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Background: The hypothalamic–pituitary–adrenal (HPA) and -gonadal (HPG) axes are two major pathways that connect the neural and endocrine systems in vertebrates. Factors such as prenatal stress and maternal exposure to exogenous steroids have been shown to affect these pathways during fetal development. Another less studied factor is the transfer of hormones across fetuses in multifetal pregnancies. This form of transfer has been shown to influence the morphology, anatomy, physiology, and behavior of the offspring in litter-bearing mammals, an influence termed the intrauterine position (IUP) effect. In this study, we sought to delineate how the IUP effects HPA and HPG brain receptors, peptides, and enzymes (hereafter components) in utero and how these influences may differ between males and females. Methods: We utilized the unconventional model of culled free-ranging nutria (Myocastor coypus), with its large natural variation. We collected brain tissues from nutria fetuses and quantified the expression of key HPA and HPG components in three brain regions: prefrontal cortex, hypothalamus, and striatum. Results: We found an interaction between sex and IUP in the mineralocorticoid receptor (MR), gonadotropin-releasing hormone receptor (GNRHR), androgen receptor (AR), and estrogen receptor alpha (ESR1). IUP was significant in both gonadotropin-releasing hormone (GnRH) and its receptor GNRHR, but in different ways. In the hypothalamus, fetuses adjacent to same-sex neighbors had higher expression of GnRH than fetuses neighboring the opposite sex. Conversely, in the cortex, GNRHR exhibited the inverse pattern, and fetuses that were neighboring the opposite sex had higher expression levels than those neighboring the same sex. Regardless of IUP, in most components that showed significant sex differences, female fetuses had higher mRNA expression levels than male fetuses. We also found that HPA and HPG components were highly related in the early stages of gestation, and that there was an interaction between sex and developmental stage. In the early stages of pregnancy, female component expression levels were more correlated than males', but in the last trimester of pregnancy, male components were more related to each other than female's. Conclusions: This study suggests that there are sexually different mechanisms to regulate the HPA and HPG axes during fetal development. Higher mRNA expression levels of endocrine axes components may be a mechanism to help females cope with prolonged androgen exposure over a long gestational period. Additionally, these findings suggest different coordination requirements of male and female endocrine axes during stages of fetal development. Highlights: This study is the first to analyze HPA and HPG axes receptors, peptides, and enzyme mRNA expression levels in the brains of fetuses in the wild. Higher HPA and HPG axes receptors mRNA expression levels in females hint towards alternative sex-specific mechanisms that regulate endocrine axes during fetal development. Coordination of HPA and HPG axes components' expression levels is different between males and females at different stages of gestation. Plain language summary: In litter-bearing mammals, the positioning of a fetus in the uterus relative to other fetuses of the same or opposite sex has been shown to directly influence fetal morphology and physiology, and later behavior, reproductive success, and survival in adults. In this study, we sought to understand the mechanisms by which the location in the uterus influences two major neuroendocrine pathways in fetal brains. We quantified expression of multiple receptors and an enzyme (referred to as 'components') of the endocrine axes in three different brain regions in fetal free-ranging nutrias. Our results showed higher expression in females than in males for some endocrine axes components. The location inside the uterus was also related to the expression of some components. Lastly, coordination between the axes was higher earlier on in gestation, and females were more coordinated than males in the second trimester, whereas males were more coordinated than females in the third trimester. The results of this study point to the mechanisms by which the sexes regulate key neuroendocrine pathways during fetal development. [ABSTRACT FROM AUTHOR]

Abstract Background The hypothalamic–pituitary–adrenal (HPA) and -gonadal (HPG) axes are two major pathways that connect the neural and endocrine systems in vertebrates. Factors such as prenatal stress and maternal exposure to exogenous steroids have been shown to affect these pathways during fetal development. Another less studied factor is the transfer of hormones across fetuses in multifetal pregnancies. This form of transfer has been shown to influence the morphology, anatomy, physiology, and behavior of the offspring in litter-bearing mammals, an influence termed the intrauterine position (IUP) effect. In this study, we sought to delineate how the IUP effects HPA and HPG brain receptors, peptides, and enzymes (hereafter components) in utero and how these influences may differ between males and females. Methods We utilized the unconventional model of culled free-ranging nutria (Myocastor coypus), with its large natural variation. We collected brain tissues from nutria fetuses and quantified the expression of key HPA and HPG components in three brain regions: prefrontal cortex, hypothalamus, and striatum. Results We found an interaction between sex and IUP in the mineralocorticoid receptor (MR), gonadotropin-releasing hormone receptor (GNRHR), androgen receptor (AR), and estrogen receptor alpha (ESR1). IUP was significant in both gonadotropin-releasing hormone (GnRH) and its receptor GNRHR, but in different ways. In the hypothalamus, fetuses adjacent to same-sex neighbors had higher expression of GnRH than fetuses neighboring the opposite sex. Conversely, in the cortex, GNRHR exhibited the inverse pattern, and fetuses that were neighboring the opposite sex had higher expression levels than those neighboring the same sex. Regardless of IUP, in most components that showed significant sex differences, female fetuses had higher mRNA expression levels than male fetuses. We also found that HPA and HPG components were highly related in the early stages of gestation, and that there was an interaction between sex and developmental stage. In the early stages of pregnancy, female component expression levels were more correlated than males’, but in the last trimester of pregnancy, male components were more related to each other than female’s. Conclusions This study suggests that there are sexually different mechanisms to regulate the HPA and HPG axes during fetal development. Higher mRNA expression levels of endocrine axes components may be a mechanism to help females cope with prolonged androgen exposure over a long gestational period. Additionally, these findings suggest different coordination requirements of male and female endocrine axes during stages of fetal development.

Vast stretches of open water bodies are gradually becoming hypoxic as a result of depletion of oxygen levels mainly due to various human anthropogenic activities. This problem of hypoxic stress on the fish population is likely to be exacerbated soon since the aquatic hypoxic environment is continuously spreading over vast areas worldwide. In recent years, various harmful effects of hypoxia to bony fishes have been reported, such as the restriction of energy-consuming metabolic processes, arrest of the growth of ovary and testes that are associated with endocrine disruption, loss of sperm and egg quality, inhibition of fertilization, hatching success, and also the reduction of larval survivability, thereby impairment of overall reproductive and developmental processes in fish. Disruption of the brain-pituitary-gonad axis, and certain enzymes related to steroidogenesis and vitellogenesis in fish have also been reported as the primary targets for an endocrine malfunction during hypoxia. Hypoxia-sensitive downregulation of key genes responsible for controlling sex hormones' synthesis has been documented in certain bony fishes. Further, continuous exposure to hypoxia was reported to induce early expression of pro-apoptotic/tumor suppressor p53 genes, thereby causing immense cell death in hypoxic embryos. However, the cellular responses to long-term hypoxia exposure and the degree of reproductive impairments in bony fishes are still not adequate to figure out the actual underlying mechanisms. The present review intends to highlight the current knowledge about the detrimental impact of chronic/acute hypoxia at different stages of fish reproduction and the associated underlying molecular mechanisms.

Background: Puberty marks the transition from childhood to adulthood and is initiated by activation of a pulsatile GnRH secretion from the hypothalamus. MKRN3 functions as a pre-pubertal break on the GnRH pulse generator and hypothalamic expression and circulating levels of MKRN3 decrease peripubertally. In rodents, microRNA miR-30b seems to directly target hypothalamic MKRN3 expression - and in boys, circulating levels of miR-30b-5p increase when puberty is pharmacologically induced. Similarly, miR-200b-3p and miR-155-5p have been suggested to inhibit expression of other proteins potentially involved in the regulation of GnRH secretion. Here we measure circulating levels of these three miRNAs as boys progress through puberty. Materials and Methods: Forty-six boys from the longitudinal part of the Copenhagen Puberty Study were included. All boys underwent successive clinical examinations including estimation of testis size by palpation. miR-30b-5p, miR-200b-3p, and miR-155-5p were measured in serum by RT-qPCR using a kit sensitive to the phosphorylation status of the miRNAs. Thirty-nine boys had miRNA levels measured in three consecutive samples (pre-, peri-, and postpubertally) and seven boys had miR-30b-5p levels measured in ten consecutive samples during the pubertal transition. Results: When circulating levels of miR-30b-5p in pre- and peri-pubertal samples were compared with post-pubertal levels, we observed a significant increase of 2.3 and 2.2-fold (p-value<6.0×10-4), respectively, and a larger fraction of miR-30b-5p appeared to be phosphorylated post-pubertally indicating an increase in its bioactivity. We also observed a negative correlation between circulating levels of miR-30b-5p and MKRN3. The inter-individual variation in circulating miR-30b levels was substantial and we could not define a clinical threshold for miR-30b-5p suggestive of imminent puberty. Also, miR-155-5p showed significantly increasing levels from the peri- to the post-pubertal stage (p=3.0×10-3), whereas miR-200b- 3p did not consistently increase. Conclusion: Both circulating levels of miR-30b-5p and its bioactivity increase during the pubertal transition in boys supporting its role in the activation of the HPG axis at the onset of physiologically normal puberty. [ABSTRACT FROM AUTHOR]

BackgroundPuberty marks the transition from childhood to adulthood and is initiated by activation of a pulsatile GnRH secretion from the hypothalamus. MKRN3 functions as a pre-pubertal break on the GnRH pulse generator and hypothalamic expression and circulating levels of MKRN3 decrease peri-pubertally. In rodents, microRNA miR-30b seems to directly target hypothalamic MKRN3 expression – and in boys, circulating levels of miR-30b-5p increase when puberty is pharmacologically induced. Similarly, miR-200b-3p and miR-155-5p have been suggested to inhibit expression of other proteins potentially involved in the regulation of GnRH secretion. Here we measure circulating levels of these three miRNAs as boys progress through puberty.Materials and MethodsForty-six boys from the longitudinal part of the Copenhagen Puberty Study were included. All boys underwent successive clinical examinations including estimation of testis size by palpation. miR-30b-5p, miR-200b-3p, and miR-155-5p were measured in serum by RT-qPCR using a kit sensitive to the phosphorylation status of the miRNAs. Thirty-nine boys had miRNA levels measured in three consecutive samples (pre-, peri-, and post-pubertally) and seven boys had miR-30b-5p levels measured in ten consecutive samples during the pubertal transition.ResultsWhen circulating levels of miR-30b-5p in pre- and peri-pubertal samples were compared with post-pubertal levels, we observed a significant increase of 2.3 and 2.2-fold (p-value

Vast stretches of open water bodies are gradually becoming hypoxic as a result of depletion of oxygen levels mainly due to various human anthropogenic activities. This problem of hypoxic stress on the fish population is likely to be exacerbated soon since the aquatic hypoxic environment is continuously spreading over vast areas worldwide. In recent years, various harmful effects of hypoxia to bony fishes have been reported, such as the restriction of energy-consuming metabolic processes, arrest of the growth of ovary and testes that are associated with endocrine disruption, loss of sperm and egg quality, inhibition of fertilization, hatching success, and also the reduction of larval survivability, thereby impairment of overall reproductive and developmental processes in fish. Disruption of the brain-pituitary-gonad axis, and certain enzymes related to steroidogenesis and vitellogenesis in fish have also been reported as the primary targets for an endocrine malfunction during hypoxia. Hypoxia-sensitive downregulation of key genes responsible for controlling sex hormones' synthesis has been documented in certain bony fishes. Further, continuous exposure to hypoxia was reported to induce early expression of pro-apoptotic/tumor suppressor p53 genes, thereby causing immense cell death in hypoxic embryos. However, the cellular responses to long-term hypoxia exposure and the degree of reproductive impairments in bony fishes are still not adequate to figure out the actual underlying mechanisms. The present review intends to highlight the current knowledge about the detrimental impact of chronic/acute hypoxia at different stages of fish reproduction and the associated underlying molecular mechanisms. [ABSTRACT FROM AUTHOR]

Study questionDoes repeat-associated non-AUG (RAN) translation play a role in fragile X-associated primary ovarian insufficiency (FXPOI), leading to the presence of polyglycine containing protein (FMRpolyG)-positive inclusions in ovarian tissue?Summary answerOvaries of a woman with FXPOI and of an Fmr1 premutation (PM) mouse model (exCGG-KI) contain intranuclear inclusions that stain positive for both FMRpolyG and ubiquitin.What is known alreadyWomen who carry the FMR1 PM are at 20-fold increased risk to develop primary ovarian insufficiency (FXPOI). A toxic RNA gain-of-function has been suggested as the underlying mechanism since the PM results in increased levels of mRNA containing an expanded repeat, but reduced protein levels of fragile X mental retardation protein (FMRP). Recently, RAN translation has been shown to occur from FMR1 mRNA that contains PM repeat expansions, leading to FMRpolyG inclusions in brain and non-CNS tissues of fragile X-associated tremor/ataxia syndrome (FXTAS) patients.Study design, size, durationOvaries of a woman with FXPOI and women without PM (controls), and ovaries from wild-type and exCGG-KI mice were analyzed by immunohistochemistry for the presence of inclusions that stained for ubiquitin and FMRpolyG . The ovaries from wild-type and exCGG-KI mice were further characterized for the number of follicles, Fmr1 mRNA levels and FMRP protein expression. The presence of inclusions was also analyzed in pituitaries of a man with FXTAS and the exCGG-KI mice.Participants/materials, setting, methodsHuman ovaries from a woman with FXPOI and two control subjects and pituitaries from a man with FXTAS and a control subjects were fixed in 4% formalin. Ovaries and pituitaries of wild-type and exCGG mice were fixed in Bouin's fluid or 4% paraformaldehyde. Immunohistochemistry was performed on the human and mouse samples using FMRpolyG, ubiquitin and Fmrp antibodies. Fmr1 mRNA and protein expression were determined in mouse ovaries by quantitative RT-PCR and Western blot analysis. Follicle numbers in mouse ovaries were determined in serial sections by microscopy.Main results and the role of chanceFMRpolyG-positive inclusions were present in ovarian stromal cells of a woman with FXPOI but not in the ovaries of control subjects. The FMRpolyG-positive inclusions colocalized with ubiquitin-positive inclusions. Similar inclusions were also observed in the pituitary of a man with FXTAS but not in control subjects. Similarly, ovaries of 40-week-old exCGG-KI mice, but not wild-type mice, contained numerous inclusions in the stromal cells that stained for both FMRpolyG- and ubiquitin, while the ovaries of 20-week-old exCGG-KI contained fewer inclusions. At 40 weeks ovarian Fmr1 mRNA expression was increased by 5-fold in exCGG-KI mice compared with wild-type mice, while Fmrp expression was reduced by 2-fold. With respect to ovarian function in exCGG-KI mice: (i) although the number of healthy growing follicles did not differ between wild-type and exCGG-KI mice, the number of atretic large antral follicles was increased by nearly 9-fold in 40-week old exCGG-KI mice (P < 0.001); (ii) at 40 weeks of age only 50% of exCGG-KI mice had recent ovulations compared with 89% in wild-type mice (P = 0.07) and (iii) those exCGG-KI mice with recent ovulations tended to have a reduced number of fresh corpora lutea (4.8 ± 1.74 versus 8.50 ± 0.98, exCGG-KI versus wild-type mice, respectively, P = 0.07).Limitations, reasons for cautionAlthough FMRpolyG-positive inclusions were detected in ovaries of both a woman with FXPOI and a mouse model of the FMR1 PM, we only analyzed one ovary from a FXPOI subject. Caution is needed to extrapolate these results to all women with the FMR1 PM. Furthermore, the functional consequence of FMRpolyG-positive inclusions in the ovaries for reproduction remains to be determined.Wider implications of the findingsOur results suggest that a dysfunctional hypothalamic-pituitary-gonadal-axis may contribute to FXPOI in FMR1 PM carriers.Study funding/competing interestsThis study was supported by grants from NFXF, ZonMW, the Netherlands Brain Foundation and NIH. The authors have no conflict of interest to declare.

Cortisol inhibits hypothalamic-pituitary-gonadal (HPG) axis whereas RF9, a potent agonist of kisspeptin receptor (GPR54) activates HPG-axis during fasting-induced stress and under normal physiological conditions. However, the effect of RF9 on the cortisol-induced repressed HPG-axis is not studied yet. This study investigated whether exogenous cortisol-induced repression of the HPG-axis can be rescued by RF9. Six intact adult male rhesus monkeys (Macaca mulatta) habituated to chair-restraint were administered hydrocortisone sodium succinate at a rate of 20 mg/kg of body weight (BW) per day for 12 days. Single blood sample was taken by venipuncture from each animal on alternate days for hormones analyses. On experimental day 12, hydrocortisone treated monkeys received a single intravenous bolus of RF9 (n = 3) and vehicle (n = 3). The animals were bled for a period of 4 h at 60 min intervals from an indwelling cannula in the saphenous vein. RF9 was administered intravenously at the dose of 0.1 mg/kg BW immediately after taking 0 min sample. Plasma cortisol and testosterone concentrations were measured by using specific enzyme immunoassays. Hydrocortisone treatment increased plasma cortisol levels (P ≤ 0.0001) and decreased plasma testosterone (P ≤ 0.0127) levels. Interestingly, compared to vehicle, RF9 treatment significantly increased plasma testosterone levels at 120 min (P ≤ 0.0037), 180 min (P ≤ 0.0016), and 240 min (P ≤ 0.0001) intervals in the hydrocortisone treated monkeys. From these results, we concluded that RF9 administration relieves the suppressed HPG-axis in term of plasma testosterone levels in the cortisol treated monkeys.

Cortisol inhibits hypothalamic-pituitary-gonadal (HPG) axis whereas RF9, a potent agonist of kisspeptin receptor (GPR54) activates HPG-axis during fasting-induced stress and under normal physiological conditions. However, the effect of RF9 on the cortisol-induced repressed HPG-axis is not studied yet. This study investigated whether exogenous cortisol-induced repression of the HPG-axis can be rescued by RF9. Six intact adult male rhesus monkeys (Macaca mulatta) habituated to chair-restraint were administered hydrocortisone sodium succinate at a rate of 20 mg/kg of body weight (BW) per day for 12 days. Single blood sample was taken by venipuncture from each animal on alternate days for hormones analyses. On experimental day 12, hydrocortisone treated monkeys received a single intravenous bolus of RF9 (n = 3) and vehicle (n = 3). The animals were bled for a period of 4 h at 60 min intervals from an indwelling cannula in the saphenous vein. RF9 was administered intravenously at the dose of 0.1 mg/kg BW immediately after taking 0 min sample. Plasma cortisol and testosterone concentrations were measured by using specific enzyme immunoassays. Hydrocortisone treatment increased plasma cortisol levels (P ≤ 0.0001) and decreased plasma testosterone (P ≤ 0.0127) levels. Interestingly, compared to vehicle, RF9 treatment significantly increased plasma testosterone levels at 120 min (P ≤ 0.0037), 180 min (P ≤ 0.0016), and 240 min (P ≤ 0.0001) intervals in the hydrocortisone treated monkeys. From these results, we concluded that RF9 administration relieves the suppressed HPG-axis in term of plasma testosterone levels in the cortisol treated monkeys. [ABSTRACT FROM AUTHOR]

• Chronic noise exposure dysregulates the neuroendocrine system leading to hyperactivity of the hypothalamic-pituitary-adrenal (HPA)-axis. • Stress hormones adversely affect cell biology and neuronal circuitry leading to impairment in behavior. • Enduring dysregulation of the HPA-axis is the most mechanism associated with the harmful noise effects. • Noise stress shows a causative association with diverse landmarks of Alzheimer's disease (AD) with a hyper-susceptibility in females. • Functional and Neuroimaging studies are suggested to quantify the contribution of noise in predisposing AD in human. This review examines the adverse impacts of different noise exposure paradigms on the neuroendocrine system, hippocampal and neocortical structures, cognitive performances, and the development of Alzheimer's disease (AD)-like neuropathological changes in the brain of laboratory animals. Studies were reviewed in three periods during the lifespan including: adult animals exposed to noise, female rodents exposed to noise during gestation, and offspring exposed to noise during the prenatal period. Findings imply that chronic noise exposure dysregulates the neuroendocrine system leading to hyperactivation of the sympathetic divisions of the autonomic nervous system (i.e., the hypothalamic-pituitary-adrenal (HPA)-axis), and increases stress hormones that affect brain and behaviour. Enduring dysregulation of the HPA-axis was the most discussed mechanism for the harmful effect of noise during the lifespan. Studies also suggest a causative association of noise with diverse indicators of the AD-like neuropathology in rodents and a hypersusceptibility in females. The results indicate the importance of future neuroimaging studies to quantify the potential contribution of noise in predisposing cognitive decline and preclinical signs of dementia in humans. [ABSTRACT FROM AUTHOR]

Paracetamol is one of the most widely sold non-prescription drugs. This study aimed to evaluate the effects of the paracetamol on reproductive, biochemical, genetic, histopathological and hematogical biomarkers by waterborne exposure. Male fish of Rhamdia quelen were exposed to environmental concentrations of paracetamol (0, 0.25, 2.5 μg/L) in a semi-static bioassay for 21 days. Hemoglobin and hematocrit were reduced upon exposure to 0.25 μg/L of paracetamol. Leukocytes and thrombocytes increased after paracetamol exposure. Paracetamol reduced testosterone levels in all exposed groups and increased estradiol levels at higher concentration. Serotonin and dopamine levels increased at exposure to 0.25 μg/L. Paracetamol also caused protein carbonyls and increased SOD activity in fish exposed to 2.5 μg/L and in addition led to an inhibition of EROD and GST activities in both concentrations. Hepatic genotoxicity occurred at the 0.25 μg/L concentration. Hepatic tissues of exposed fish showed mild blood congestion and leucocytes infiltration. The results showed that paracetamol disrupted the hypothalamic-pituitary-gonadal axis, changed hematological parameters and caused hepatotoxicity in Rhamdia quelen . The findings suggest that this drug merits attention relative to its potential endocrine disrupter effect and hepatotoxicity, even at concentrations found in the aquatic environment. [ABSTRACT FROM AUTHOR]

ABSTRACT This introduction sets out to present a series of paper about a novel perspective regarding stress and sex hormones, or what the authors within this special issue term 'coupling' of hypothalamic-pituitary-adrenal and-gonadal axes. This view postulates that these axes do not necessarily operate in opposition, but can operate together as evidenced empirically as a positive within-person association between stress hormones like cortisol or sex hormones like testosterone. A wealth of papers within the special issue demonstrate positive coupling across acute, diurnal, basal, and longitudinal timeframes and across several different types of contexts. Reviews were meant to challenge whether this was physiologically plausible. Consistently, sophisticated statistical models were utilized in order to show a template for how to model positive coupling and to ensure that coupling was a within-person phenomenon. We cautiously considered positive coupling until the consistency of observing coupling was robust enough for us to consider challenging the prevailing oppositional view of these axes. We do so to acknowledge that there are contexts, moments and stages in which the function of these axes should work together: for example when contexts are both stressful and challenging or at developmental stages (like adolescence) in which the youth must grow up despite the storm and stress of youth. We hope that by putting forward a functional dual-axis approach, the field will be able to consider when and how these axes work together. © 2015 Wiley Periodicals, Inc. Dev Psychobiol 57: 643-653, 2015. [ABSTRACT FROM AUTHOR]

The hypothalamic–pituitary–adrenal (HPA) axis, which plays a major role in the response to stress, and the hypothalamic–pituitary–gonadal (HPG) axis are closely linked with the ability to inhibit the other. Testosterone, a product of the HPG, has many beneficial effects beyond its functions as a sex hormone including anti-anxiety properties. In this study we examined the effect of stress exposure on gonadal hormones, and their efficacy in modulating anxiety-like response in an animal model of PTSD. Male rats were exposed to predator scent stress, followed by analysis of brain expression of androgen receptor (AR) receptor and estrogen receptor α (ERα). The behavioral effects of immediate treatment with testosterone, testosterone receptor antagonist (flutamide) or vehicle were evaluated using the elevated plus-maze, acoustic startle response and trauma-cue response. Levels of circulating corticosterone and testosterone were also measured after treatment. The behavioral effects of delayed testosterone treatment were explored in the same manner. We report that animals whose behavior was extremely disrupted (EBR) selectively displayed significant down-regulation of AR and ERα in the hippocampus. Immediate treatment with flutamide or delayed treatment with testosterone significantly increased prevalence rates of minimal behavioral response (MBR) and decreased prevalence of EBR with favorable behavioral results. Testosterone levels were higher in control un-exposed animals, while corticosterone was higher in control exposed animals. This study suggests that gonadal steroid hormones are involved in the neurobiological response to predator scent stress and thus warrant further study as a potential therapeutic avenue for the treatment of anxiety-related disorders. [ABSTRACT FROM AUTHOR]

Abstract: Glucocorticoids affect reproductive hormone production in many species. In chickens, elevated plasma corticosterone down-regulates testosterone and progesterone concentrations in plasma, but also in egg yolk. This suppression could be mediated via the hypothalamic-pituitary system but also via local inhibition of gonadal activity by glucocorticoids. As the latter has not been tested in birds yet, we tested if corticosterone directly inhibits ovarian steroid synthesis under in vitro conditions. We hypothesized that degradation of corticosterone by follicular cells impairs their ability to synthesize reproductive hormones due to either inhibition of enzymes or competition for common co-factors. Therefore, we first established whether follicles degrade corticosterone. Follicular tissue was harvested from freshly euthanized laying hens and incubated with radiolabelled corticosterone. Radioactive metabolites were visualized and quantified by autoradiography. Follicles converted corticosterone in a time-dependent manner into metabolites with a higher polarity than corticosterone. The predominant metabolite co-eluted with 20β-dihydrocorticosterone. Other chicken tissues mostly formed the same metabolite when incubated with corticosterone. In a second experiment, follicles were incubated with either progesterone or dehydroepiandrosterone. Corticosterone was added in increasing dosages up to 1000ng per ml medium. Corticosterone did not inhibit the conversion of progesterone and dehydroepiandrosterone into a number of different metabolites, including 17α-hydroxyprogesterone, androstenedione and testosterone. In conclusion, avian tissues degrade corticosterone mostly to 20β-dihydrocorticosterone and even high corticosterone dosages do not affect follicular hormone production under in vitro conditions. [Copyright &y& Elsevier]

Abstract: Seasonal breeding in temperate zone vertebrates is characterised by pronounced variation in both central and peripheral reproductive physiology as well as behaviour. In contrast, many tropical species have a comparatively longer and less of a seasonal pattern of breeding than their temperate zone counterparts. These extended, more “flexible” reproductive periods may be associate with a lesser degree of annual variation in reproductive physiology. Here we investigated variation in the neuroendocrine control of reproduction in relation to the changes in the neural song control system in a tropical breeding songbird the rufous-collared sparrows (Zonotrichia capensis). Using in situ hybridization, we show that the optical density of GnRH1 mRNA expression is relatively constant across pre-breeding and breeding states. However, males were found to have significantly greater expression compared to females regardless of breeding state. Both males and females showed marked variation in measures of peripheral reproductive physiology with greater gonadal volumes and concentrations of sex steroids in the blood (i.e. testosterone in males; estrogen in females) during the breeding season as compared to the pre-breeding season. These findings suggest that the environmental cues regulating breeding in a tropical breeding bird ultimately exert their effects on physiology at the level of the median eminence and regulate the release of GnRH1. In addition, histological analysis of the song control system HVC, RA and Area X revealed that breeding males had significantly larger volumes of these brain nuclei as compared to non-breeding males, breeding females, and non-breeding females. Females did not exhibit a significant difference in the size of song control regions across breeding states. Together, these data show a marked sex difference in the extent to which there is breeding-associated variation in reproductive physiology and brain plasticity that is dependent on the reproductive state in a tropical breeding songbird. [Copyright &y& Elsevier]

Purpose: In this study, we investigated the effects of maternal transfer of bisphenol A (BPA) and di(2-ethylhexyl) phthalate (DEHP) during gestational and weaning periods on gonadal development of male offspring. Methods: Pregnant CD-1 mice were administered by gavages in corn oil with 0.1, 1, or 10 mg/kg/day of BPA and DEHP from gestational days (GD1-21) to the weaning period (postnatal days (PND) 1-21). Results: Our data indicated that the exposure significantly reduced the male-to-female sex ratio and the sizes of the gonads of male pups as recorded at PND15. The testes of the perinatally exposed male pups were developed less and the expression levels of testicular anti-mullerian hormone, androgen receptor, cyclin A, and StAR were significantly lesser than the control male pups. The less developed testes were accompanied with significant reductions in the expression levels of Gnrh and Fsh at the hypothalamic-pituitary levels. The negative effects were found to be persistent in the sexually mature pups at PND42. Conclusion: Our data reveal that the maternal transfer of BPA and DEHP may impose negative influence on the development and functions of the reproductive system of male pups. [ABSTRACT FROM AUTHOR]

Abstract: The comorbidity of major depressive disorder (MDD) and cardiovascular disease (CVD) is among the 10th leading cause of morbidity and mortality worldwide. Thus, understanding the co-occurrence of these disorders will have major public health significance. MDD is associated with an abnormal stress response, manifested in brain circuitry deficits, gonadal dysfunction, and autonomic nervous system (ANS) dysregulation. Contribution of the relationships between these systems to the pathophysiology of MDD is not well understood. The objective of this preliminary study was to investigate, in parallel, relationships between HPG-axis functioning, stress response circuitry activation, and parasympathetic reactivity in healthy controls and women with MDD. Using fMRI with pulse oximetry [from which we calculated the high frequency (HF) component of R-R interval variability (HF-RRV), a measure of parasympathetic modulation] and hormone data, we studied eight women with recurrent MDD in remission and six controls during a stress response paradigm. We demonstrated that hypoactivations of hypothalamus, amygdala, hippocampus, anterior cingulate cortex (ACC), orbitofrontal cortex (OFC), and subgenual ACC were associated with lower parasympathetic cardiac modulation in MDD women. Estradiol and progesterone attenuated group differences in the effect of HF-RRV on hypoactivation in the amygdala, hippocampus, ACC, and OFC in MDD women. Findings have implications for understanding the relationship between mood, arousal, heart regulation, and gonadal hormones, and may provide insights into MDD and CVD risk comorbidity. [Copyright &y& Elsevier]

To study mechanisms underlying generalized effects of 3β hydroxysteroid dehydrogenase (HSD3B) inhibition, reproductively mature zebrafish (Danio rerio) were exposed to trilostane at two dosages for 24, 48, or 96h and their gonadal RNA samples profiled with Agilent zebrafish microarrays. Trilostane had substantial impact on the transcriptional dynamics of zebrafish, as reflected by a number of differentially expressed genes (DEGs) including transcription factors (TFs), altered TF networks, signaling pathways, and Gene Ontology (GO) biological processes. Changes in gene expression between a treatment and its control were mostly moderate, ranging from 1.3 to 2.0 fold. Expression of genes coding for HSD3B and many of its transcriptional regulators remained unchanged, suggesting transcriptional up-regulation is not a primary compensatory mechanism for HSD3B enzyme inhibition. While some trilostane-responsive TFs appear to share cellular functions linked to endocrine disruption, there are also many other DEGs not directly linked to steroidogenesis. Of the 65 significant TF networks, little similarity, and therefore little cross-talk, existed between them and the hypothalamic–pituitary–gonadal (HPG) axis. The most enriched GO biological processes are regulations of transcription, phosphorylation, and protein kinase activity. Most of the impacted TFs and TF networks are involved in cellular proliferation, differentiation, migration, and apoptosis. While these functions are fairly broad, their underlying TF networks may be useful to development of generalized toxicological screening methods. These findings suggest that trilostane-induced effects on fish endocrine functions are not confined to the HPG-axis alone. Its impact on corticosteroid synthesis could also have contributed to some system wide transcriptional changes in zebrafish observed in this study. [Copyright &y& Elsevier]

Abstract: It is well documented that acute stress activates the sympathetic nervous system (SNS) and the Hypothalamus–Pituitary–Adrenal (HPA) axis. Results regarding the hypothalamus pituitary gonadal (HPG) axis, in contrast, are less consistent. Stress-associated increases as well as decreases have been reported for testosterone and estradiol. In the present study, healthy young male (n=39) and female participants (n=44, all tested in the luteal phase) were randomly assigned to a well-evaluated psychosocial stress protocol (“Trier Social Stress Test”, TSST) or to a non-stressful control condition (“Placebo-TSST”). Salivary concentrations of cortisol, alpha-amylase, testosterone, progesterone, and estradiol were measured immediately before and twice (10 and 25min) after the treatment. As was to be expected, cortisol- and sAA-concentrations increased in response to the stressor. Stressed men showed a more pronounced increase of cortisol than stressed women. In contrast, acute stress did not affect testosterone-, progesterone-, and estradiol-concentrations. The results of the present study suggest that an acute psychosocial laboratory stress or has no strong rapid effects on salivary gonadal steroids. In line with several previous studies the findings might suggest that stress-induced changes in gonadal steroids occur in response to physical stressors, to competitive stressors or to more severe stressors only. [Copyright &y& Elsevier]

Objective. Few studies are available on the temporal sequence and effect of ethnicity, socioeconomic status and environment on pubertal changes leading to sexual maturation in boys; therefore, we describe normative values for developmental changes in physical and endocrine characteristics at onset and during progression of the pubertal process in a cohort of Pakistani boys. Design. This cross-sectional study involved 234 healthy, 8-18 years old, school-based boys. Methods. Body weight, height, appearance of pubic hair patterns and testicular volume (TV) along with serum FSH, LH, testosterone and GH levels were measured. Results. Pubarche was first recorded at a mean age of 11.3 years [Tanner stage 2]. TV of 3 ml and the first significant increase in mean serum FSH and LH levels were detected at 10 years of age. The mean percent increase in TV/year was maximal from 12-14 years, coinciding with rising testosterone levels. The levels of gonadotropins increased more than 2-fold between 12-14 years. Whereas, LH continued to increase in postpubertal boys and FSH levels plateaued at 15 years. GH concentrations were shown to be maximal at 12-13 years and declined thereafter to prepubertal values. However, BW and height were significantly correlated with age; yet no significant correlation was seen between body mass index (BMI) and age. Conclusion. The present data among boys indicates an earlier transition to the Tanner stage 2 and an increase in TV, resulting in a slightly more extended period of pubertal development, as compared to European and American children pointing to ethnic, social and economic differences. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is becoming increasingly more prevalent worldwide and is a costly, devastating disease. The fact that females are more likely to be diagnosed with AD than men has contributed to the large amount of research and literature on estrogen's ability to rescue cognitive decline in aging females. However, recent results from the Women's Health Initiative Memory Study (WHIMS) and the Research into Memory, Brain Function and Estrogen Replacement (REMEMBER) study, in which estrogen-replacement therapy is shown not to be beneficial to cognition in postmenopausal women, especially in women of more advanced ages, have opened the study of hormones and hormone-based therapies beyond that of sex steroids. As such, recent findings, and the focus of this review, indicate that gonadotropins such as luteinizing hormone have a role on cognitive function and AD. It is likely that the interplay of age, and the timing of estrogen and these other less studied hormones will allow us to gain a better understanding of hypothalamic-pituitary-gonadal axis regulation after menopause and how it relates to AD, and will hopefully lead to new avenues of treatment for AD. [ABSTRACT FROM AUTHOR]

Our previous studies suggested that salmon gonadotropin-releasing hormone (sGnRH) neurons regulate both final maturation and migratory behavior in homing salmonids. Activation of sGnRH neurons can occur during upstream migration. We therefore examined expression of genes encoding the precursors of sGnRH, sGnRH-I, and sGnRH-II, in discrete forebrain loci of prespawning chum salmon, Oncorhynchus keta. Fish were captured from 1997 through 1999 along their homing pathway: coastal areas, a midway of the river, 4 km downstream of the natal hatchery, and the hatchery. Amounts of sGnRH mRNAs in fresh frozen sections including the olfactory bulb (OB), terminal nerve (TN), ventral telencephalon (VT), nucleus preopticus parvocellularis anterioris (PPa), and nucleus preopticus magnocellularis (PM) were determined by quantitative real-time polymerase chain reactions. The amounts of sGnRH-II mRNA were higher than those of sGnRH-I mRNA, while they showed similar changes during upstream migration. In the OB and TN, the amounts of sGnRH mRNAs elevated from the coast to the natal hatchery. In the VT and PPa, they elevated along with the progress of final maturation. Such elevation was also observed in the rostroventral, middle, and dorsocaudal parts of the PM. The amounts of gonadotropin IIβ and somatolactin mRNAs in the pituitary also increased consistently with the elevation of gene expression for sGnRH. These results, in combination with lines of previous evidence, indicate that sGnRH neurons are activated in almost all the forebrain loci during the last phases of spawning migration, resulting in coordination of final gonadal maturation and migratory behavior to the spawning ground. © 2005 Wiley Periodicals, Inc. J Neurobiol, 2005 [ABSTRACT FROM AUTHOR]

Individuals who engage in sexual offenses may be afflicted with a paraphilic disorder or sexual deviation syndrome. Paraphilias are psychiatric disorders characterized by deviant and culturally non-sanctioned sexual fantasies, thoughts, and/or behaviors. A proportion of these individuals may also stifler from symptoms of mental illness that can go unrecognized. Although the etiology and pathophysiology of paraphilic disorders continue to be under investigation, data from empirical, biomedical, and psychopharmacological studies suggest abnormalities at a biological level. This article will discuss and review clinical and neurobiological characteristics of the paraphilias. To this end, we will begin with a general exploration and overview of basic principles that are germane to the subject matter and will conclude with an examination of the most recent relevant research findings. [ABSTRACT FROM AUTHOR]

• Early life Hg exposure impairs reproduction in adult zebrafish. • Early life Hg exposure has intergenerational effect on reproduction of F 1 females. • Reproductive damage caused by early life Hg exposure is recovered in F 1 males. • Reproductive damage caused by early life Hg exposure is recovered in F 2 females. Mercury (Hg) is a global pollutant that poses potential threats to health of fishes. Although effects of Hg on reproduction of fishes have been documented, little is known about effects of exposure to Hg2+ during early life stages on subsequent reproductive fitness of adults or whether these effects can be transferred to offspring. In this study, zebrafish embryos were exposed to environmentally relevant concentrations of Hg2+ (0.6, 3 or 15 μg/L) for 5 days and then depurated in clean water for another 115 days. Exposure to Hg2+ during early life stages disturbed the balance of sex hormones and gametogenesis by altering expression of mRNA for genes involved in the hypothalamic-pituitary-gonadal axis, which resulted in delayed gonadal development and lesser gonado-somatic index, thereby resulting in lesser fecundity. A similar, but less pronounced effect was observed in F 1 females that were not exposed directly to Hg, whereas such damage was neither observed in F 1 males nor either sex during the F 2 generation. Exposure to Hg2+ during early life can impair subsequent reproduction in adults and has intergenerational effects on F 1 females, but this reproductive damage can be recovered in F 1 males and in F 2 females. [ABSTRACT FROM AUTHOR]

• Pre-treatment testosterone was not related to fear levels during exposure, but predicted reductions in social anxiety symptom severity. • Rises in endogenous testosterone in preparation to challenging encounters seem to facilitate social approach and anxiety reduction. • This paper provides the first evidence that the HPG-axis reactivity constitutes a promising biomarker of response to exposure therapy in SAD. • Findings provide direct starting points for personalized treatment optimization based on HPG-assessments and testosterone administration. The Hypothalamus-Pituitary-Gonadal (HPG)-axis, and testosterone in particular, play an important role in social motivational behavior. Socially avoidant behavior, characteristic of social anxiety disorder (SAD), has been linked to low endogenous testosterone levels, and can be alleviated by testosterone administration in SAD. Although these beneficial effects of testosterone may translate to exposure therapy, it remains unknown whether testosterone increases prior to exposure improve therapy outcomes. In this proof-of-principle study, we tested whether pre-exposure (reactive and baseline) endogenous testosterone levels were predictive of exposure outcome in SAD. Seventy-three participants (52 females) with a principal SAD diagnosis performed four speech exposures: three during one standardized exposure therapy session and one at post-assessment one week later. Subjective fear levels were assessed before and after each speech exposure and social anxiety symptoms were assessed at pre- and post-treatment. Pre-treatment testosterone levels were assessed before (baseline) and in response to a pre-exposure instruction session (reactive). Pre-treatment testosterone levels were not related to fear levels during exposure therapy, but predicted pre- to post-treatment reductions in social anxiety symptom severity. Specifically, low baseline and high reactive pre-treatment testosterone levels were associated with larger reductions in social anxiety symptom severity. These findings support the role of HPG-axis in social fear reduction. Specifically, our finding that high reactive testosterone as well as low baseline testosterone predicted exposure outcome in SAD, suggests that good reactivity of the HPG-axis is a promising marker for the symptom-reducing effects of exposure therapy. [ABSTRACT FROM AUTHOR]

This research explores the hypothalamus-pituitary-gonadal (HPG) axis activity for the control of spermatogenesis and quality sperm production. Topics covered include the characteristics of a primitive HPG in hagfish, review articles about the control of fetal and postnatal development of both Leydig and germ cells and the importance of antioxidant defenses, kisspeptins, estradiol, endocannabinoids and gonadotropin-releasing hormone (GnRH).

The use of a gonadotrophin-releasing hormone agonist slow-release implant (GnRH A-SRI) has become increasingly popular as an alternative for surgical contraception in many species. Although these implants have proven to be very effective in some species (eg, ferrets, rats, chicken, psittacines, and iguanas), they have been found less effective in other species (eg, male guinea pigs and rabbits, veiled chameleons, slider turtles, and leopard geckos). This review provides an overview of the available literature on the effects of GnRH A-SRIs in companion exotic animals., (Copyright © 2018 Elsevier Inc. All rights reserved.)