH secretion through central suppression of kisspeptin and NKB in male sheep.Lay summaryWhile undernutrition is known to impair reproduction at the level of the brain, the components responsible for this in the brain remain to be fully understood. Using male sheep we examined the effect of undernutrition on two stimulatory molecules in the brain critical for reproduction: kisspeptin and neurokinin B. Feed restriction for several weeks resulted in decreased luteinizing hormone in the blood indicating reproductive function was suppressed. In addition, undernutrition also reduced both kisspeptin and neurokinin B levels within a region of the brain involved in reproduction, the hypothalamus. Given that they have stimulatory roles in reproduction, we believe that undernutrition acts in the brain to reduce kisspeptin and neurokinin B levels leading to the reduction in luteinizing hormone secretion. In summary, long-term undernutrition inhibits reproductive function in sheep through suppression of kisspeptin and neurokinin B within the brain.

Gonadotropin-releasing hormone-independent effects of recombinant vertebrate ancient long opsin in the goldfish Carassius auratus reveal alternative reproduction pathways.

Vertebrate ancient long (VAL)-opsin is a green-sensitive photoreceptor that shows high sequence similarity to vertebrate ancient opsin, which is considered to play a role in sexual maturation via gonadotropin-releasing hormone (GnRH); however, the role of VAL-opsin in vertebrate sexual maturity remains unclear. Therefore, we investigated the possible role of VAL-opsin in reproduction in the goldfish Carassius auratus under a state of GnRH inhibition. Goldfish were injected with recombinant VAL-opsin protein (0.5μg/g body mass) and/or the GnRH antagonist cetrorelix (0.5μg/fish), and changes in the mRNA expression levels of genes associated with goldfish reproduction were measured by quantitative polymerase chain reaction, including those involved in the hypothalamus-pituitary-gonad (HPG) axis, VAL-opsin, GnRH, the gonadotropins (GTHs) luteinizing hormone and follicle-stimulating hormone, and estrogen receptor (ER). Moreover, the fish were irradiated with a green light-emitting diode (520nm) to observe the synergistic effect on the HPG axis with VAL-opsin. Green LED exposure significantly and slightly increased the VAL-opsin and GnRH levels, respectively; however, these effects were blocked in groups injected with cetrorelix at all time points. Cetrorelix significantly decreased the mRNA levels of GTHs and ER, whereas these hormones recovered by co-treatment with VAL-opsin. These results indicate that green LED is an effective light source to promote the expression of sex hormones in fish. Moreover, VAL-opsin not only affects activity of the HPG axis but also appears to act on the pituitary gland directly to stimulate a new sexual maturation pathway that promotes the secretion of GTHs independent of GnRH.

GnRH impairs diabetic wound healing through enhanced NETosis

It has been reported that neutrophil extracellular traps (NETs) impair wound healing in diabetes and that inhibiting NET generation (NETosis) improves wound healing in diabetic mice. Gonadotropin-releasing hormone (GnRH) agonists are associated with a greater risk of diabetes. However, the role of GnRH in diabetic wound healing is unclear. We determined whether GnRH-promoted NETosis and induced more severe and delayed diabetic wound healing. A mouse model of diabetes was established using five injections with streptozotocin. Mice with blood glucose levels >250 mg/dL were then used in the experiments. GnRH agonist treatment induced delayed wound healing and increased NETosis at the skin wounds of diabetic mice. In contrast, GnRH antagonist treatment inhibited GnRH agonist-induced delayed wound healing. The expression of NETosis markers PAD4 and citrullinated histone H3 were increased in the GnRH-treated diabetic skin wounds in diabetic mice and patients. In vitro experiments also showed that neutrophils expressed a GnRH receptor and that GnRH agonist treatment increased NETosis markers and promoted phorbol myristate acetate (PMA)-induced NETosis in mouse and human neutrophils. Furthermore, GnRH antagonist treatment suppressed the expression of NETosis markers and PMA-induced NETosis, which were increased by GnRH treatment. These results indicated that GnRH-promoted NETosis and that increased NETosis induced delayed wound healing in diabetic skin wounds. Thus, inhibition of GnRH might be a novel treatment of diabetic foot ulcers.

The Anti-proliferative Activity of GnRH Through Downregulation of the Akt/ERK Pathways in Pancreatic Cancer.

Gonadotropin-releasing hormone (GnRH) has been demonstrated to exert anti-proliferative functions on various tumor cells in endometrial, ovarian, bladder, or prostate cancer as a part of the autocrine system. In addition, the expression levels of GnRH and its receptor had been identified in breast cancer or non-reproductive cancers, such as glioblastoma and pancreatic cancer. Previous studies have reported abnormal GnRH expression in several malignant tumors, suggesting that GnRH and its receptor might be essential for tumourigenesis. In the present study, we attempted to clarify the mechanisms underlying GnRH function in cell proliferation in pancreatic cancer. Our results indicated that GnRH expression might be essential for the malignancy of pancreatic cancer. We then found that GnRH overexpression can induce cell apoptosis through activating the Bcl-2/Bax pathway and autophagy might be involved in the GnRH-mediated apoptosis in Panc1 cells. Further investigation showed that the inhibition of GnRH may promote tumor invasion and migration through upregulation of MMP2 expression in pancreatic cancer cells. Moreover, our results indicated that GnRH can regulate the Akt/ERK1/2 pathways to promote cell proliferation by inhibiting cell apoptosis in Panc1 cells. Therefore, our finding exhibited that the regulation of GnRH expression may be essential for tumourigenesis in pancreatic cancer, and might be a potential target for the treatment of the patients with pancreatic cancer.

RF9: May it be a new therapeutic option for hypogonadotropic hypogonadism?

Hypogonadotropic hypogonadism (secondary hypogonadism), congenital or acquired, is a form of hypogonadism that is due to problems with either the hypothalamus or pituitary gland affecting gonadotropin levels. Pulsatile secretion of gonadotropin-releasing hormone (GnRH) by hypothalamus is a primer step to initiate the release of pituitary gonadotropins. Kisspeptin and gonadotropin-inhibitory hormone (GnIH) are accepted as two major players in the activation and inhibition of GnRH regarding the neuroendocrine functioning of the hypothalamic pituitary gonadal axis. Kisspeptin is known as the most potent activator of GnRH. Regarding the inhibition of GnRH, RF-amide-related peptide-3 (RFRP-3) is accepted as the mammalian orthologue of GnIH in avian species. RF9 (1-adamantane carbonyl-Arg-Phe-NH2) is an antagonist of RFRP-3/GnIH receptor (neuropeptide FF receptor 1 (NPFFR1; also termed as GPR147). In recent years, several studies have indicated that RF9 activates GnRH neurons and gonadotropins in a kisspeptin receptor (Kiss1r, formerly known as GPR54) dependent manner. These results suggest that RF9 may have a bimodal function as both an RFRP-3 antagonist and a kisspeptin agonist or it may be a kiss1r agonist rather than an RFRP-3/GnIH receptor antagonist. These interactions are possible because Kisspeptin and GnIH are members of the RF-amide family, and both possibilities are not far from explaining the potent gonadotropin stimulating effects of RF9. Therefore, we hypothesize that RF9 may be a new therapeutic option for the hypogonadotropic hypogonadism due to its potent GnRH stimulating effects. A constant or repeated administration of RF9 provides a sustained increase in plasma gonadotrophin levels. However, applications in the same way with GnRH analogues and kisspeptin may result in desensitization of the gonadotropic axis. The reasons reported above contribute to our hypothesis that RF9 may be a good option in the GnRH stimulating as a kisspeptin agonist. We suggest that further studies are needed to elucidate the potential effects of RF9 in the treatment of the hypogonadotropic hypogonadism.

Thyroid disrupting pesticides impair the hypothalamic-pituitary-testicular axis of a wildlife bird, Amandava amandava

The effect of two thyroid disrupting pesticides (TDPs) mancozeb (MCZ) and imidacloprid (IMI) on the hypothalamic-pituitary-gonadal/testicular (HPG) axis of a seasonally breeding bird, Amandava amandava has been evaluated. Male birds (n=8/group) were exposed to each of the pesticide (0.25% LD50 of respective pesticide) as well as to their two equimixture doses (0.25% of LD50 of each and 0.5% LD50 of each) through food for 30d during pre-breeding stage of the reproductive cycle. Reduction in weight, volume and other histopathological features revealed testicular regression. Suppression of gonadotropin releasing hormone, increased expression of gonadotropin inhibitory hormone in the hypothalamus of exposed groups as well as impairment of plasma levels of the reproduction related hormones indicated the disruption of the HPG axis. The pesticides interference of the thyroid function during the critical phase of reproductive development impaired the HPG axis; more significantly in co-exposed groups suggesting the cumulative toxicity.

Poster Presentations

Gonadotropin-inhibitory hormone (GnIH) acts to inhibit reproduction at all levels of the hypothalamo–pituitary–gonad axis. GnIH expression and/or immunoreactivity in the hypothalamus increase with acute stress in some birds and mammals, and thus may be involved in stress-induced reproductive inhibition. Much is known about GnIH and stress in seasonal and continuous breeders, but far less is known about these interactions in opportunistic breeders. For opportunistically breeding animals, reproductive readiness is closely associated with unpredictable environmental cues, and thus the GnIH system may be more sensitive to stress. To test this, we collected tissues from zebra finches immediately following capture or after 60 min of restraint. Restraint significantly increased plasma corticosterone in males and females but, contrary to studies on other species, restrained birds had significantly fewer GnIH immunoreactive (GnIH-ir) cell bodies than control birds. GnIH-ir cell number did not differ between the sexes. Stressed females had lower mRNA expression of the beta subunit of follicle stimulating hormone (FSHβ) in the pituitary, suggesting that the reduction in observed GnIH immunoreactivity in females may have been due to increased GnIH release in response to acute stress. GnIH expression increased in the testes, but not the ovaries, of restrained animals. Our data suggest that although GnIH responsiveness to stress appears to be conserved across species, specific tissue response and direction of GnIH regulation is not. Variation in the GnIH response to stress between species might be the result of ecological adaptations or other species differences in the response of the GnIH system to stress.

Postmenopausal Hyperandrogenism in a Patient With an Adrenal Adenoma: How Should We Approach It?

ABSTRACT Objective: To report the case of a postmenopausal woman with adrenal adenoma and severe hyperandrogenism due to bilateral ovarian hyperthecosis. Methods: We describe the clinical findings and diagnostic tests used to determine the source of excess androgen. Results: A 57-year-old postmenopausal woman with a 3-year history of alopecia and hirsutism was referred for evaluation. Laboratory evaluations revealed an elevated testosterone concentration. Transvaginal ultrasonography was normal but computed tomography showed a left adrenal nodule. Ovarian and adrenal vein sampling showed a gradient of testosterone between peripheral and right ovarian veins. Her testosterone concentration normalized following treatment with a gonadotropin-releasing hormone agonist. Following bilateral oophorectomy, her elevated testosterone concentration returned to normal and signs of hyperandrogenism gradually receded. Conclusion: Suppression of gonadotropin-releasing hormone and both adrenal and ovarian venous sampling ...

Differential response of GnIH in the brain and gonads following acute stress in a songbird

Gonadotropin-inhibitory hormone (GnIH) acts to inhibit reproduction at all levels of the hypothalamo–pituitary–gonad axis. GnIH expression and/or immunoreactivity in the hypothalamus increase with acute stress in some birds and mammals, and thus may be involved in stress-induced reproductive inhibition. Much is known about GnIH and stress in seasonal and continuous breeders, but far less is known about these interactions in opportunistic breeders. For opportunistically breeding animals, reproductive readiness is closely associated with unpredictable environmental cues, and thus the GnIH system may be more sensitive to stress. To test this, we collected tissues from zebra finches immediately following capture or after 60min of restraint. Restraint significantly increased plasma corticosterone in males and females but, contrary to studies on other species, restrained birds had significantly fewer GnIH immunoreactive (GnIH-ir) cell bodies than control birds. GnIH-ir cell number did not differ between the sexes. Stressed females had lower mRNA expression of the beta subunit of follicle stimulating hormone (FSHβ) in the pituitary, suggesting that the reduction in observed GnIH immunoreactivity in females may have been due to increased GnIH release in response to acute stress. GnIH expression increased in the testes, but not the ovaries, of restrained animals. Our data suggest that although GnIH responsiveness to stress appears to be conserved across species, specific tissue response and direction of GnIH regulation is not. Variation in the GnIH response to stress between species might be the result of ecological adaptations or other species differences in the response of the GnIH system to stress.

Involvement of prolactin in the meloxicam-dependent inflammatory response of the gonadotropic axis to prolonged lipopolysaccharide treatment in anoestrous ewes.

An immune challenge can affect the reproductive process in females. Peripheral administration of bacterial endotoxin (lipopolysaccharide; LPS) decreases LH secretion and disrupts ovarian cyclicity. The aim of the present study was to determine the effects of a cyclo-oxygenase (COX)-2 inhibitor (meloxicam) on gonadotropin-releasing hormone (GnRH) and LH secretion in anoestrous ewes during systemic inflammation induced by LPS. LPS (400ngkg-1 per day) suppressed LH release. In three individuals, meloxicam (500μgkg-1, i.v.) abolished LPS-induced LH suppression. In another three ewes LH was ineffective. Similar changes were observed in hypothalamic GnRH expression. The effect of meloxicam depended on the circulating level of prolactin: meloxicam abolished inflammatory-dependent suppression of GnRH and LH secretion when plasma prolactin levels were similar to those in untreated animals, but was ineffective in those with elevated levels of prolactin. We conclude that COX-2 inhibitors minimise the negative effect of inflammation on the reproductive system but that this effect may be antagonised by prolactin.

A new pathway mediating social effects on the endocrine system: female presence acting via norepinephrine release stimulates gonadotropin-inhibitory hormone in the paraventricular nucleus and suppresses luteinizing hormone in quail.

Rapid effects of social interactions on transient changes in hormonal levels are known in a wide variety of vertebrate taxa, ranging from fish to humans. Although these responses are mediated by the brain, neurochemical pathways that translate social signals into reproductive physiological changes are unclear. In this study, we analyzed how a female presence modifies synthesis and/or release of various neurochemicals, such as monoamines and neuropeptides, in the brain and downstream reproductive hormones in sexually active male Japanese quail. By viewing a female bird, sexually active males rapidly increased norepinephrine (NE) release in the paraventricular nucleus (PVN) of the hypothalamus, in which gonadotropin-inhibitory hormone (GnIH) neuronal cell bodies exist, increased GnIH precursor mRNA expression in the PVN, and decreased luteinizing hormone (LH) concentration in the plasma. GnIH is a hypothalamic neuropeptide that inhibits gonadotropin secretion from the pituitary. It was further shown that GnIH can rapidly suppress LH release after intravenous administration in this study. Centrally administered NE decreased plasma LH concentration in vivo. It was also shown that NE stimulated the release of GnIH from diencephalic tissue blocks in vitro. Fluorescence double-label immunohistochemistry indicated that GnIH neurons received noradrenergic innervations, and immunohistochemistry combined with in situ hybridization have further shown that GnIH neurons expressed α2A-adrenergic receptor mRNA. These results indicate that a female presence increases NE release in the PVN and stimulates GnIH release, resulting in the suppression of LH release in sexually active male quail.

Short-term treatment with a gonadotropin-releasing hormone antagonist, cetrorelix, in rheumatoid arthritis (AGRA): a randomized, double-blind, placebo-controlled study

Objectives: Gonadotropin-releasing hormone (GnRH) stimulates immune responses; therefore, antagonizing GnRH with cetrorelix may have anti-inflammatory effects. The aim of this study was to assess short-term cetrorelix therapy in rheumatoid arthritis (RA) patients.Method: In this proof-of-concept, randomized, double-blind study involving 99 patients with active, long-standing RA, 48 patients received subcutaneous cetrorelix (5 mg/day on days 1 and 2; 3 mg/day on days 3–5) and 51 received placebo. The primary end-point was the change in the 28-joint Disease Activity Score based on C-reactive protein (DAS28-CRP) by day 5, when the greatest GnRH suppression was anticipated. Secondary end-points included the change in tumour necrosis factor (TNF)-α, and achievement of American College of Rheumatology (ACR) responses and DAS28-CRP < 2.6 by day 5. Patients were followed up on days 10 and 15.Results: By day 5, DAS28-CRP was non-significantly reduced by 0.82 in the cetrorelix group compared to a 0.57 reduction in the placebo group (p = 0.091), TNF-α (log pg/mL) was significantly reduced in the cetrorelix group compared with the placebo group [0.55, 95% confidence interval (CI) 0.08–1.01, p = 0.023], and more patients on cetrorelix achieved ACR20 responses (40% vs. 18%, p = 0.015) and DAS28-CRP < 2.6 (13% vs. 0%, p = 0.009). Inflammatory markers increased towards baseline levels after withdrawal of treatment. Rates of adverse events were similar in both groups.Conclusions: Although there was no significant difference in the primary end-point between groups, antagonizing GnRH led to significant improvements in key secondary end-points. Thus, GnRH antagonists may have rapid anti-inflammatory effects in RA, already occurring within 5 days. The data suggest a novel mode of action for TNF-α inhibition in RA, and potentially in other autoimmune diseases.

Inflammation links ageing to the brain

Inflammation-activated signalling pathways in the brain's hypothalamus control the production of ageing-related hormones. This finding provides a link between inflammation, stress responses and systemic ageing. See Article p.211 Ageing is closely associated with both nutrition and inflammation, and certain neurons can mediate environmental influences on ageing in Caenorhabditis elegans and Drosophila. This study focuses on the hypothalamus, a brain region that is critical for the neuroendocrine interaction between the central nervous system and the periphery. Guo Zhang et al. show that activation of IKK-β and NF-κB in the hypothalamus of mice accelerates the ageing process and shortens lifespan. Inhibition of IKK-β and NF-κB, mediators of metabolic inflammation, delays ageing and extends lifespan. NF-κB activation results in a decline of gonadotropin-releasing hormone (GnRH) levels and suppresses neurogenesis. GnRH treatment amends ageing-impaired neurogenesis and decelerates ageing. These results suggest that NF-κB-mediated inhibition of GnRH may shut down reproduction and ensure the quality of the species, but it initiates systemic ageing at the same time.

Neuroendocrine regulation of gonadotropin secretion in seasonally breeding birds

Seasonally breeding birds detect environmental signals, such as light, temperature, food availability, and presence of mates to time reproduction. Hypothalamic neurons integrate external and internal signals, and regulate reproduction by releasing neurohormones to the pituitary gland. The pituitary gland synthesizes and releases gonadotropins which in turn act on the gonads to stimulate gametogenesis and sex steroid secretion. Accordingly, how gonadotropin secretion is controlled by the hypothalamus is key to our understanding of the mechanisms of seasonal reproduction. A hypothalamic neuropeptide, gonadotropin-releasing hormone (GnRH), activates reproduction by stimulating gonadotropin synthesis and release. Another hypothalamic neuropeptide, gonadotropin-inhibitory hormone (GnIH), inhibits gonadotropin synthesis and release directly by acting on the pituitary gland or indirectly by decreasing the activity of GnRH neurons. Therefore, the next step to understand seasonal reproduction is to investigate how the activities of GnRH and GnIH neurons in the hypothalamus and their receptors in the pituitary gland are regulated by external and internal signals. It is possible that locally-produced triiodothyronine resulting from the action of type 2 iodothyronine deiodinase on thyroxine stimulates the release of gonadotropins, perhaps by action on GnRH neurons. The function of GnRH neurons is also regulated by transcription of the GnRH gene. Melatonin, a nocturnal hormone, stimulates the synthesis and release of GnIH and GnIH may therefore regulate a daily rhythm of gonadotropin secretion. GnIH may also temporally suppress gonadotropin secretion when environmental conditions are unfavorable. Environmental and social milieus fluctuate seasonally in the wild. Accordingly, complex interactions of various neuronal and hormonal systems need to be considered if we are to understand the mechanisms underlying seasonal reproduction.

Review: regulatory mechanisms of gonadotropin-inhibitory hormone (GnIH) synthesis and release in photoperiodic animals

Gonadotropin-inhibitory hormone (GnIH) is a novel hypothalamic neuropeptide that was discovered in quail as an inhibitory factor for gonadotropin release. GnIH inhibits gonadotropin synthesis and release in birds through actions on gonadotropin-releasing hormone (GnRH) neurons and gonadotropes, mediated via the GnIH receptor (GnIH-R), GPR147. Subsequently, GnIH was identified in mammals and other vertebrates. As in birds, mammalian GnIH inhibits gonadotropin secretion, indicating a conserved role for this neuropeptide in the control of the hypothalamic-pituitary-gonadal (HPG) axis across species. Identification of the regulatory mechanisms governing GnIH expression and release is important in understanding the physiological role of the GnIH system. A nocturnal hormone, melatonin, appears to act directly on GnIH neurons through its receptor to induce expression and release of GnIH in quail, a photoperiodic bird. Recently, a similar, but opposite, action of melatonin on the inhibition of expression of mammalian GnIH was shown in hamsters and sheep, photoperiodic mammals. These results in photoperiodic animals demonstrate that GnIH expression is photoperiodically modulated via a melatonin-dependent process. Recent findings indicate that GnIH may be a mediator of stress-induced reproductive disruption in birds and mammals, pointing to a broad role for this neuropeptide in assessing physiological state and modifying reproductive effort accordingly. This paper summarizes the advances made in our knowledge regarding the regulation of GnIH synthesis and release in photoperiodic birds and mammals. This paper also discusses the neuroendocrine integration of environmental signals, such as photoperiods and stress, and internal signals, such as GnIH, melatonin, and glucocorticoids, to control avian and mammalian reproduction.