Pituitary Responsiveness Research Articles

9325 Obesity Alters Pomc And Kisspeptin Neuron Crosstalk Leading To Lower Luteinizing Hormone

Abstract Disclosure: P. Villa: None. R. Ruggiero-Ruff: None. B. Jamieson: None. R. Campbell: None. D. Coss: None. Obesity is a significant public health concern due to its high prevalence and numerous comorbidities. It is associated with hypogonadism in males, characterized by low testosterone and sperm number. Previous studies determined that these stem from dysregulation of hypothalamic circuitry that regulates reproduction, by unknown mechanisms, since studies are confounded by chronic nature of this condition that leads to synaptic changes and alterations in neuron responsiveness to stimuli. Herein, we used mice fed chronic high-fat diet, that mimics human obesity, to determine mechanisms of impairment at the level of the hypothalamus, in particular gonadotropin-releasing hormone (GnRH) neurons that regulate luteinizing hormone levels (LH), which in turn regulates testosterone synthesis. Consistent with obese humans, we demonstrated lower LH, and lower pulse frequency of LH secretion, but unchanged pituitary responsiveness to GnRH. Pulse frequency of LH is regulated by pulsatile GnRH secretion, which is controlled by kisspeptin. Peripheral and central kisspeptin injections, and DREADD-mediated activation of kisspeptin neurons, demonstrated that kisspeptin neurons were suppressed in obese mice. Thus, we investigated regulators of kisspeptin secretion. We determined that LH response to NMDA was lower in obese mice, corresponding to fewer glutamate receptors in kisspeptin neurons, which may be critical for kisspeptin synchronization. Given that kisspeptin neurons also interact with POMC neurons, which regulate satiety and are particularly affected by obesity, we examined their crosstalk, and determined that LH response to either DREADD-mediated activation of POMC neurons or central injection of αMSH, a product of POMC, is abolished in obese mice. This was accompanied by diminished levels of αMSH receptor, MC4R, in kisspeptin neurons. The reason may be that chronically higher activity of POMC neurons in response to obesity, downregulates αMSH receptors on target neurons, including kisspeptin. This may lead to suppression of kisspeptin neurons, and their inability to regulate pulsatile secretion of GnRH. Together, our studies determined that obesity leads to downregulation of receptors that regulate kisspeptin neurons, which is associated with lower LH pulse frequency, leading to lower LH and hypogonadism. Presentation: 6/2/2024

Developmental exposures to common environmental pollutants result in long-term Reprogramming of hypothalamic-pituitary axis in mice

Humans are exposed to a range of endocrine disrupting chemicals (EDCs). Many studies demonstrate that exposures to EDCs during critical windows of development can permanently affect endocrine health outcomes. Most experimental studies address changes in secretion of hormones produced by gonads, thyroid gland and adrenals, and little is known about the ability of EDCs to produce long-term changes in the hypothalamic-pituitary (HP) control axes. Here, we examined the long-term effects of three common EDCs on male mouse HP gene expression, following developmental exposures. Pregnant mice were exposed to 0.2 mg/ml solutions of bisphenol S (BPS), 2,2′,4,4′-tetrabromodiphenyl ether (BDE-47), or 3,3′,5,5′-tetrabromobisphenol A (TBBPA) from pregnancy day 8 through lactation day 21 (weaning day). Male offspring were left untreated until postnatal day 140, where pituitaries and hypothalami were collected. Pituitaries were assed for gene expression via RNA sequencing, while specific genes were assessed for expression in hypothalami via RT-qPCR. Differential expression, as well as gene enrichment and pathway analysis, indicated that all three chemicals induced long-term changes, (mostly suppression) in pituitary genes involved in its endocrine function. BPS and BDE-47 produced effects overlapping significantly at the level of effected genes and pathways. All three chemicals altered pathways of gonad and liver HP axes, while BPS altered HP-adrenal and BDE-47 altered HP-thyroid pathways specifically. All three chemicals reduced expression of immune genes in the pituitaries. Targeted gene expression in the hypothalamus indicates down regulation of hypothalamic endocrine control genes by BPS and BDE-47 groups, concordant with changes in the pituitary, suggesting that these chemicals suppress overall HP endocrine function. Interestingly, all three chemicals altered pituitary genes of GPCR-mediated intracellular signaling molecules, key signalers common to many pituitary responses to hormones. The results of this study show that developmental exposures to common EDCs have long-term impacts on hormonal feedback control at the hypothalamic-pituitary level.

Early-Life Resource Scarcity in Mice Does Not Alter Adult Corticosterone or Preovulatory Luteinizing Hormone Surge Responses to Acute Psychosocial Stress.

Early-life stressors can affect reproductive development and change responses to adult stress. We tested if resource scarcity in the form of limited bedding and nesting (LBN) from postnatal days (PND) 4 to 11 delayed sexual maturation in male and female mice and/or altered the response to an acute, layered, psychosocial stress (ALPS) in adulthood. Contrary to the hypotheses, age and mass at puberty were unaffected by the present application of LBN. Under basal conditions and after ALPS, corticosterone concentrations in males, diestrous females, and proestrous females reared in standard (STD) or LBN environments were similar. ALPS disrupts the luteinizing hormone (LH) surge in most mice when applied on the morning of proestrus; this effect was not changed by resource scarcity. In this study, the paucity of effects in the offspring may relate to a milder response of CBA dams to the paradigm. While LBN dams exited the nest more often and their offspring were smaller than STD-reared offspring on PND11, dam corticosterone concentrations were similar on PND11. To test if ALPS disrupts the LH surge by blunting the increase in excitatory GABAergic input to gonadotropin-releasing hormone (GnRH) neurons on the afternoon of proestrus, we conducted whole-cell voltage-clamp recordings. The frequency of GABAergic postsynaptic currents in GnRH neurons was not altered by LBN, ALPS, or their interaction. It remains possible that ALPS acts at afferents of GnRH neurons, changes response of GnRH neurons to input, and/or alters pituitary responsiveness to GnRH and that a more pronounced resource scarcity would affect the parameters studied.

O-192 Kisspeptin as a test of hypothalamic function in women presenting with oligo-amenorrhea

Abstract Study question Can kisspeptin be used as a novel tool to interrogate hypothalamic function in women presenting with oligo-amenorrhea? Summary answer The hormonal response to kisspeptin offers a novel approach for the assessment of hypothalamic function in patients presenting with oligo-amenorrhea of different aetiologies. What is known already Polycystic ovary syndrome (PCOS) and functional hypothalamic amenorrhea (FHA) are the two commonest causes of anovulation causing oligo-amenorrhea in pre-menopausal women. Additionally, congenital (CHH) and functional hypogonadotropic hypogonadism can present with similar endocrine profiles. Importantly, these conditions are caused and characterised by abnormal hypothalamic function. For instance, gonadotropin-releasing hormone (GnRH) pulsatility is increased in PCOS but reduced in FHA. Despite differences in pathophysiology, differentiating these diagnoses can be challenging in clinical practice. Kisspeptin is known to stimulate hypothalamic GnRH neurons. Thus, kisspeptin could represent a novel tool to interrogate hypothalamic function in women presenting with reproductive disorders causing oligo-amenorrhea. Study design, size, duration Single-centre, prospective, experimental study of healthy women (n = 33), women with PCOS (n = 30), FHA (n = 30), or CHH (n = 8), aged 18-35 years and not taking hormonal treatment. Participants were recruited for clinical studies between September 2019 and September 2023 and underwent two separate study visits. The visits assessed the gonadotropin response to hypothalamic stimulation with an intravenous bolus of kisspeptin-54 (9.6nmol/kg) and the pituitary response to an intravenous bolus of GnRH (100 mcg). Participants/materials, setting, methods All participants took part in two study visits. Serum luteinizing hormone (LH), and follicle stimulating hormone (FSH) levels were measured every 15 minutes for 8 hours after administration of kisspeptin-54 and GnRH. The maximal rise in LH and FSH from baseline was compared between groups using an unpaired t-test. Receiver operator characteristic (ROC) analysis was used to assess the discriminatory potential of the hormone response to kisspeptin and GnRH. Main results and the role of chance The gonadotropin response to kisspeptin was increased in women with FHA compared to all other groups. The mean (SD) of the maximal rise in LH (IU/L) after kisspeptin was 9.7 (11.4) in healthy women, 9.7 (8.3) in women with PCOS, 17.6 (10.8) in women with FHA, and 1.0 (1.1) in women with CHH. The mean (SD) of the maximal rise in FSH (IU/L) after kisspeptin was 4.2 (3.4) in healthy women, 2.8 (2.1) in women with PCOS, 9.2 (5.6) in women with FHA, and 0.7 (0.5) in women with CHH. In lean women (BMI <25 kg/m2), the maximal rise in FSH after kisspeptin differentiated women with PCOS from those with FHA (area under ROC curve 0.91, p = 0.0001). Furthermore, the maximal rise in FSH after kisspeptin differentiated women with FHA from women with CHH (auROC 1.00, p < 0.0001), whereas the equivalent auROC for FSH rise after GnRH was 0.7 (p = 0.086). Limitations, reasons for caution Participants included in this study had clearcut diagnoses of PCOS, FHA, or CHH prior to inclusion, however this could increase the risk of spectrum bias. Whilst this study provides mechanistic insight into hypothalamic dysfunction in these conditions, further prospective validation of discriminatory thresholds in different settings is required. Wider implications of the findings The specific action of kisspeptin at hypothalamic GnRH neurons enables its use to assess hypothalamic function in patients with oligo-amenorrhea due to different anovulatory disorders. Our data suggests that the hormonal response to kisspeptin has promising diagnostic potential to aid in the evaluation of women with oligo-amenorrhea. Trial registration number ISRCTN21681316

Obesity Alters POMC and Kisspeptin Neuron Cross Talk Leading to Reduced Luteinizing Hormone in Male Mice.

Obesity is associated with hypogonadism in males, characterized by low testosterone and sperm number. Previous studies determined that these stem from dysregulation of hypothalamic circuitry that regulates reproduction, by unknown mechanisms. Herein, we used mice fed chronic high-fat diet, which mimics human obesity, to determine mechanisms of impairment at the level of the hypothalamus, in particular gonadotropin-releasing hormone (GnRH) neurons that regulate luteinizing hormone (LH), which then regulates testosterone. Consistent with obese humans, we demonstrated lower LH, and lower pulse frequency of LH secretion, but unchanged pituitary responsiveness to GnRH. LH pulse frequency is regulated by pulsatile GnRH secretion, which is controlled by kisspeptin. Peripheral and central kisspeptin injections, and DREADD-mediated activation of kisspeptin neurons, demonstrated that kisspeptin neurons were suppressed in obese mice. Thus, we investigated regulators of kisspeptin secretion. We determined that the LH response to NMDA was lower in obese mice, corresponding to fewer glutamate receptors in kisspeptin neurons, which may be critical for kisspeptin synchronization. Given that kisspeptin neurons also interact with anorexigenic POMC neurons, which are affected by obesity, we examined their cross talk, and determined that the LH response to either DREADD-mediated activation of POMC neurons or central injection of αMSH, a product of POMC, is abolished in obese mice. This was accompanied by diminished levels of αMSH receptor, MC4R, in kisspeptin neurons. Together, our studies determined that obesity leads to the downregulation of receptors that regulate kisspeptin neurons, which is associated with lower LH pulse frequency, leading to lower LH and hypogonadism.

Estradiol action in the female hypothalamo-pituitary-gonadal axis.

It has now been about a century since a flurry of discoveries identified first the pituitary, then more specifically the anterior pituitary and soon thereafter the central nervous system as components regulating gonadal and downstream reproductive functions. This was an era of ablation/replacement designs using at first rudimentary and then increasingly pure preparations of gonadal and pituitary "activities" or transplanting actual glands, whole or homogenized, among subjects. There was, of course, controversy as is typical of lively and productive scientific debates to this day. The goals of this commentary are to briefly review the history of this work and how the terms referring to interactions among the components of the hypothalamo (as the central neural component was soon associated with)-pituitary-gonadal (HPG) axis evolved, and then to question if the current terms used have kept up with our understanding of the system. The focus in this review will be the actions of estradiol primarily upon the hypothalamus. Important actions of progesterone on the hypothalamus as well as both steroids on the pituitary response to hypothalamic factors are both acknowledged and largely ignored in this document, as are any sex differences as we focus on females.

The Musashi RNA binding proteins direct the translational activation of key pituitary mRNAs

The pituitary functions as a master endocrine gland that secretes hormones critical for regulation of a wide variety of physiological processes including reproduction, growth, metabolism and stress responses. The distinct hormone-producing cell lineages within the pituitary display remarkable levels of cell plasticity that allow remodeling of the relative proportions of each hormone-producing cell population to meet organismal demands. The molecular mechanisms governing pituitary cell plasticity have not been fully elucidated. Our recent studies have implicated a role for the Musashi family of sequence-specific mRNA binding proteins in the control of pituitary hormone production, pituitary responses to hypothalamic stimulation and modulation of pituitary transcription factor expression in response to leptin signaling. To date, these actions of Musashi in the pituitary appear to be mediated through translational repression of the target mRNAs. Here, we report Musashi1 directs the translational activation, rather than repression, of the Prop1, Gata2 and Nr5a1 mRNAs which encode key pituitary lineage specification factors. We observe that Musashi1 further directs the translational activation of the mRNA encoding the glycolipid Neuronatin (Nnat) as determined both in mRNA reporter assays as well as in vivo. Our findings suggest a complex bifunctional role for Musashi1 in the control of pituitary cell function.

Associations between cortisol stress responses and limbic volume and thickness in young adults: An exploratory study.

The investigation of the relationship between neural measures of limbic structures and hypothalamic pituitary adrenal axis responses to acute stress exposure in healthy young adults has so far focused in particular on task-based and resting state functional connectivity studies. Thus, the present study examined the association between limbic volume and thickness measures and acute cortisol responses to the psychosocial stress paradigm ScanSTRESS. Using Permutation Analysis of Linear Models controlling for sex, age and total brain volume, the associations between (sex-specific) cortisol increases and human connectome project style anatomical variables of limbic structures (i.e. volume and thickness) were investigated in 66 healthy and young (18-33 years) subjects (35 men, 31 women taking oral contraceptives). In addition, exploratory (sex-specific) bivariate correlations between cortisol increases and structural measures were conducted. The present data provide interesting new insights into the involvement of striato-limbic structures in psychosocial stress processing, suggesting that acute cortisol stress responses are also associated with mere structural measures of the human brain. Thus, our preliminary findings suggest that not only situation- and context-dependent reactions of the limbic system (i.e. blood oxygenation level-dependent reactions) are related to acute (sex-specific) cortisol stress responses but also basal and somewhat more constant structural measures. Our study hereby paves the way for further analyses in this context and highlights the relevance of the topic.

SAT599 Molecular Analysis Of Pituitary Transdifferentiation In Response To Physiological Cues

Abstract Disclosure: J. Lim: None. In mammals, the control of cell fate is imperative to the development of multicellular organisms as well as tissue homeostasis/regeneration in the adult. The anterior pituitary (AP) controls growth, metabolism, reproduction, and stress responses through the synthesis and secretion of specific hormones by distinct AP cell lineages. Interestingly, the anterior pituitary exhibits a high level of adult cell plasticity that allows committed hormone-producing cells to alter their cell fate and produce different hormones to meet altered organismal demands. The molecular mechanisms underlying this adult cell plasticity have not been fully characterized. To investigate the mechanism(s) of pituitary cell transdifferentiation, our lab has employed a rat GH3 cell culture model that undergoes somatotrope to lactotrope conversion in response to a cocktail of 3 growth factors (EGF, estradiol and insulin). Upon stimulation of lactotrope transdifferentiation, we confirmed a significant reduction of Growth hormone (Gh1) and reciprocal elevation of Prolactin (Prl) protein and transcript levels in the treated group compared to untreated controls. Proteomic and transcriptomic analyses from the same samples detected upregulation of 124 proteins and 553 transcripts and downregulation of 28 proteins and 556 transcripts respectively. Gene ontology analyses identified a number of upregulated proteins involved in autophagy (e.g. autolysosome), MTORC1 signaling, and a number of upregulated transcripts involved in the regulation of cell proliferation and apoptosis. A number of the upregulated proteins and transcripts are involved in Epithelial-to-mesenchymal transition (EMT) and metabolic change (i.e. glycolysis, hypoxia), while downregulated transcripts involved in neurogenesis (i.e. Notch1, Notch2, Sox2, Sox5). Further, differential expression analyses comparing the proteomic and transcriptomic levels of the treated vs. control GH3 cells identified a number of upregulated proteins with no change in their corresponding transcripts related to MTORC1 signaling and glycolysis as well as a number of unchanged proteins with corresponding upregulated transcripts involved in mitochondrial activity suggesting a broad role for post-transcriptional regulation during transdifferentiation. In a complementary in vivo study, we assessed pituitary cell fate changes in response to hypothyroidism, using a similar integrated proteogenomic profiling. Together, we identify a number of altered molecular pathways that underlie distinct pituitary cell plasticity responses to physiological cues. Presentation: Saturday, June 17, 2023

Copeptin analysis in endocrine disorders.

Copeptin is cleaved from the same precursor as arginine vasopressin and is released in equimolar amounts with arginine vasopressin from the posterior pituitary in response to the same stimuli. Its level of stability in the blood, quick and simple analysis, and ease of automation make it much easier to analyze than arginine vasopressin, thereby offering a suitable alternative to measuring arginine vasopressin in endocrine disorders. Research has demonstrated the suitability of copeptin in adults for the differentiation of arginine vasopressin resistance and arginine vasopressin deficiency from primary polydipsia, in addition to the early identification of arginine vasopressin deficiency following pituitary surgery; however, further research is still required in the Syndrome of Inappropriate Antidiuretic Hormone (SIADH) and the pediatric population.

Chronic estradiol exposure suppresses luteinizing hormone surge without affecting kisspeptin neurons and estrogen receptor alpha in anteroventral periventricular nucleus†.

Mammalian ovulation is induced by a luteinizing hormone surge, which is triggered by elevated plasma estrogen levels; however, chronic exposure to high levels of estradiol is known to inhibit luteinizing hormone secretion. In the present study, we hypothesized that the inhibition of the luteinizing hormone surge by chronic estradiol exposure is due to the downregulation of the estrogen receptor alpha in kisspeptin neurons at hypothalamic anteroventral periventricular nucleus, which is known as the gonadotropin-releasing hormone/luteinizing hormone surge generator. Animals exposed to estradiol for 2days showed an luteinizing hormone surge, whereas those exposed for 14days showed a significant suppression of luteinizing hormone. Chronic estradiol exposure did not affect the number of kisspeptin neurons and the percentage of kisspeptin neurons with estrogen receptor alpha or c-Fos in anteroventral periventricular nucleus, but it did affect the number of kisspeptin neurons in arcuate nucleus. Furthermore, chronic estradiol exposure did not affect gonadotropin-releasing hormone neurons. In the pituitary, 14-day estradiol exposure significantly reduced the expression of Lhb mRNA and LHβ-immunoreactive areas. Gonadotropin-releasing hormone-induced luteinizing hormone release was also reduced significantly by 14-day estradiol exposure. We revealed that the suppression of an luteinizing hormone surge by chronic estradiol exposure was induced in association with the significant reduction in kisspeptin neurons in arcuate nucleus, luteinizing hormone expression in the pituitary, and pituitary responsiveness to gonadotropin-releasing hormone, and this was not caused by changes in the estrogen receptor alpha-expressing kisspeptin neurons in anteroventral periventricular nucleus and gonadotropin-releasing hormone neurons, which are responsible for estradiol positive feedback.

Investigation of subfertility in the female Nsmf knockout mouse

To study if a pituitary or ovarian defect contributes to subfertility of the female Nsmf knockout (KO) mouse, an animal model of the hypogonadotropic hypogonadism gene NSMF. Analysis of hypothalamic, pituitary and ovarian gene expression at baseline, serum gonadotropin levels before and after gonadotropin-releasing hormone (GnRH) stimulation, ovarian response and implantation after superovulation, gonadotropin effects after ovariectomy, and ovarian NSMF protein expression. University research laboratory. None; mice were used. Gonadotropin-releasing hormone stimulation, superovulation, and ovariectomy in separate experiments. Gene expression in the hypothalamus, pituitary, and ovary; ovarian response and implantation after superovulation; serum gonadotropins after GnRH stimulation and ovariectomy; Western blot to measure ovarian NSMF expression. We found increased hypothalamic Kiss1, Gnrh1, and Jak2 mRNA expression in female Nsmf KO vs. wild type (WT) mice. However, pituitary gonadotropin, and GnRH receptor gene expression was not affected, and serum gonadotropin levels were normal. Gonadotropins increased after ovariectomy for both groups. Baseline Kiss1, Fshr, Prkaca, Prkar1a, and Gdf9 ovarian mRNA expression was increased and Cyp19a1 expression was decreased in Nsmf KO mice, while superovulated Nsmf KO mice had reduced ovarian Kiss1r, Prkar1a, and Fshr mRNA expression, 50% less oocytes, and normal implantation. Western blot demonstrated NSMF protein expression in the ovary of WT mice. Altered hypothalamic and ovarian gene expression was demonstrated in female Nsmf KO mice. It is possible that increased hypothalamic Gnrh1 and Kiss1 mRNA expression could compensate for reduced NSMF enabling a normal pituitary gonadotropin response. Impaired superovulation response, altered ovarian gene expression, and decreased number of oocytes indicate ovarian dysfunction, but a uterine factor cannot be excluded. These findings provide an anatomic basis for future mechanistic studies of subfertility in female Nsmf KO mice.

Prevalence of refractoriness when testing growth hormone levels in children

ObjectiveLate night spontaneous growth hormone (GH) pulses may influence the pituitary GH response to provocation tests. We evaluated GH response during arginine-insulin-tolerance test (AITT) after a GH peak during a short spontaneous nocturnal profile (SSNP) in children with short stature or low growth velocity. DesignUsing SSNP and subsequent AITT, we examined 257 children 4–18 years old (138 (53.7%) males) recruited from three hospitals. Medical records were reviewed retrospectively. Refractory children were defined as a GH peak ≥7 μg/L during SSNP but no GH peak ≥7 μg/L during AITT. ResultsIn total, 201/257 children had a GH peak ≥7 μg/L at SSNP and/or AITT. Of these, 21.9% were refractory. The proportion of males (p = 0.033) and body mass index (BMI) standard deviation score (SDS) (p = 0.037) were higher in the refractory group than in children with a GH peak ≥7 μg/L during AITT. The median period between last GH peak ≥7 μg/L during SSNP and GHmax at AITT was 210 (30–390) minutes. The GHmax at AITT occurred 30 min earlier for children without a peak ≥7 μg/L during the SSNP (p = 0.004). The number of refractoriness differed somewhat between the hospitals (p = 0.025). ConclusionsMany children with short stature were refractory at testing; among them we found few clinical characteristics. Refractoriness might be influenced by some differences in procedure, but needs to be considered when evaluating GH response in children.

Sex-specific responses to GnRH challenge, but not food supply, in kittiwakes: Evidence for the “sensitivity to information” hypothesis

Seasonal timing of breeding is usually considered to be triggered by endogenous responses linked to predictive cues (e.g., photoperiod) and supplementary cues that vary annually (e.g., food supply), but social cues are also important. Females may be more sensitive to supplementary cues because of their greater role in reproductive timing decisions, while males may only require predictive cues. We tested this hypothesis by food-supplementing female and male colonial seabirds (black-legged kittiwakes, Rissa tridactyla) during the pre-breeding season. We measured colony attendance via GPS devices, quantified pituitary and gonadal responses to gonadotropin releasing hormone (GnRH) challenge, and observed subsequent laying phenology. Food supplementation advanced laying phenology and increased colony attendance. While female pituitary responses to GnRH were consistent across the pre-breeding season, males showed a peak in pituitary sensitivity at approximately the same time that most females were initiating follicle development. The late peak in male pituitary response to GnRH questions a common assumption that males primarily rely on predictive cues (e.g., photoperiod) while females also rely on supplementary cues (e.g., food availability). Instead, male kittiwakes may integrate synchronising cues from their social environment to adjust their reproductive timing to coincide with female timing.

Targeting PDK2 rescues stress-induced impaired brain energy metabolism.

Depression is a mental illness frequently accompanied by disordered energy metabolism. A dysregulated hypothalamus pituitary adrenal axis response with aberrant glucocorticoids (GCs) release is often observed in patients with depression. However, the associated etiology between GCs and brain energy metabolism remains poorly understood. Here, using metabolomic analysis, we showed that the tricarboxylic acid (TCA) cycle was inhibited in chronic social defeat stress (CSDS)-exposed mice and patients with first-episode depression. Decreased mitochondrial oxidative phosphorylation was concomitant with the impairment of the TCA cycle. In parallel, the activity of pyruvate dehydrogenase (PDH), the gatekeeper of mitochondrial TCA flux, was suppressed, which is associated with the CSDS-induced neuronal pyruvate dehydrogenase kinase 2 (PDK2) expression and consequently enhanced PDH phosphorylation. Considering the well-acknowledged role of GCs in energy metabolism, we further demonstrated that glucocorticoid receptors (GR) stimulated PDK2 expression by directly binding to its promoter region. Meanwhile, silencing PDK2 abrogated glucocorticoid-induced PDH inhibition, restored the neuronal oxidative phosphorylation, and improved the flux of isotope-labeled carbon (U-13C] glucose) into the TCA cycle. Additionally, in vivo, pharmacological inhibition and neuron-specific silencing of GR or PDK2 restored CSDS-induced PDH phosphorylation and exerted antidepressant activities against chronic stress exposure. Taken together, our findings reveal a novel mechanism of depression manifestation, whereby elevated GCs levels regulate PDK2 transcription via GR, thereby impairing brain energy metabolism and contributing to the onset of this condition.

The association between stress, emotional states, and tinnitus: a mini-review.

Extensive literature supporting the view of tinnitus induced stress in patients is available. However, limited evidence has been produced studying the opposite, that is, does stress cause tinnitus? The hypothalamus pituitary adrenal axis, one of the main neuroendocrine systems involved in stress response, is commonly disturbed in tinnitus patients. Patients with chronic tinnitus have been shown to develop abnormal responses to psycho-social stress, where the hypothalamus pituitary adrenal axis response is weaker and delayed, suggesting chronic stress contributes to the development of chronic tinnitus. The sympathetic branch of the autonomic nervous system also plays a major role in stress response and its chronic hyperactivity seems to be involved in developing tinnitus. Psycho-social stress has been shown to share the same probability of developing tinnitus as occupational noise and contributes to worsening tinnitus. Additionally, exposure to high stress levels and occupational noise doubles the likelihood of developing tinnitus. Interestingly, short-term stress has been shown to protect the cochlea in animals, but chronic stress exposure has negative consequences. Emotional stress also worsens pre-existing tinnitus and is identified as an important indicator of tinnitus severity. Although there is limited body of literature, stress does seem to play a vital role in the development of tinnitus. This review aims to highlight the association between stress, emotional states, and the development of tinnitus while also addressing the neural and hormonal pathways involved.

Chicken pituitary transcriptomic responses to acute heat stress

BackgroundPoultry production is vulnerable to increasing temperatures in terms of animal welfare and in economic losses. With the predicted increase in global temperature and the number and severity of heat waves, it is important to understand how chickens raised for food respond to heat stress. This knowledge can be used to determine how to select chickens that are adapted to thermal challenge. As neuroendocrine organs, the hypothalamus and pituitary provide systemic regulation of the heat stress response.Methods and ResultsHere we report a transcriptome analysis of the pituitary response to acute heat stress. Chickens were stressed for 2 h at 35 °C (HS) and transcriptomes compared with birds maintained in thermoneutral temperatures (25 °C).ConclusionsThe observations were evaluated in the context of ontology terms and pathways to describe the pituitary response to heat stress. The pituitaries of heat stressed birds exhibited responses to hyperthermia through altered expression of genes coding for chaperones, cell cycle regulators, cholesterol synthesis, transcription factors, along with the secreted peptide hormones, prolactin, and proopiomelanocortin.

Clinical applications of gonadotropin-releasing hormone analogues: a broad impact on reproductive medicine

Gonadotropin-releasing hormone (GnRH) is central to the control of the entire hypothalamic-pituitary-gonadal axis. Manipulation of GnRH, in turn, regulates pituitary response and ovarian hormone production. Gonadotropin-releasing hormone analogues have revolutionized assisted reproductive technology and gynecologic practice. The recent advent of oral GnRH antagonists with an inherent rapid onset of action continues to transform the treatment options available for several common gynecologic conditions, including endometriosis and fibroids. Herein, we review neuroendocrine GnRH activity and discuss modulation of the reproductive axis by GnRH analogues for diverse clinical applications.

Developmental programming of the neuroendocrine axis by steroid hormones: Insights from the sheep model of PCOS.

The reproductive neuroendocrine system is a key target for the developmental programming effects of steroid hormones during early life. While gonadal steroids play an important role in controlling the physiological development of the neuroendocrine axis, human fetuses are susceptible to adverse programming due to exposure to endocrine disrupting chemicals with steroidal activity, inadvertent use of contraceptive pills during pregnancy, as well as from disease states that result in abnormal steroid production. Animal models provide an unparalleled resource to understand the effects of steroid hormones on the development of the neuroendocrine axis and their role on the developmental origins of health and disease. In female sheep, exposure to testosterone (T) excess during fetal development results in an array of reproductive disorders that recapitulate those seen in women with polycystic ovary syndrome (PCOS), including disrupted neuroendocrine feedback mechanisms, increased pituitary responsiveness to gonadotropin-releasing hormone (GnRH), luteinizing hormone (LH) hypersecretion, functional hyperandrogenism, multifollicular ovarian morphology, and premature reproductive failure. Similar to a large proportion of women with PCOS, these prenatally T-treated sheep also manifest insulin resistance and cardiovascular alterations, including hypertension. This review article focuses on the effects of prenatal androgens on the developmental programming of hypothalamic and pituitary alterations in the sheep model of PCOS phenotype, centering specifically on key neurons, neuropeptides, and regulatory pathways controlling GnRH and LH secretion. Insights obtained from the sheep model as well as other animal models of perinatal androgen excess can have important translational relevance to treat and prevent neuroendocrine dysfunction in women with PCOS and other fertility disorders.

A tale of two hierarchies: Hormonal and behavioral factors underlying sex differences in social dominance in cooperative breeding callitrichids

Callitrichid primates are recognized for high levels of sociality in small groups, their great behavioral flexibility, and single-female dominant hierarchies. Previous work has highlighted that dominant, breeding callitrichids engage in behavioral and hormonal reproductive suppression of related and unrelated subordinates by both producing more offspring, having higher levels of ovulatory hormones, and accessing more sociosexual opportunities. This suppression constitutes a nexus of changes in pituitary responsiveness, ovarian cyclicity, sexual behavior, affiliation, and aggression. In this review, I will highlight important features that characterize callitrichid social hierarchies across broad social contexts. Dominant females sometimes exert reproductive suppression on subordinate nonbreeding females, but this suppression varies across callitrichids based on social stability and changes in group composition, particularly related to the number, experience, and age of nonbreeding subordinates. Meanwhile, dominant males may induce suppression of reproduction in subordinate males, but these effects occur by different behavioral and endocrine mechanisms and to a much lesser extent than their female counterparts; While dominant female callitrichids usually show higher levels of aggression relative to their male counterparts, callitrichids show a general absence of intersexual dominance, likely as an effort of maintaining a cohesive breeding pair within a stable social group and social cooperation. Future efforts are needed to identify precise neuroendocrine mechanisms underlying the presence of sex differences in callitrichid behavior separate from peripheral reproductive function. This is especially important with regard to parental experience, social relationships, development and aging, with larger implications toward understanding sex differences in overall health and wellbeing.