Gonadal Steroid Hormone Receptors and Sex Differences in the Hypothalamo-Pituitary-Adrenal Axis

The rapid activation of stress-responsive neuroendocrine systems is a basic reaction of animals to perturbations in their environment. One well-established response is that of the hypothalamo-pituitary-adrenal (HPA) axis. In rats, corticosterone is the major adrenal steroid secreted and is released in direct response to adrenocorticotropin (ACTH) secreted from the anterior pituitary gland. ACTH in turn is regulated by the hypothalamic factor, corticotropin-releasing hormone. A sex difference exists in the response of the HPA axis to stress, with females reacting more robustly than males. It has been demonstrated that in both sexes, products of the HPA axis inhibit reproductive function. Conversely, the sex differences in HPA function are in part due to differences in the circulating gonadal steroid hormone milieu. It appears that testosterone can act to inhibit HPA function, whereas estrogen can enhance HPA function. One mechanism by which androgens and estrogens modulate stress responses is through the binding to their cognate receptors in the central nervous system. The distribution and regulation of androgen and estrogen receptors within the CNS suggest possible sites and mechanisms by which gonadal steroid hormones can influence stress responses. In the case of androgens, data suggest that the control of the hypothalamic paraventricular nucleus is mediated trans-synaptically. For estrogen, modulation of the HPA axis may be due to changes in glucocorticoid receptor-mediated negative feedback mechanisms. The results of a variety of studies suggest that gonadal steroid hormones, particularly testosterone, modulate HPA activity in an attempt to prevent the deleterious effects of HPA activation on reproductive function.     

Plasticity in the adrenocortical response of a free-living vertebrate: the role of pre- and post-natal developmental stress

Optimal functioning of the hypothalamo–pituitary–adrenal (HPA) axis is paramount to maximizing fitness in vertebrates. Research in laboratory mammals has suggested that maternally-induced stress can cause significant variation in the responsiveness of an offspring's HPA axis involving both pre- and post-natal developmental mechanisms. However, very little is known regarding effects of maternal stress on the variability of offspring adrenocortical functioning in free-living vertebrates. Here we use an experimental approach that independently lowers the quality of both the pre- and post-natal developmental environment to examine programming and plasticity in the responsiveness of the HPA axis in fledglings of a free-living passerine, the European starling (Sturnus vulgaris). We found that mimicking a hormonal signal of poor maternal condition via an experimental pre-natal increase in yolk corticosterone decreased the subsequent responsiveness of the HPA axis in fledglings. Conversely, decreasing the quality of the post-natal developmental environment (by decreasing maternal provisioning capability via a maternal feather-clipping manipulation) increased subsequent responsiveness of the HPA axis in fledglings, apparently through direct effects on nestling body condition. The plasticity of these responses was sex-specific with smaller female offspring showing the largest increase in HPA reactivity. We suggest that pre-natal, corticosterone-induced, plasticity in the HPA axis may be a ‘predictive adaptive response’ (PAR): a form of adaptive developmental plasticity where the advantage of the induced phenotype is manifested in a future life-history stage. Further, we introduce a new term to define the condition-driven post-natal plasticity of the HPA axis to an unpredictable post-natal environment, namely a ‘reactive adaptive response’ (RAR). This study confirms that the quality of both the pre- and post-natal developmental environment can be a significant source of variation in the responsiveness of the HPA axis, and provides a frame-work for examining ecologically-relevant sources of stress-induced programming and plasticity in this endocrine system in a free-living vertebrate, respectively.     

Effects of perinatal maternal food restriction on pituitary-gonadal axis and plasma leptin level in rat pup at birth and weaning and on timing of puberty

The effects of maternal 50% food restriction (FR) during the last week of gestation and/or lactation on pituitary-gonadal axis (at birth and weaning), on circulating levels of leptin (at weaning), and on the onset of puberty have been determined in rats at birth and at weaning. Maternal FR during pregnancy has no effect at term on the litter size, on the basal level of testosterone in male pups, and on the drastic surge of circulating testosterone that occurs 2 h after birth. At weaning, similar retardation of body growth is observed in male and female pups from mothers exposed to FR. This undernutrition induces the most drastic effects when it is performed during both gestation and lactation or during lactation alone. Drastic retardation of testicle growth with reduction of cross-sectional area and intratubular lumen of the seminiferous tubules is observed in male pups from mothers exposed to undernutrition during both gestation and lactation or during lactation alone. Maternal FR during the perinatal period reduces circulating levels of FSH in male pups without affecting LH and testosterone concentrations. Maternal FR does not affect circulating levels of LH, estradiol, and progesterone in female pups. Female pups from mothers exposed to FR during both gestation and lactation show a significant increase of plasma FSH as well as a drastic retardation of ovarian growth. The follicular population was also altered. The number of antral follicles of small size (vesicular follicles) was increased, although the number of antral follicles of large size (graafian follicles) was reduced. Maternal FR occurring during both late gestation and lactation (male and female pups), during lactation alone (male and female pups), or during late gestation (female pups) induces a drastic reduction of plasma leptin and fat mass in pups at weaning. The onset of puberty is delayed in pups of both sexes from mothers exposed to FR during lactation and during both gestation and lactation. In conclusion, these data demonstrate that a perinatal growth retardation induced by maternal FR has long-term consequences on both size and histology of the genitals, on plasma gonadotropins and leptin levels, on fat stores at weaning, and on the onset of puberty.     

Maternal glucocorticoid treatment programs HPA regulation in adult offspring: sex-specific effects

Pregnant guinea pigs were treated with dexamethasone (1 mg/kg) or vehicle on days 40--41, days 50--51, and days 60--61 of gestation. Adult offspring were split into two groups. Group 1 guinea pigs were catheterized, and the hypothalamo-pituitary-adrenal (HPA) axis was tested in basal and activated states. Group 2 guinea pigs were euthanized with no further manipulation. In male offspring, prenatal dexamethasone exposure resulted in a significant reduction in brain-to-body weight ratio. Dexamethasone-exposed male offspring exhibited reduced basal and activated plasma cortisol levels, which was associated with elevated hippocampal mineralocorticoid receptor (MR) mRNA and increased plasma testosterone. In females exposed to glucocorticoids in utero, basal and stimulated plasma cortisol levels were higher in the follicular and early luteal phases of the cycle, but this effect was reversed in the late luteal phase, indicating a significant interaction of sex steroids. In female offspring (at estrus), glucocorticoid receptor mRNA levels were lower in the paraventricular nucleus and pars distalis but higher in the hippocampus in animals exposed to dexamethasone in utero. Hippocampal MR mRNA levels were significantly lower (approximately 50%) than in controls. In conclusion, repeated antenatal glucocorticoid treatment programs HPA function in a sex-specific manner, and these changes are associated with modification of corticosteroid receptor expression in the adult brain and pituitary.     

LHRH and LH in peripubertal female rats following prenatal and/or postnatal ethanol exposure

The effects of pre- and postnatal exposure to ethanol (ETOH) on LHRH and LH were investigated. Pregnant and/or lactating dams were fed ETOH during: 1) gestation, 2) lactation, or 3) gestation-lactation. Female offspring were decapitated at 30 or 40 days-of-age; trunk blood was collected for plasma LH RIA; and hypothalamic tissues were collected for LHRH RIA. Hypothalamic LHRH content of all ETOH-exposed groups was less than that of non-ETOH-fed controls at 30 and 40 days-of-age (p less than 0.05). Plasma LH concentrations of all ETOH-exposed groups were less than those of non-ETOH-fed controls at 30 and 40 days-of-age (p less than 0.05). Also, at 30 and 40 days-of-age, the plasma LH concentrations of the animals exposed to ETOH during lactation and gestation-lactation were less than those of the animals exposed to ETOH during gestation (p less than 0.05). These data suggest that ETOH exposure during gestation and/or lactation negatively affects hypothalamic LHRH content of female rat offspring. Decreased hypothalamic LHRH content with corresponding lowered plasma LH concentration suggests that ETOH influences development or maturation of hypothalamic LHRH neurons by possibly decreasing their number or synthesizing capability.     

Sex difference in the relationship between the hypothalamic-pituitary-adrenal axis and sex hormones in obesity

Objective: This study was carried out to investigate the role of sex in the regulation of the hypothalamic‐pituitary‐adrenal (HPA) axis and its relationship with testosterone levels in male and female obesity. Research Methods and Procedures: Twenty‐two obese men (OB‐M) and 29 obese women (OB‐W) participated in the study. Two groups of normal weight men (NW‐M) and women (NW‐W), respectively, served as controls. In basal conditions, blood concentrations of major androgens, sex hormone—binding protein, and gonadotropins were assessed, and the free androgen index (testosterone ×100/ sex hormone‐binding globulin) was calculated. All subjects underwent a combined corticotropin‐releasing hormone plus arginine‐vasopressin stimulation test. Results: OB‐M and NW‐M had higher basal adrenal cortical tropic hormone (ACTH) and cortisol levels than their female counterparts. In addition, ACTH, but not cortisol basal, levels were significantly higher in obese than in normal weight controls in both sexes. OB‐W had a higher response than OB‐M to the combined corticotropin‐releasing hormone plus arginine‐vasopressin test of both ACTH and cortisol [expressed as incremental percentage of area under the curve (AUC%)]. The same finding was present between NW‐W and NW‐M. Basal luteinizing hormone levels were negatively correlated to ACTH_AUC% in both OB‐W and OB‐M. In the OB‐W, however, a positive correlation was found between cortisol_AUC% and testosterone (r = 0.48; p = 0.002), whereas a tendency toward a negative correlation was present in OB‐M. Discussion: In conclusion, we have shown a significant positive relationship between the activity of the HPA axis and testosterone in obese women, which suggests a partial responsibility of increased HPA axis activity in determining testosterone levels. In addition, it clearly seems that, as reported in normal weight subjects, a sex difference in the HPA axis activity still persists even in the presence of obesity.     

Embryonic exposure to corticosterone modifies aggressive behavior through alterations of the hypothalamic pituitary adrenal axis and the serotonergic system in the chicken

Exposure to excess glucocorticoids (GCs) during embryonic development influences offspring phenotypes and behaviors and induces epigenetic modifications of the genes in the hypothalamic–pituitary–adrenal (HPA) axis and in the serotonergic system in mammals. Whether prenatal corticosterone (CORT) exposure causes similar effects in avian species is less clear. In this study, we injected low (0.2 μg) and high (1 μg) doses of CORT into developing embryos on day 11 of incubation (E11) and tested the changes in aggressive behavior and hypothalamic gene expression on posthatch chickens of different ages. In ovo administration of high dose CORT significantly suppressed the growth rate from 3 weeks of age and increased the frequency of aggressive behaviors, and the dosage was associated with elevated plasma CORT concentrations and significantly downregulated hypothalamic expression of arginine vasotocin (AVT) and corticotropin-releasing hormone (CRH). The hypothalamic content of glucocorticoid receptor (GR) protein was significantly decreased in the high dose group (p < 0.05), whereas no changes were observed for GR mRNA. High dose CORT exposure significantly increased platelet serotonin (5-HT) uptake, decreased whole blood 5-HT concentration (p < 0.05), downregulated hypothalamic tryptophan hydroxylase 1 (TPH1) mRNA and upregulated 5-HT receptor 1A (5-HTR1A) and monoamine oxidase A (MAO-A) mRNA, but not monoamine oxidase B (MAO-B). High dose CORT also significantly increased DNA methylation of the hypothalamic GR and CRH gene promoters (p < 0.05). Our findings suggest that embryonic exposure to CORT programs aggressive behavior in the chicken through alterations of the HPA axis and the serotonergic system, which may involve modifications in DNA methylation.     

Paternal aggression towards a brood predator during parental care in wild smallmouth bass is not correlated with circulating testosterone and cortisol concentrations

Male smallmouth bass (Micropterus dolomieu) provide sole parental care including frequent aggressive actions towards conspecifics and potential brood predators. Failure to defend the brood through continual vigilance results in predation reducing the number of offspring and promoting abandonment by the nesting male. However, little is known about how biochemical and endocrine factors and brood size collectively influence paternal aggression. Behavioral assays were conducted during the egg stage of offspring development by placing a brood predator in a jar on the nest to quantify aggression (number of attacks on the potential brood predator in a minute). To determine the correlates of parental aggression, we temporarily removed fish from their nests and measured circulating levels of testosterone and indicators of the primary (plasma cortisol) and secondary stress response (plasma glucose, Cl⁻, Na⁺, K⁺) from non-lethal blood samples. While the male was removed from the nest, a snorkeler quantified the size of the brood. Brood size was positively correlated with male aggression. The only biochemical correlate of parental aggression was plasma glucose, which also had a positive relationship with brood size. When the effect of brood size was removed, no biochemical or endocrine factors were predictive of male aggression. Hence, brood value appeared to influence parental aggression independent of biochemical or endocrine status. While several-fold individual differences in aggression towards brood predators were noted, the role of androgens and glucocorticoids in mediating these behaviors is currently not well understood.     

Hormonal status modifies renin-angiotensin system-regulating aminopeptidases and vasopressin-degrading activity in the hypothalamus-pituitary-adrenal axis of male mice

Local renin-angiotensin systems (RAS) have been postulated in brain, pituitary and adrenal glands. These local RAS have been implicated, respectively, in the central regulation of the cardiovascular system and body water balance, the secretion of pituitary hormones and the secretion of aldosterone by adrenal glands. By other hand, it is known that the hypothalamus-pituitary-adrenal (HPA) axis is involved in blood pressure regulation, and is affected by sex hormones. The aim of the present work is to analyze the influence of testosterone on RAS-regulating aminopeptidase A, B and M activities and vasopressin-degrading activity in the HPA axis, measuring these activities in their soluble and membrane-bound forms in the hypothalamus, pituitary and adrenal glands of orchidectomized males and orchidectomized males treated subcutaneously with several doses of testosterone. The present data suggest that in male mice, testosterone influences the RAS- and vasopressin-degrading activities at all levels of the HPA axis.     

Prenatal Restraint Stress is Associated with Demethylation of Corticotrophin Releasing Hormone (CRH) Promoter and Enhances CRH Transcriptional Responses to Stress in Adolescent Rats

Maternal stress can disturb normal fetal neurodevelopmental progress, and lead to negative behavioral and neuroendocrine consequences for the offspring. These effects may be related to alterations in the hypothalamic–pituitary–adrenal (HPA) axis. Early life events disrupting the function of the HPA axis may be associated with epigenetic modification. This study investigated the effect of maternal stress on the methylation rate of the corticotrophin-releasing hormone (CRH) promoter and HPA axis response to acute stress in the adolescent offspring of Sprague–Dawley rats. Pregnant dams were randomly assigned to two groups: restraint stress group and normal control group. Adolescent male and female offspring were used from each group. The results showed that prenatal stress is associated with the demethylation of the CRH promoter, and leads to anxiety-like behaviors in adolescent life stages, as well as hyper-responsiveness of the HPA axis. Together, these results imply that prenatal stress alters the normal HPA function, which may be via the epigenetic mechanism.     

Antenatal glucocorticoids reset the level of baseline and hypoxemia-induced pituitary-adrenal activity in the sheep fetus during late gestation

This study examined the effects of dexamethasone treatment on basal hypothalamo-pituitary-adrenal (HPA) axis function and HPA responses to subsequent acute hypoxemia in the ovine fetus during late gestation. Between 117 and 120 days (term: approximately 145 days), 12 fetal sheep and their mothers were catheterized under halothane anesthesia. From 124 days, 6 fetuses were continuously infused intravenously with dexamethasone (1.80 +/- 0.15 microg.kg(-1).h(-1) in 0.9% saline at 0.5 ml/h) for 48 h, while the remaining 6 fetuses received saline at the same rate. Two days after infusion, when dexamethasone had cleared from the fetal circulation, acute hypoxemia was induced in both groups for 1 h by reducing the maternal fraction of inspired O2. Fetal dexamethasone treatment transiently lowered fetal basal plasma cortisol, but not ACTH, concentrations. However, 2 days after treatment, fetal basal plasma cortisol concentration was elevated without changes in basal ACTH concentration. Despite elevated basal plasma cortisol concentration, the ACTH response to acute hypoxemia was enhanced, and the increment in plasma cortisol levels was maintained, in dexamethasone-treated fetuses. Correlation of fetal plasma ACTH and cortisol concentrations indicated enhanced cortisol output without a change in adrenocortical sensitivity. The enhancements in basal cortisol concentration and the HPA axis responses to acute hypoxemia after dexamethasone treatment were associated with reductions in pituitary and adrenal glucocorticoid receptor mRNA contents, which persisted at 3-4 days after the end of treatment. These data show that prenatal glucocorticoids alter the basal set point of the HPA axis and enhance HPA axis responses to acute stress in the ovine fetus during late gestation.     

Modeling inter-sex and inter-individual variability in response to chronopharmacological administration of synthetic glucocorticoids

ABSTRACT

Endogenous glucocorticoids have diverse physiological effects and are important regulators of metabolism, immunity, cardiovascular function, musculoskeletal health and central nervous system activity. Synthetic glucocorticoids have received widespread attention for their potent anti-inflammatory activity and have become an important class of drugs used to augment endogenous glucocorticoid activity for the treatment of a host of chronic inflammatory conditions. Chronic use of synthetic glucocorticoids is associated with a number of adverse effects as a result of the persistent dysregulation of glucocorticoid sensitive pathways. A failure to consider the pronounced circadian rhythmicity of endogenous glucocorticoids can result in either supraphysiological glucocorticoid exposure or severe suppression of endogenous glucocorticoid secretion, and is thought be a causal factor in the incidence of adverse effects during chronic glucocorticoid therapy. Furthermore, given that synthetic glucocorticoids have potent feedback effects on the hypothalamic-pituitary-adrenal (HPA) axis, physiological factors which can give rise to individual variability in HPA axis activity such as sex, age, and disease state might also have substantial implications for therapy. We use a semi-mechanistic mathematical model of the rodent HPA axis to study how putative sex differences and individual variability in HPA axis regulation can influence the effects of long-term synthetic exposure on endogenous glucocorticoid circadian rhythms. Model simulations suggest that for the same drug exposure, simulated females exhibit less endogenous suppression than males considering differences in adrenal sensitivity and negative feedback to the hypothalamus and pituitary. Simulations reveal that homeostatic regulatory variability and chronic stress-induced regulatory adaptations in the HPA axis network can result in substantial differences in the effects of synthetic exposure on the circadian rhythm of endogenous glucocorticoids. In general, our results provide insight into how the dosage and exposure profile of synthetic glucocorticoids could be manipulated in a personalized manner to preserve the circadian dynamics of endogenous glucocorticoids during chronic therapy, thus potentially minimizing the incidence of adverse effects associated with long-term use of glucocorticoids     

Hypothalamic metabolism of neurotransmitters (serotonin,norepinephrine, dopamine) and NPY,and gonadal and adrenal activities,during the early postnatal period in the rat

It is noteworthy that in the rat the early postnatal life is marked by an activation of both the corticostimulating function of the adenohypophysis in neonates of both sexes and of the gonadostimulating function mainly in males. In order to specify if such neuroendocrine variations are temporally correlated with changes in the hypothalamic metabolism of neurotransmitters, the hypothalamic metabolism of serotonin (5 HT), norepinephrine (NE), and dopamine (DA) and the hypothalamic content of neuropeptide Y (NPY) have been investigated in newborn rats of both sexes, delivered at term by cesarean section, as well as changes in the activity of both the hypothalamo-pituitary adrenal axis (HPA) and the hypothalamo-pituitary gonadal axis (HPG). Experimental data suggested that 1) in males a rise in hypothalamic metabolism of 5 HT, NE and DA occurs during the first two hours after delivery, whereas in females, only the metabolism of NE increases. Moreover, the postnatal metabolism of NE was higher in females than in littermate males; 2) NPY content of the hypothalamus, which was at birth significantly higher in males than in females, dropped in the former but not in the latter; 3) in newborn males, an early surge of plasma testosterone occurs, suggesting postnatal activation of the HPG axis; on the other hand, in females, a late and slight increase in plasma estradiol is observed; 4) in early postnatal life, a sex-independent rise in plasma ACTH and adrenal and plasma corticosterone levels suggest a comparable activation of the HPA axis in newborns of both sexes. In conclusion, the early postnatal activation of the corticostimulating function in neonates of both sexes and that of the gonadostimulating function, mainly in males, could be temporally correlated with a rise in the hypothalamic metabolism of two neurotransmitters, 5 HT and NE, and of NPY content. According to our data, a sex-dependent metabolsim of neurotransmitters in the hypothalamus is already apparent in early postnatal life.     

Prenatal alcohol exposure and fetal programming: effects on neuroendocrine and immune function

Alcohol abuse is known to result in clinical abnormalities of endocrine function and neuroendocrine regulation. However, most studies have been conducted on males. Only recently have studies begun to investigate the influence of alcohol on endocrine function in females and, more specifically, endocrine function during pregnancy. Alcohol-induced endocrine imbalances may contribute to the etiology of fetal alcohol syndrome. Alcohol crosses the placenta and can directly affect developing fetal cells and tissues. Alcohol-induced changes in maternal endocrine function can disrupt maternal-fetal hormonal interactions and affect the female's ability to maintain a successful pregnancy, thus indirectly affecting the fetus. In this review, we focus on the adverse effects of prenatal alcohol exposure on neuroendocrine and immune function, with particular emphasis on the hypothalamic-pituitary-adrenal (HPA) axis and the concept of fetal programming. The HPA axis is highly susceptible to programming during fetal development. Early environmental experiences, including exposure to alcohol, can reprogram the HPA axis such that HPA tone is increased throughout life. We present data that demonstrate that maternal alcohol consumption increases HPA activity in both the maternal female and the offspring. Increased exposure to endogenous glucocorticoids throughout the lifespan can alter behavioral and physiologic responsiveness and increase vulnerability to illnesses or disorders later in life. Alterations in immune function may be one of the long-term consequences of fetal HPA programming. We discuss studies that demonstrate the adverse effects of alcohol on immune competence and the increased vulnerability of ethanol-exposed offspring to the immunosuppressive effects of stress. Fetal programming of HPA activity may underlie some of the long-term behavioral, cognitive, and immune deficits that are observed following prenatal alcohol exposure.     

Long‐term Effects of Prenatal Stress and Glucocorticoid Exposure

There is a growing body of evidence suggesting that events during prenatal life can have long‐lasting effects on development and adult health. Stress during pregnancy is common and has been linked to increased incidence of a range of affective and behavioral outcomes in the offspring in later life and also some somatic outcomes. Glucocorticoids, and their actions on the fetus, which are regulated by placental 11β‐hydroxysteroid dehydrogenase type 2 (11β‐HSD2), are hypothesized to mediate these effects. Animal studies have demonstrated long‐term effects of stress and glucocorticoid administration on behavioral outcomes, as well as increased blood pressure, altered hypothalamic pituitary adrenal axis (HPA) function, and decreased glucose tolerance and brain size. In humans, licorice, which inhibits placental 11β‐HSD2 when consumed during pregnancy, has been shown to increase the risk of behavioral problems linked to altered HPA activity. Synthetic glucocorticoids administered during pregnancy to improve fetal lung maturity in threatened preterm birth have been shown to reduce birth weight and head circumference, but have not been linked to grosschanges in long‐term health todate. It is important to consider thelong‐term consequences of stress, and medication that mimics stress, during pregnancy. Birth Defects Research (PartC) 96:315–324, 2012. © 2013 Wiley Periodicals, Inc.     

Hypothalamic-pituitary-adrenal axis regulation of inflammation in rheumatoid arthritis

The profound anti-inflammatory effects of glucocorticoids in drug therapy are reflected in the effects in vivo of endogenous glucocorticoids produced by the adrenals. The production of adrenal glucocorticoids is driven by the hypothalamus and pituitary, which in turn are responsive to circulating products of the inflammatory response, especially cytokines. That inflammation can drive the production of anti-inflammatory glucocorticoids denotes the hypothalamic-pituitary-adrenal (HPA)-immune axis as a classic negative feedback control loop. Defects in HPA axis function are implicated in susceptibility to, and severity of, animal models of rheumatoid arthritis (RA), and are hypothesized to contribute to the human disease. In this paper, data supporting the concept of the HPA axis as a regulator of the inflammatory response in animal models of arthritis are reviewed, along with data from studies in humans. Taken together, these data support the hypothesis that the HPA axis provides one of the key mechanisms for inhibitory regulation of the inflammatory response. Manipulation of HPA axis-driven endogenous anti-inflammatory responses may provide new methods for the therapeutic control of inflammatory diseases.     

Testosterone has antidepressant-like efficacy and facilitates imipramine-induced neuroplasticity in male rats exposed to chronic unpredictable stress

Hypogonadal men are more likely to develop depression, while testosterone supplementation shows antidepressant-like effects in hypogonadal men and facilitates antidepressant efficacy. Depression is associated with hypothalamic–pituitary–adrenal (HPA) axis hyperactivity and testosterone exerts suppressive effects on the HPA axis. The hippocampus also plays a role in the feedback regulation of the HPA axis, and depressed patients show reduced hippocampal neuroplasticity. We assessed the antidepressant-like effects of testosterone with, or without, imipramine on behavioral and neural endophenotypes of depression in a chronic unpredictable stress (CUS) model of depression. A 21-day CUS protocol was used on gonadectomized male Sprague–Dawley rats treated with vehicle, 1 mg of testosterone propionate, 10 mg/kg of imipramine, or testosterone and imipramine in tandem. Testosterone treatment reduced novelty-induced hypophagia following CUS exposure, but not under non-stress conditions, representing state-dependent effects. Further, testosterone increased the latency to immobility in the forced swim test (FST), reduced basal corticosterone, and reduced adrenal mass in CUS-exposed rats. Testosterone also facilitated the effects of imipramine by reducing the latency to immobility in the FST and increasing sucrose preference. Testosterone treatment had no significant effect on neurogenesis, though the combination of testosterone and imipramine increased PSA-NCAM expression in the ventral dentate gyrus. These findings demonstrate the antidepressant- and anxiolytic-like effects of testosterone within a CUS model of depression, and provide insight into the mechanism of action, which appears to be independent of enhanced hippocampal neurogenesis.     

Mammalian reproductive strategies: A generalized relation of litter size to body size

Summary A generalized relationship of litter size to mammalian body size was predicted by a graph model. The model was used to generate hypotheses explaining specific features of variation in gestation time, relative litter weight, birth weight, and reproductive capacity. The predictions were tested by means of data from the literature.Mammals were assumed to maximize neonatal survival of offspring to the limits allowed by litter weight per female body weight. Gestation time correlated negatively with the foetal growth rate of relative litter weight. Gestation time did not correlate with the foetal growth rate of individual offspring.Relative litter weight correlated negatively with adult body weight. This relationship was explained by the higher assimilation rate per unit weight relative to metabolic rate in small mammals.Birth weight correlated positively with body weight. However, small mammals produce larger offspring than predicted by the linear relationship of birth weight to body weight in large mammals. There is obviously a minimum birth weight which cannot be decreased without special arrangements for parental care.The prediction of the relationship of litter size to body size was derived from the relations of relative litter weight and birth weight to body weight. In small mammals (less than 1 kg) litter the correlation was negative. When litter size was compared with body length, the correlation was positive in small mammals (less than 30 cm) and negative in large mammals. In both sets of data there was a negative overall correlation between litter size and body size.Reproductive capacity, defined as the number of offspring per season, correlated negatively with life-span.     

The Activity of the Hypothalamic‐Pituitary‐Adrenal Axis and the Sympathetic Nervous System in Relation to Waist/Hip Circumference Ratio in Men

Objective: To investigate possible differences, between generally and abdominally obese men, in activity and regulation of the hypothalamic‐pituitary‐adrenal (HPA) axis and the sympathetic nervous system. Research Methods and Procedures: Fifty non‐diabetic, middle‐aged men were selected to obtain two groups with similar body mass index (BMI) but different waist/hip circumference ratio (WHR). Measurements were performed of the activity of the HPA axis and the sympathetic nervous system, as well as metabolic and endocrine variables. Results: Men with a high WHR, in comparisons with men with a low WHR, had higher insulin, glucose, and triglyceride values in the basal state and higher glucose and insulin after an oral glucose tolerance test. Men with high WHR had elevated diurnal adrenocorticotropic hormone (ACTH) values but similar cortisol values, except lower cortisol values in the morning. Diurnal growth hormone concentrations showed reduced peak size. Stimulation of the HPA axis with corticotropin‐releasing hormone (CRH) and laboratory stress showed no difference in ACTH values between groups, but cortisol values were lower in men with high WHR. In comparison with men with a low WHR, men with a high WHR had elevated pulse pressure and heart rate in the basal state and after challenges by CRH and laboratory stress. They also had increased urinary excretion of catecholamine metabolites. Discussion: These results suggest a mild dysregulation of the HPA axis, occurring with elevated WHR independent of the BMI. The results also indicate a central activation of the sympathetic nervous system, such as in the early phases of hypertension, correlating with insulin resistance.     

Hypothalamic Neuroendocrine Circuitry is Programmed by Maternal Obesity: Interaction with Postnatal Nutritional Environment

Objective

Early life nutrition is critical for the development of hypothalamic neurons involved in energy homeostasis. We previously showed that intrauterine and early postnatal overnutrition programmed hypothalamic neurons expressing the appetite stimulator neuropeptide Y (NPY) and suppressor proopiomelanocortin (POMC) in offspring at weaning. However, the long-term effects of such programming and its interactions with post-weaning high-fat-diet (HFD) consumption are unclear.

Research Design and Methods

Female Sprague Dawley rats were exposed to chow or HFD for 5 weeks before mating, throughout gestation and lactation. On postnatal day 1, litters were adjusted to 3/litter to induce postnatal overnutrition (vs. 12 in control). At postnatal day 20, half of the rats from each maternal group were weaned onto chow or HFD for 15 weeks. Hypothalamic appetite regulators, and fuel (glucose and lipid) metabolic markers were measured.

Results

Offspring from obese dams gained more weight than those from lean dams independent of post-weaning diet. Maternal obesity interacted with post-weaning HFD consumption to cause greater levels of hyperphagia, adiposity, hyperlipidemia, and glucose intolerance in offspring. This was linked to increased hypothalamic NPY signaling and leptin resistance in adult offspring. Litter size reduction had a detrimental impact on insulin and adiponectin, while hypothalamic NPY and POMC mRNA expression were suppressed in the face of normal energy intake and weight gain.

Conclusions

Maternal obesity, postnatal litter size reduction and post-weaning HFD consumption caused obesity via different neuroendocrine mechanims. There were strong additive effects of maternal obesity and post-weaning HFD consumption to increase the metabolic disorders in offspring.