Journal of Neuroendocrinology

Environmental and social stresses have deleterious effects on reproductive function in vertebrates. Global climate change, human disturbance and endocrine disruption from pollutants are increasingly likely to pose additional stresses that could have a major impact on human society. Nonetheless, some populations of vertebrates (from fish to mammals) are able to temporarily resist environmental and social stresses, and breed successfully. A classical trade‐off of reproductive success for potential survival is involved. We define five examples. (i) Aged individuals with minimal future reproductive success that should attempt to breed despite potential acute stressors. (ii) Seasonal breeders when time for actual breeding is so short that acute stress should be resisted in favour of reproductive success. (iii) If both members of a breeding pair provide parental care, then loss of a mate should be compensated for by the remaining individual. (iv) Semelparous species in which there is only one breeding period followed by programmed death. (v) Species where, because of the transience of dominance status in a social group, individuals may only have a short window of opportunity for mating. We suggest four mechanisms underlying resistance of the gonadal axis to stress. (i) Blockade at the central nervous system level, i.e. an individual no longer perceives the perturbation as stressful. (ii) Blockade at the level of the hypothalamic‐pituitary‐adrenal axis (i.e. failure to increase secretion of glucocorticosteroids). (iii) Blockade at the level of the hypothalamic‐pituitary‐gonad axis (i.e. resistance of the reproductive system to the actions of glucocorticosteroids). (iv) Compensatory stimulation of the gonadal axis to counteract inhibitory glucocorticosteroid actions. Although these mechanisms are likely genetically determined, their expression may depend upon a complex interaction with environmental factors. Future research will provide valuable information on the biology of stress and how organisms cope. Such mechanisms would be particularly insightful as the spectre of global change continues to unfold.

The supraoptic and paraventricular nuclei of the hypothalamus undergo reversible anatomical changes under conditions of intense neurohypophysial hormone secretion, such as lactation, parturition and chronic dehydration. This morphological remodelling includes a reduction in astrocytic coverage of neurones resulting in an increase in the number and extent of directly juxtaposed somatic and dendritic surfaces. There is a growing body of evidence indicating that such anatomical plasticity is of functional significance. Astrocytic‐dependent clearance of electrolytes and neurotransmitters from the extracellular space appears to be altered under conditions where glial coverage of magnocellular neurones is reduced. Glutamate, for example, has been found to accumulate in the extracellular space in the supraoptic nucleus of lactating animals and cause a modulation of synaptic efficacy. On the other hand, the range of action of substances released from astrocytes and acting on adjacent magnocellular neurones is expected to be limited during such anatomical remodelling. It thus appears that the structural plasticity of the magnocellular nuclei does affect neuroglial interactions, inducing significant changes in signal transmission and processing.

Damage observed in the hippocampus of the adult spontaneously hypertensive rat (SHR) resembles the neuropathology of mineralocorticoid‐induced hypertension, supporting a similar endocrine dysfunction in both entities. In the present study, we tested the hypothesis that increased expression of the hippocampal mineralocorticoid receptor (MR) in SHR animals is associated with a prevalent expression of pro‐inflammatory over anti‐inflammatory factors. Accordingly, in the hippocampus, we measured mRNA expression and immunoreactivity of the MR and glucocorticoid receptor (GR) using a quantitative polymerase chain reaction and histochemistry. We also measured serum‐glucocorticoid‐activated kinase 1 (Sgk1 mRNA), the number and phenotype of Iba1+ microglia, as well as mRNA expression levels of the pro‐inflammatory factors cyclo‐oxygenase 2 (Cox2), Nlrp3 inflammasome and tumour necrosis factor α (Tnfα). Expression of anti‐inflammatory transforming growth factor (Tgf)β mRNA and the NADPH‐diaphorase activity of nitric oxide synthase (NOS) were also determined. The results showed that, in the hippocampus of SHR rats, expression of MR and the number of immunoreactive MR/GR co‐expressing cells were increased compared to Wistar‐Kyoto control animals. Expression of Sgk1, Cox2, Nlrp3 and the number of ramified glia cells positive for Iba1+ were also increased, whereas Tgfβ mRNA expression and the NADPH‐diaphorase activity of NOS were decreased. We propose that, in the SHR hippocampus, increased MR expression causes a bias towards a pro‐inflammatory phenotype characteristic for hypertensive encephalopathy.

Sex steroid hormones and neurotrophic factors are involved in pruning and shaping the adolescent brain and have been implicated in the pathogenesis of neurodevelopmental disorders, including mental illness. We aimed to determine the association between altered levels of sex steroid hormones during adolescent development and neurotrophic signalling in the C57Bl/6 mouse. We first performed a week by week analysis from pre‐pubescence to adulthood in male and female C57Bl/6 mice, measuring serum levels of testosterone and oestradiol in conjunction with western blot analysis of neurotrophin expression in the forebrain and hippocampal regions. Second, we manipulated adolescent sex steroid hormone levels by gonadectomy and hormone replacement at the pre‐pubescent age of 5 weeks. Young‐adult forebrain and hippocampal neurotrophin expression was then determined. Male mice showed significant changes in brain‐derived neurotrophic factor (BDNF) expression in the forebrain regions during weeks 7–10, which corresponded significantly with a surge in serum testosterone. Castration and testosterone or di‐hydrotestosterone replacement experiments revealed an androgen receptor‐dependent effect on BDNF‐tyrosine kinase (Trk) B signalling in the forebrain and hippocampal regions during adolescence. Female mice showed changes in BDNF‐TrkB signalling at a much earlier time point (weeks 4–8) in the forebrain and hippocampal regions and these did not correspond with changes in serum oestradiol. Ovariectomy actually increased BDNF expression but decreased TrkB phosphorylation in the forebrain regions. 17β‐Oestradiol replacement had no effect, suggesting a role for other ovarian hormones in regulating BDNF‐TrkB signalling in the adolescent female mouse brain. These results suggest the differential actions of sex steroid hormones in modulating BDNF‐TrkB signalling during adolescence. These data provide insight into how the male and female brain changes in response to altered levels of circulating sex steroid hormones and could help to explain some of the developmental sex differences in the pathogenesis of neurodevelopmental disorders, including mental illness.

Gonadotrophin‐inhibitory hormone (GnIH) was discovered 8 years ago in birds. Its identification raised the possibility that gonadotrophin‐releasing hormone (GnRH) is not the sole hypothalamic neuropeptide that directly influences pituitary gonadotrophin release. Initial studies on GnIH focused on the avian anterior pituitary as comprising the only physiological target of GnIH. There are now several lines of evidence indicating that GnIH directly inhibits pituitary gonadotrophin synthesis and release in birds and mammals. Histological studies on projections from hypothalamic GnIH neurones subsequently implied direct actions of GnIH within the brain and in the periphery. In addition to actions on the pars distalis via the median eminence, GnIH axons and terminals are present in multiple brain areas in birds, and the GnIH receptor is expressed on GnRH‐I and ‐II neurones. Furthermore, we have demonstrated the presence of GnIH and its receptor in avian and mammalian gonads. Thus, GnIH can act directly at multiple levels: within the brain, on the pituitary and in the gonads. In sum, our data indicate that GnIH and its related peptides are important modulators of reproductive function at the level of the GnRH neurone, the gonadotroph and the gonads. Here, we provide an overview of the known levels of GnIH action in birds and mammals. In addition, environmental and physiological factors that are involved in GnIH regulation are reviewed.

Two structurally related neuropeptides, pituitary adenylate cyclase‐activating polypeptide (PACAP), colocalized with glutamate in neurones of the retinohypothalamic tract, and vasoactive intestinal peptide (VIP), present in light‐responsive cells of the suprachiasmatic nuclei (SCN), appear to play distinct and important roles in the control of mammalian circadian rhythms. Mice deficient in the PACAP‐selective PAC₁ receptor exhibit altered responsiveness of the SCN clock to light‐induced phase‐shifts, but display robust circadian patterns of wheel‐running behaviour. By contrast, our studies of mice lacking the VPAC₂ receptor, which responds to both PACAP and VIP, indicate that this receptor plays a critical role in rhythm generation in the SCN. The predominant factor determining wheel‐running activity in VPAC₂ receptor null (Vipr2^–/–) mice is ‘masking’ by light. Mutant animals re‐entrain immediately to advances or delays in the light/dark cycle and do not exhibit robust circadian rhythms of behaviour when in constant darkness. The mice do not exhibit circadian expression of core clock genes (mPer1, mPer2, mCry1), or of the clock‐controlled gene arginine vasopressin (AVP), in the SCN. We propose that VIP signalling between SCN neurones provides a paracrine reinforcing signal that is essential for sustained rhythm generation. The presence of VIP signalling in the SCN may explain why SCN neurones are capable of generating long‐lasting self‐sustained oscillations, whereas rhythmic clock gene expression in other tissues is dependent on periodic reinforcement by neural or hormonal signals.

Using quantitative in‐situ hybridization, this study monitored diurnal changes in the abundance of the gene transcripts of two corticotropin‐releasing peptides, arginine vasotocin (AVT) and isotocin in hypothalamic neurones, and of pro‐opiomelanocortin (POMC) mRNA in the pituitary of the rainbow trout (Oncorhynchus mykiss). A significant diurnal pattern of gene expression was only displayed in the hypothalamus by the parvocellular AVT neurones of the preoptic nucleus. Abundance of AVT mRNA in these neurones was low at lights on (06.00 h), increased during the morning to reach a plateau of peak values between 14.00 h and 22.00 h, and then declined during the dark phase. This pattern was the inverse of that shown by plasma cortisol values. Changes in AVT transcript abundance are also considered in terms of the reported diurnal change in circulating AVT concentration. Pituitary and hypothalamic AVT peptide content did not change. Transcripts of both POMC genes (POMC‐A and POMC‐B) were monitored in pituitary corticotropes and melanotropes. Only POMC‐A mRNA was detected in corticotropes where it showed no diurnal change in abundance. Transcripts of both POMC genes were found in the melanotropes, although, judging from autoradiographic intensity, POMC‐A mRNA predominated. Both genes showed diurnal differences in their transcription with POMC‐A mRNA showing peak values at 10.00 h and a nadir at 02.00 h, while POMC‐B mRNA showed an inverse pattern. The results indicate that the two POMC genes can be independently regulated.

This study aimed to investigate whether there are differences in serum testosterone levels between male patients with Alzheimer's disease (AD) and cognitively normal male controls. Testosterone and sex hormone binding globulin (SHBG) levels were measured from 14 patients with mild to moderate AD and 16 age‐matched control males. The AD patients had higher levels of serum total (P = 0.02) and free testosterone (P < 0.001), and higher free androgen index (FAI) (P = 0.02) compared to controls. No differences were found for the SHBG levels. These data provide no support for hypotheses of (disproportionally) decreased levels of serum testosterone in AD. These data also show that all cognitively normal controls had an FAI below the normal range.

The hypothalamic‐pituitary‐adrenal axis is hyporesponsive to stress in late pregnancy, exemplified as reduced adrenocorticotropic hormone (ACTH) and corticosterone responses to restraint, but the mechanisms are unknown. We investigated forward drive and negative feedback upon the hypothalamic‐pituitary‐adrenal axis in pregnant rats. Corticotropin‐releasing hormone (CRH) and vasopressin mRNA expression in the parvocellular paraventricular nucleus and mineralocorticoid and glucocorticoid receptor expression in the paraventricular nucleus and hippocampus were quantified with in situ hybridization. Because it can enhance the corticosterone negative feedback signal, 11β‐hydroxysteroid dehydrogenase type 1 (11β‐HSD1) bioactivity in these brain regions and anterior pituitary was measured in vitro, and ACTH and corticosterone stress responses were measured after intracerebroventricular glycyrrhetinic acid, an 11β‐HSD inhibitor. Changes in corticosterone feedback on ACTH secretion were examined after pharmacological adrenalectomy by metyrapone and aminoglutethimide. Parvocellular paraventricular nucleus CRH mRNA content was reduced on day 21 and the CRH mRNA : vasopressin mRNA ratio was unaltered, indicating decreased production of both CRH and vasopressin. An increase in glucocorticoid receptor mRNA expression in the dentate gyrus (mineralocorticoid receptor mRNA expression was unaltered) and increased 11β‐HSD1 activity in the paraventricular nucleus and anterior pituitary suggest an increase in slow negative feedback mechanisms in pregnancy, but glycyrrhetinic acid did not modify the stress response. After metyrapone/aminoglutethimide treatment, corticosterone decreased ACTH secretion more slowly in pregnancy, indicating a decrease in rapid feedback sensitivity. Thus, reduced forward drive rather than increased effectiveness of glucocorticoid negative feedback may underlie stress hyporesponsiveness of the hypothalamic‐pituitary‐adrenal axis in pregnancy.

Melanin‐concentrating hormone (MCH) may have a regulatory role in the control of luteinizing hormone (LH) release. We have investigated if gonadal steroids induce changes in the expression of pre‐pro MCH (ppMCH) that are associated with changes in the pattern of LH release. Using quantitative in‐situ hybridization histochemistry we have determined the effect of administration of either oestradiol benzoate (5 μg/rat) or oestradiol benzoate followed 44 or 48 h later by progesterone (0.5 mg/rat) to ovariectomized rats on the expression of ppMCH in the medial and lateral zona incerta and the lateral hypothalamus. The prevalence of ppMCH transcripts in the intact female rat at 12.00 and 19.00 h on proestrus and the first day of dioestrus was also examined. Oestrogen reduced the intensity of hybridization signal for ppMCH mRNA and this was associated with both a decrease in the number of cells in which the message was detected in the medial zona incerta and a negative feedback effect on LH release in ovariectomized rats. Progesterone administration to oestradiol benzoate‐primed rats did not alter the reduced expression in the medial zona incerta in spite of its positive feedback effect on LH release. We suggest that progesterone may act only on post‐translational events. Expression in the MCH cell bodies of the lateral zona incerta were not affected but there was a transient decrease 4 h after progesterone treatment in the oestradiol benzoate‐primed rats in expression in the lateral hypothalamus. No changes in ppMCH mRNA were seen in intact animals on proestrus or the first day of dioestrus indicating that gonadal steroids are not important in the modulation of ppMCH gene expression during the oestrous cycle. In other steroid‐dependent physiological situations, however, oestrogen may influence the expression of ppMCH in a subpopulation of cell bodies in the medial zona incerta.