Hypothalamo Pituitary Research Articles

Trait sensitivity to stress and cognitive bias processes in fish: A brief overview.

Like other animals, fish have unique personalities that can affect their cognition and responses to environmental stressors. These individual personality differences are often referred to as "behavioural syndromes" or "stress coping styles" and can include personality traits such as boldness, shyness, aggression, exploration, locomotor activity, and sociability. For example, bolder or proactive fish may be more likely to take risks and present lower hypothalamo-pituitary-adrenal/interrenal axis reactivity as compared to shy or reactive individuals. Likewise, learning and memory differ between fish personalities. Reactive or shy individuals tend to have faster learning and better association recall with aversive stimuli, while proactive or bold individuals tend to learn more quickly when presented with appetitive incentives. However, the influence of personality on cognitive processes other than cognitive achievement in fish has been scarcely explored. Cognitive bias tests have been employed to investigate the interplay between emotion and cognition in both humans and animals. Fish present cognitive bias processes (CBP) in which fish's interpretation of stimuli could be influenced by its current emotional state and open to environmental modulation. However, no study in fish has explored whether CBP, like in other species, can be interpreted as long-lasting traits and whether other individual characteristics may explain its variation. We hold the perspective that CBP could serve as a vulnerability factor for the onset, persistence, and recurrence of stress-related disorders. Therefore, studying fish's CBP as a state or trait and its interactions with individual variations may be valuable in future efforts to enhance our understanding of anxiety and stress neurobiology in animal models and humans.

Multivariable Model to Predict an ACTH Stimulation Test to Diagnose Adrenal Insufficiency Using Previous Test Results.

The adrenocorticotropin hormone stimulation test (AST) is used to diagnose adrenal insufficiency, and is often repeated in patients when monitoring recovery of the hypothalamo-pituitary-adrenal axis. To develop and validate a prediction model that uses previous AST results with new baseline cortisol to predict the result of a new AST. This was a retrospective, longitudinal cohort study in patients who had undergone at least 2 ASTs, using polynomial regression with backwards variable selection, at a Tertiary UK adult endocrinology center. Model was developed from 258 paired ASTs over 5 years in 175 adults (mean age 52.4 years, SD 16.4), then validated on data from 111 patients over 1 year (51.8, 17.5) from the same center, data collected after model development. Candidate prediction variables included previous test baseline adrenocorticotropin hormone (ACTH), previous test baseline and 30-minute cortisol, days between tests, and new baseline ACTH and cortisol used with calculated cortisol/ACTH ratios to assess 8 candidate predictors. The main outcome measure was a new test cortisol measured 30 minutes after Synacthen administration. Using 258 sequential ASTs from 175 patients for model development and 111 patient tests for model validation, previous baseline cortisol, previous 30-minute cortisol and new baseline cortisol were superior at predicting new 30-minute cortisol (R2 = 0.71 [0.49-0.93], area under the curve [AUC] = 0.97 [0.94-1.0]) than new baseline cortisol alone (R2 = 0.53 [0.22-0.84], AUC = 0.88 [0.81-0.95]). Results of a previous AST can be objectively combined with new early-morning cortisol to predict the results of a new AST better than new early-morning cortisol alone. An online calculator is available at https://endocrinology.shinyapps.io/sheffield_sst_calculator/ for external validation.

The impact of radiotherapy on the hypothalamo-pituitary axis: old vs new radiotherapy techniques.

Multimodality cancer therapy has led to remarkable improvements in survival of childhood and young adult cancer, with survival rates exceeding 85%. Such remission rates come with their own adverse sequelea or 'late effects'. Although the cause of these late effects is multi-factorial, radiation-related adverse effects are one of the most prevalent. Hypopituitarism is a recognised complication of irradiation of brain tumours distant to the hypothalamo-pituitary (HP) axis when the axis is included within the exposed field. Much of the data concerning the development of hypopituitarism, however, relate to early forms of photon-based radiotherapy. In this narrative review, we discuss advances in individual radiotherapy techniques currently used in treating brain tumours and their theoretical benefits based primarily on dosimetric studies. Increasingly precise radiation techniques, including advances in the delivery of photons (i.e. intensity-modulated radiotherapy) and proton beam therapy, are now available options. The premise behind these newer techniques is to reduce the dose and volume of normal tissue irradiated whilst maintaining an effective radiation dose to target tissue. When treating brain tumours distant to the HP axis the expectation, based upon dosimetric studies, is that newer forms of radiotherapy will less frequently involve the HP axis in the exposed field, and where incorporated within the field it will be exposed to a lower radiotherapy dosage. Intuitively the dosimetric studies should translate into significant reductions in the prevalence of HP dysfunction. These data are promising; however, to date there are minimal robust clinical data to determine if the theoretical benefits of these newer techniques on HP dysfunction is to be realised.

Mapping of corticotropin-releasing factor, receptors, and binding protein mRNA in the chicken telencephalon throughout development.

Understanding the neural mechanisms that regulate the stress response is critical to know how animals adapt to a changing world and is one of the key factors to be considered for improving animal welfare. Corticotropin-releasing factor (CRF) is crucial for regulating physiological and endocrine responses, triggering the activation of the sympathetic nervous system and the hypothalamo-pituitary-adrenal axis (HPA) during stress. In mammals, several telencephalic areas, such as the amygdala and the hippocampus, regulate the autonomic system and the HPA responses. These centers include subpopulations of CRF containing neurons that, by way of CRF receptors, play modulatory roles in the emotional and cognitive aspects of stress. CRF binding protein also plays a role, buffering extracellular CRF and regulating its availability. CRF role in activation of the HPA is evolutionary conserved in vertebrates, highlighting the relevance of this system to help animals cope with adversity. However, knowledge on CRF systems in the avian telencephalon is very limited, and no information exists on detailed expression of CRF receptors and binding protein. Knowing that the stress response changes with age, with important variations during the first week posthatching, the aim of this study was to analyze mRNA expression of CRF, CRF receptors 1 and 2, and CRF binding protein in chicken telencephalon throughout embryonic and early posthatching development, using in situ hybridization. Our results demonstrate an early expression of CRF and its receptors in pallial areas regulating sensory processing, sensorimotor integration and cognition, and a late expression in subpallial areas regulating the stress response. However, CRF buffering system develops earlier in the subpallium than in the pallium. These results help to understand the mechanisms underlying the negative effects of noise and light during prehatching stages in chicken, and suggest that stress regulation becomes more sophisticated with age.

Recognition and Management of the Long-term Effects of Cranial Radiation.

Cranial radiation is ubiquitous in the treatment of primary malignant and benign brain tumors as well as brain metastases. Improvement in radiotherapy targeting and delivery has led to prolongation of survival outcomes. As long-term survivorship improves, we also focus on prevention of permanent side effects of radiation and mitigating the impact when they do occur. Such chronic treatment-related morbidity is a major concern with significant negative impact on patient's and caregiver's respective quality of life. The actual mechanisms responsible for radiation-induced brain injury remain incompletely understood. Multiple interventions have been introduced to potentially prevent, minimize, or reverse the cognitive deterioration. Hippocampal-sparing intensity modulated radiotherapy and memantine represent effective interventions to avoid damage to regions of adult neurogenesis. Radiation necrosis frequently develops in the high radiation dose region encompassing the tumor and surrounding normal tissue. The radiographic findings in addition to the clinical course of the patients' symptoms are taken into consideration to differentiate between tissue necrosis and tumor recurrence. Radiation-induced neuroendocrine dysfunction becomes more pronounced when the hypothalamo-pituitary (HP) axis is included in the radiation treatment field. Baseline and post-treatment evaluation of hormonal profile is warranted. Radiation-induced injury of the cataract and optic system can develop when these structures receive an amount of radiation that exceeds their tolerance. Special attention should always be paid to avoid irradiation of these sensitive structures, if possible, or minimize their dose to the lowest limit.

The role of phoenixin in the proliferation and migration of ectopic epithelial cells in vitro

AimEndometriosis is one of the most common gynecologic diseases in women of reproductive age. The pathophysiology of endometriosis is still not fully understood. Phoenixin (PNX-14) is a newly discovered neuropeptide that regulates the hypothalamo–pituitary–gonadal (HPG) axis and reproductive functions. Recently, we reported that PNX-14, its precursor protein and receptor were expressed in human endometrium. Moreover, PNX-14 serum levels in endometriosis were reduced. This study aimed to evaluate the in vitro biological functions of physiological PNX-14 concentrations on the ectopic endometrium Z12 cells. MethodsThe proliferation and migration of Z12 cells were assessed using the xCELLigence® RTCA DP system following 72 h of stimulation with 0.05 and 0.2 nM of PNX-14. GPR173 and small integral membrane protein 20 (SMIM20) gene expression was evaluated using quantitative polymerase chain reaction (qPCR) and the protein levels of GPR173 were analyzed using Western blot analysis. ResultsPNX-14 at the concentration observed in the serum of patients with endometriosis (0.05 nM) reduced GPR173 and increased SMIM20 expression, while protein levels of GPR173 remained unchanged. Cell proliferation was increased by the 0.02 nM PNX-14— the concentration found in healthy subjects. The 0.2 nM of PNX-14 decreased SMIM20 expression with no change to GPR173 expression and reduced ectopic epithelial cell proliferation during the first 5 h after stimulation. However, at 72 h, the proliferation increased. ConclusionsThis study shows that PNX-14 at endometriosis specific concentration desensitized ectopic epithelium to PNX-14, and increased the expression of SMIM20 to restore the physiological levels of PNX-14.

Effect of acute predator stress on learning and memory in a zebrafish model

Background: In zebrafish, the stress system is represented by the hypothalamo–pituitary–interrenal axis which is similar to human HPA axis. Several studies have reported that stress affects the learning and memory in humans and rodents. Like humans, zebrafish form spatial memories and its cholinergic system is involved in learning and memory. In one study, it has been reported that exposing zebrafish to its natural predator stress (Indian Leaf Fish) has resulted in significant behavioral response. Therefore, here, we propose this study to model learning and memory in zebrafish using predator stress. Aims and Objectives: The study aims to model learning and memory in zebrafish using predator stress and evaluate the influence of predator stress on learning and memory in zebrafish. Materials and Methods: 12 adult zebrafishes (Danio rerio) were divided into two groups: Stress group (n = 6) and control group (n = 6). Fish in the stress group individually was exposed to Indian leaf fish (predator stress) for 20 min (acute exposure) through live simulated video with audio intervention under completely closed environment without any entry of outside light source. Control group fish was not exposed to any stress. Plus maze learning session was conducted in both stress (before and after stress) and control fish, and short-term memory (STM) and long-term memory (LTM) were recorded. Results: Between day 1 and day 6 of training among the stress group and control group fishes, both showed a significant establishment of memory of the location of the food arm. The test group fishes showed significant changes in STM, immediately after exposure to the predator stress, but not in control group. LTM did not have any significant changes in both groups. Conclusion: Stress in the form of predator produced an acute change in STM established in these fishes. This effect in zebrafish observed could be effect of the traumatic event in the form of predator that the zebrafish is exposed to and that has resulted in an acute state of confusion and memory loss.

Chasing the Perplexing Purple Butterfly through Biopsychosocial Model-based Precision Medicine: the Enigma of Fibromyalgia Unraveled Biopsychosocial perspectives in fibromyalgia care

A purple butterfly symbolizes the heightened sensitivity to even a gentle touch in fibromyalgia (FM), which is a common syndrome with persistent widespread pain and tenderness. The biopsychosocial model is currently the main framework used to appreciate different factors contributing to chronic pain in FM. Widespread pain in fibromyalgia is effected by multiple biopsychosocial factors (cognitive ability, depression, somatization, psychological trauma, anxiety, and social deprivation/isolation), which interact and contribute to chronic persistent pain. Interaction of influences such as gender, neuroendocrine milieu, and the hypothalamo–pituitary–adrenal axis also affect FM susceptibility and its clinical expression. Multiple neuroanatomic and neurochemical systems with many autonomic, cognitive & affective processes manifest as multisymptom illness in FM. While the etiology of FM is elusive, the associated symptoms indicate the role of autonomic dysfunction in its pathophysiology. Fatigue and widespread pain characterizing FM may be consequent to peripheral tissue ischemia caused by sympathetically mediated vasoconstriction. In light of some common denominators among FM patients, which include genetic variation, sympathetic hyper-activation, maladaptive thoughts, ineffective coping strategies, and nonrestorative sleep, an individualized care approach can help subgroup and phenotype these patients for specific diagnosis and management. A multidisciplinary approach involving person-centered approaches to biopsychosocial concepts in FM, incorporating relaxation therapy, physical activity, and psychotherapy targeting negative emotions that amplify pain, maladaptive coping strategies, and environmental stressors, can help manage FM's course, outcomes, and treatment.

Changes in DNA Methylation of Clock Genes in Obese Adolescents after a Short-Term Body Weight Reduction Program: A Possible Metabolic and Endocrine Chrono-Resynchronization

Circadian rhythms are generated by a series of genes, collectively named clock genes, which act as a self-sustained internal 24 h timing system in the body. Many physiological processes, including metabolism and the endocrine system, are regulated by clock genes in coordination with environmental cues. Loss of the circadian rhythms has been reported to contribute to widespread obesity, particularly in the pediatric population, which is increasingly exposed to chronodisruptors in industrialized society. The aim of the present study was to evaluate the DNA methylation status of seven clock genes, namely clock, arntl, per1-3 and cry1-2, in a cohort of chronobiologically characterized obese adolescents (n: 45: F/M: 28/17; age ± SD: 15.8 ± 1.4 yrs; BMI SDS: 2.94 [2.76; 3.12]) hospitalized for a 3-week multidisciplinary body weight reduction program (BWRP), as well as a series of cardiometabolic outcomes and markers of hypothalamo-pituitary-adrenal (HPA) function. At the end of the intervention, an improvement in body composition was observed (decreases in BMI SDS and fat mass), as well as glucometabolic homeostasis (decreases in glucose, insulin, HOMA-IR and Hb1Ac), lipid profiling (decreases in total cholesterol, LDL-C, triglycerides and NEFA) and cardiovascular function (decreases in systolic and diastolic blood pressures and heart rate). Moreover, the BWRP reduced systemic inflammatory status (i.e., decrease in C-reactive protein) and HPA activity (i.e., decreases in plasma ACTH/cortisol and 24 h urinary-free cortisol excretion). Post-BWRP changes in the methylation levels of clock, cry2 and per2 genes occurred in the entire population, together with hypermethylation of clock and per3 genes in males and in subjects with metabolic syndrome. In contrast to the pre-BWRP data, at the end of the intervention, cardiometabolic parameters, such as fat mass, systolic and diastolic blood pressures, triglycerides and HDL-C, were associated with the methylation status of some clock genes. Finally, BWRP induced changes in clock genes that were associated with markers of HPA function. In conclusion, when administered to a chronodisrupted pediatric obese population, a short-term BWRP is capable of producing beneficial cardiometabolic effects, as well as an epigenetic remodeling of specific clock genes, suggesting the occurrence of a post-BWRP metabolic and endocrine chronoresynchronization, which might represent a "biomolecular" predictor of successful antiobesity intervention.

Expression of phoenixin-14 and nesfatin-1 in the hypothalamo–pituitary–gonadal axis in the phases of the estrous cycle

Phoenixin-14 (PNX-14) and nucleobindin 2 (NUCB2)/nesfatin-1 are regulatory neuropeptides expressed in the hypothalamus. These neuropeptides can be effective in hormonal regulation of the hypothalamo–pituitary–gonadal (HPG) axis and reproductive functions. In the present study, the distribution of PNX-14 and NUCB2/nesfatin-1 in the hypothalamus, pituitary, ovary, and uterus tissues during the phases of the estrous cycle in female rats was investigated. Eighteen Wistar Albino rats determined among animals showing regular estrous cycle by vaginal smear method were divided into three groups: proestrus (Group I), estrus (Group II) and diestrus (Group III). Serum gonadotropin-releasing hormone (GnRH), plasma PNX-14, and NUCB2/nesfatin-1 concentrations were the highest, moderate, and lowest in estrus, diestrus, and proestrus phases, respectively. PNX-14 immunoreactivity in the supraoptic and arcuate nuclei of the hypothalamus and NUCB2/nesfatin-1 immunoreactivity in the paraventricular nuclei were particularly evident in the estrus phase. These neuropeptide immunoreactivities were decreased in different cells of anterior pituitary during proestrus compared with those during estrus and diestrus. PNX-14 immunoreactivity in the ovary, especially during the estrus phase, was diffuse and intense in the granulosa and luteal cells and oocytes, and it was few and weak in theca cells. In addition, NUCB2/nesfatin-1 immunoreactivity was abundant and strong in granulosa and luteal cells, theca and interstitial cells, and oocytes during estrus. In the estrus phase, PNX-14 immunoreactivity was strong in the glandular epithelial cells and stromal cells of the endometrium, also NUCB2/nesfatin-1 immunoreactivity was strong in the epithelial and glandular epithelial cells. As a result, when the estrous cycle was evaluated, it was concluded that the changes in the distribution of PNX-14 and NUCB2/nesfatin-1 at all phases were related to GnRH and that these neuropeptides showed the highest immunoreactivity especially in the HPG axis and uterus tissues of estrus rats.

Genetic analysis of failed male puberty using whole exome sequencing.

Although at least 598 genes are involved in the development of the hypothalamo-pituitary-testicular (HPT) axis, mutations in only 75 genes have so far been shown to cause delayed puberty. Six male patients with failed puberty, manifested as absence of pubertal changes by 18 years of age, underwent whole exome sequencing of genomic DNA with subsequent bioinformatics analysis and confirmation of selected variants by Sanger sequencing. Genes having plausibly pathogenic non-synonymous variants were characterized as group A (previously reported to cause delayed puberty), group B (expressed in the HPT-axis but no mutations therein were reported to cause delayed puberty) or group C (not reported previously to be connected with HPT-axis). We identified variants in genes involved in GnRH neuron differentiation (2 in group A, 1 in group C), GnRH neuron migration (2 each in groups A and C), development of GnRH neural connections with supra-hypothalamic and hypothalamic neurons (2 each in groups A and C), neuron homeostasis (1 in group C), molecules regulating GnRH neuron activity (2 each in groups B and C), receptors/proteins expressed on GnRH neurons (1 in group B), signaling molecules (3 in group C), GnRH synthesis (1 in group B), gonadotropins production and release (1 each ingroups A, B, and C) and action of the steroid hormone (1in group A). Non-synonymous variants were identified in 16 genes of the HPT-axis, which comprised 4 in group A that contains genes previously reported to cause delayed puberty, 4 in group B that are expressed along HPT-axis but no mutations therein were reported previously to cause delayed puberty and 8 in group C that contains novel candidate genes, suggesting wider genetic causes of failed male puberty.

Effects of kisspeptin-10 on the reproductive performance of sows in a fixed-time artificial insemination programme

Kisspeptin (KP) is a major positive regulator of the hypothalamo–pituitary–gonadal axis and affects female reproductive cyclicity in mammals. It offers an attractive alternative strategy to control reproduction in fixed-time artificial insemination (FTAI) protocols. We aimed to evaluate the effects of different doses of kisspeptin-10 (KP-10) on sow reproductive performance in FTAI protocols. One hundred ninety-eight weaned sows were divided into three groups at random. A FTAI–GnRH group of sows (n = 98) received 100 µg (2 mL) gonadotropin-releasing hormone (GnRH; gonadorelin) by intramuscular injection at 96 h after weaning (t = 0 h); FTAI–KPL (KPL: low-dose KP-10, n = 50), and FTAI–KPH groups of sows (KPH: high-dose KP-10, n = 50) received 0.5 or 1 mg KP-10 (2 mL) respectively at 96 h after weaning. Sows were checked twice daily for oestrus. Ultrasonographic evaluations were performed to determine the follicular diameter and time of ovulation; blood samples were collected immediately before injection (t0 = 0 min) and at 15, 30, 45, 60, 75, 90 min, 24 and 48 h postinjection. Sows were inseminated at 112 and 132 h after weaning. The oestrus rates (96 vs 92%; 96 vs 88%) and weaning-to-oestrus intervals (98.9 vs 98.6 h; 98.9 vs 97.1 h) were not affected by treatment, but oestrus in the FTAI–KPL group was significantly longer than in the FTAI–GnRH group (38.7 vs 30.0 h; P < 0.05). The peak LH concentrations were 1.29 times greater than at t0 = 0 in the FTAI–GnRH group, and 1.45 and 1.44 times greater than at t0 = 0 in the FTAI–KPL and FTAI–KPH groups, respectively. Follicular diameters and pregnancy rates (86 vs 88%, 86 vs 80%, respectively) did not differ between the treatments. Moreover, the total numbers of piglets born and those born alive did not differ among the three groups. These findings suggested that 0.5 mg KP-10 given at 96 h after weaning could be used in FTAI programmes to manage batch farrowing in sows.

Differences in Corticosterone Release Rates of Larval Spring Salamanders (Gyrinophilus porphyriticus) in Response to Native Fish Presence.

Simple SummaryIn amphibians, glucocorticoid hormones play a key role in the response to predation stress. Predators can directly affect prey via injury and death, but they can also have indirect effects due to the activity of glucocorticoids. The regulation of glucocorticoids can differ between populations that have co-evolved with predators and those that have not. We measured glucocorticoids at baseline and in response to a novel stressor in free-living larval salamanders that either live with or without fish predators naturally. We found that salamanders living with fish predators had lower measures of glucocorticoids than those without fish predators. Our study indicates that predator presence alters glucocorticoid regulation, which may allow species to better cope with native and introduced predators.Invasive fish predators are an important factor causing amphibian declines and may have direct and indirect effects on amphibian survival. For example, early non-lethal exposure to these stressors may reduce survival in later life stages, especially in biphasic species. In amphibians, the glucocorticoid hormone corticosterone is released by the hypothalamo–pituitary–interrenal axis (HPI), as an adaptive physiological response to environmental stressors. The corticosterone response (baseline and response to acute stressors) is highly flexible and context dependent, and this variation can allow individuals to alter their phenotype and behavior with environmental changes, ultimately increasing survival. We sampled larvae of the spring salamander (Gyrinophilus porphyriticus) from two streams that each contained predatory brook trout (Slavelinus fontinalis) in the lower reaches and no predatory brook trout in the upper reaches. We measured baseline and stress-induced corticosterone release rates of larvae from the lower and upper reaches using a non-invasive water-borne hormone assay. We hypothesized that corticosterone release rates would differ between larvae from fish-present reaches and larvae from fish-free reaches. We found that baseline and stressor-induced corticosterone release rates were downregulated in larvae from reaches with fish predators. These results indicate that individuals from reaches with predatory trout are responding to fish predators by downregulating corticosterone while maintaining an active HPI axis. This may allow larvae more time to grow before metamorphosing, while also allowing them to physiologically respond to novel stressors. However, prolonged downregulation of corticosterone release rates can impact growth in post-metamorphic individuals.

Measurement of corticosterone in the plasma, eggs and faeces of laying hens

Context Stress responses in chickens are commonly assessed from measurements of corticosterone in blood, but there is an increasing research effort to develop non-blood means of assessing the activity of the hypothalamo–pituitary (HPA) axis. It is common to measure corticosterone in the eggs and faeces. Aims We extended previous work by undertaking a study of caged laying hens comparing basal concentrations of corticosterone in plasma, faeces, egg albumen and egg yolk on a between-cage basis. We tested the hypothesis that there are positive relationships between corticosterone in plasma and corticosterone in each of the other matrices. Methods Blood samples were collected from each bird at a single point in time. In Experiment 1, these comparisons (between plasma concentrations of corticosterone on Day 1 and egg albumen, egg yolk and faecal concentrations of corticosterone on Days 1, 3 and 4 of the study) were made for hens of two ages under basal conditions, whereas, in Experiment 2, the comparisons (between plasma concentrations of corticosterone on Day 3 and egg albumen, egg yolk and faecal concentrations of corticosterone on Days 1 and 2 of the study) were made for hens housed at different space allowances with and without access to a nest box. The birds without a nest box had not had experience with a nest box prior to sampling. Key results There was a statistically significant (P = 0.012), but limited, positive relationship between plasma and egg albumen concentrations of corticosterone under basal conditions in Experiment 2. There were no other statistically significant (P &gt; 0.05) relationships in either experiment. These results suggest that measures of corticosterone in the albumen, yolk and faeces of laying hens are unlikely to be robust predictors of basal concentrations of corticosterone in the blood. Conclusions Although there was some indication that concentrations of corticosterone in albumen may be related to concentrations in blood under basal conditions, based on all the results, this suggestion is made cautiously. Implications More comprehensive research is required to establish if measures of corticosterone in egg components and faeces are related to chronic basal activity of the hypothalamo–pituitary axis in laying hens. There is also a need to understand the impact of corticosterone on production, reproduction and welfare in hens from measures in both blood and non-blood matrices.

Clinical advances in the pharmacotherapy of congenital adrenal hyperplasia.

BackgroundPatients with 21-hydroxylase deficiency congenital adrenal hyperplasia (21OHD-CAH) have poor health outcomes with increased mortality, short stature, impaired fertility, and increased cardiovascular risk factors such as obesity. To address this, there are therapies in development that target the clinical goal of treatment, which is to control excess androgens with an adrenal replacement dose of glucocorticoid.MethodsNarrative review of publications on recent clinical developments in the pharmacotherapy of congenital adrenal hyperplasia.SummaryTherapies in clinical development target different levels of the hypothalamo–pituitary–adrenal axis. Two corticotrophin-releasing factor type 1 (CRF1) receptor antagonists, Crinecerfont and Tildacerfont, have been trialled in poorly controlled 21OHD-CAH patients, and both reduced ACTH and androgen biomarkers while patients were on stable glucocorticoid replacement. Improvements in glucocorticoid replacement include replacing the circadian rhythm of cortisol that has been trialled with continuous s.c. infusion of hydrocortisone and Chronocort, a delayed-release hydrocortisone formulation. Chronocort optimally controlled 21OHD-CAH in 80% of patients on an adrenal replacement dose of hydrocortisone, which was associated with patient-reported benefits including restoration of menses and pregnancies. Adrenal-targeted therapies include the steroidogenesis-blocking drug Abiraterone acetate, which reduced adrenal androgen biomarkers in poorly controlled patients.ConclusionsCRF1 receptor antagonists hold promise to avoid excess glucocorticoid replacement in patients not controlled on standard or circadian glucocorticoid replacement such as Chronocort. Gene and cell therapies are the only therapeutic approaches that could potentially correct both cortisol deficiency and androgen excess.

Mechanisms of Central Hypogonadism.

Reproductive function depends upon an operational hypothalamo–pituitary–gonadal (HPG) axis. Due to its role in determining survival versus reproductive strategies, the HPG axis is vulnerable to a diverse plethora of signals that ultimately manifest with Central Hypogonadism (CH) in all its many guises. Acquired CH can result from any pituitary or hypothalamic lesion, including its treatment (such as surgical resection and/or radiotherapy). The HPG axis is particularly sensitive to the suppressive effects of hyperprolactinaemia that can occur for many reasons, including prolactinomas, and as a side effect of certain drug therapies. Physiologically, prolactin (combined with the suppressive effects of autonomic neural signals from suckling) plays a key role in suppressing the gonadal axis and establishing temporary CH during lactation. Leptin is a further key endocrine regulator of the HPG axis. During starvation, hypoleptinaemia (from diminished fat stores) results in activation of hypothalamic agouti-related peptide neurons that have a dual purpose to enhance appetite (important for survival) and concomitantly suppresses GnRH neurons via effects on neural kisspeptin release. Obesity is associated with hyperleptinaemia and leptin resistance that may also suppress the HPG axis. The suppressibility of the HPG axis also leaves it vulnerable to the effects of external signals that include morphine, anabolic-androgenic steroids, physical trauma and stress, all of which are relatively common causes of CH. Finally, the HPG axis is susceptible to congenital malformations, with reports of mutations within >50 genes that manifest with congenital CH, including Kallmann Syndrome associated with hyposmia or anosmia (reduction or loss of the sense of smell due to the closely associated migration of GnRH with olfactory neurons during embryogenesis). Analogous to the HPG axis itself, patients with CH are often vulnerable, and their clinical management requires both sensitivity and empathy.

Effect of age at first egg on reproduction performance and characterization of the hypothalamo–pituitary–gonadal axis in chickens

As an important indicator of sexual maturity of hens, age at first egg (AFE) is significantly associated with reproduction performance. In this study, 400 hens were divided into 6 groups based on AFE to analyze the difference of reproduction performance, reproduction hormone levels and the characterization of the hypothalamo–pituitary–gonadal axis in chickens. The results showed that the egg production of the hens in the late-maturing groups was significantly lower than that of the ones in other groups and the precocious hens had a lower egg production rate. The hens in late-maturing group had a lower fertility rate, LH levels and shorter duration of peak of egg production (PEP), the precocious hens had lower PRL levels. In addition, the characterization of the hypothalamo–pituitary–gonadal axis showed that the individuals with normal AFE had higher GNRH, GNRHR, ESR1, KITLG, and CYP11A1 expression levels than late-maturing and precocious individuals, which indicated that the chickens with normal AFE advantages on reproduction regulation system.

Cortisol, chronotype, and coping styles as determinants of tolerance of nursing staff to rotating shift work

ABSTRACT Hypothalamo–pituitary–adrenal axis activity and cortisol patterns are likely to play a role in shift work tolerance, i.e., ability to adapt to shift work without suffering stress-related consequences. Yet, the evidence is scanty. Here, salivary cortisol output during night shifts and leisure days was assessed in fast-forward rotating shift work nursing staff (N = 30), and possible links with a series of variables – gender (30% male), age (M = 39.6, SEM = 1.57 y), years of service (M = 12.43, SEM = 1.48 y), BMI (M = 23.29, SEM = 0.66 Kg/m2), self-rated chronotype, sleep quality, and psycho-behavioral factors – were investigated. Main results show that cortisol output during night shifts: i) is larger in morning-oriented chronotypes, thus affected by the circadian misalignment between biological and working rhythms; ii) associates with dysfunctional coping styles at work; iii) positively correlates with diurnal cortisol secretion on leisure days, i.e., individuals with larger cortisol output during shifts display higher cortisol secretion on non-working days. Chronotype and psycho-behavioral factors explain most of the correlational weight linking cortisol output during the night shift and off-days. In conclusion, we confirm salivary cortisol testing as a suitable objective marker of occupational stress and propose it as a valuable index for monitoring shift work tolerance, in combination with chronotype. Moreover, we emphasize the importance of evaluating psycho-behavioral factors in professional settings, because these modifiable variables can be addressed with tailored psychological interventions to ameliorate poor job satisfaction, reduce work-related distress, and avoid chronic cortisol excess experienced by shift workers.

Chapter 6 - The hypothalamo–pituitary–adrenal axis and the autonomic nervous system in burnout

Burnout constitutes a serious health concern in the modern working environment. It is a stress-related condition that has developed as a result of a prolonged psychosocial stress exposure causing a persistent mismatch between demands and resources. The main symptom is emotional exhaustion, but physical fatigue, diminished professional efficacy, cynicism, and cognitive impairments are also associated with this condition. Burnout has been used both as a psychologic term in occupational settings and as a clinical diagnosis in patient populations, and there is currently no universally accepted definition and diagnostic criteria of burnout. It has been hypothesized that the two main stress response systems, the autonomic nervous system (ANS) and the hypothalamus-pituitary-adrenal axis (HPA axis), are involved in the pathogenesis of burnout. A common hypothesis is that in the early stages of chronic stress, the HPA axis and sympathetic ANS activity tend to be higher, while it will decrease with a longer duration of chronic stress to ultimately reach a state of hypoactivity in clinical burnout. The current research in this field shows many contradictory results. Thus there is no compelling evidence of either ANS or HPA dysfunction in burnout. However, there is partial support for the hypothesis of HPA and sympathetic hyperactivity in early stages, and HPA hyporeactivity and low vagal activity in more severe burnout cases, but high-quality studies investigating the causal links are still lacking.

MANAGEMENT OF ENDOCRINE DISEASE: Thyroid and female infertility: more questions than answers?!

Severe thyroid dysfunction may lead to menstrual disorders and infertility via direct and indirect interactions with the hypothalamo-pituitary-ovarian axis and the reproductive organs. However, the exact prevalence of infertility in women with thyroid disorders remains unknown. Fertility problems may persist even after restoring normal thyroid function, and then surgery and/or an assisted reproductive technology (ART) may be necessary to obtain a pregnancy. The initial step in an ART treatment is the ovarian stimulation, putting strain on the thyroid gland, potentially leading to (permanent) hypothyroidism in women with thyroid autoimmunity (TAI) or when already treated with thyroid hormones (LT4). Moreover, women with ovarian and unexplained causes of infertility have a higher prevalence of TAI. In women treated with LT4, a serum TSH level <2.5 mIU/L should be targeted before ART. In women with TSH levels >4.0 mIU/L, fertilisation rates, embryo quality and live birth rates may be impaired but also improved with LT4 therapy. In euthyroid women with TAI, LT4 should not be given systematically, but on a case-by-case basis if serum TSH is >2.5 mIU/L. For all of the above reasons, women of infertile couples should be screened routinely for the presence of thyroid disorders. In this review, we will focus on the gaps in the current knowledge, the remaining questions on the associations between thyroid (disorders) and (assisted) reproduction and make proposals for future investigations that may lead to a better understanding and contribute to novel treatment options in the long term.