The Hypothalamus-pituitary-adrenocortical Response to Critical Illness: A Concept in Need of Revision.

Based on insights obtained during the past decade, the classical concept of an activated hypothalamus-pituitary-adrenocortical axis in response to critical illness is in need of revision. After a brief central hypothalamus-pituitary-adrenocortical axis activation, the vital maintenance of increased systemic cortisol availability and action in response to critical illness is predominantly driven by peripheral adaptations rather than by an ongoing centrally activated several-fold increased production and secretion of cortisol. Besides the known reduction of cortisol-binding proteins that increases free cortisol, these peripheral responses comprise suppressed cortisol metabolism in liver and kidney, prolonging cortisol half-life, and local alterations in expression of 11ßHSD1, glucocorticoid receptor-α (GRα), and FK506 binding protein 5 (FKBP51) that appear to titrate increased GRα action in vital organs and tissues while reducing GRα action in neutrophils, possibly preventing immune-suppressive off-target effects of increased systemic cortisol availability. Peripherally increased cortisol exerts negative feed-back inhibition at the pituitary level impairing processing of pro-opiomelanocortin into ACTH, thereby reducing ACTH-driven cortisol secretion, whereas ongoing central activation results in increased circulating pro-opiomelanocortin. These alterations seem adaptive and beneficial for the host in the short term. However, as a consequence, patients with prolonged critical illness who require intensive care for weeks or longer may develop a form of central adrenal insufficiency. The new findings supersede earlier concepts such as "relative," as opposed to "absolute," adrenal insufficiency and generalized systemic glucocorticoid resistance in the critically ill. The findings also question the scientific basis for broad implementation of stress dose hydrocortisone treatment of patients suffering from acute septic shock solely based on assumption of cortisol insufficiency.

[Physiology of the Hypothalamic-Pituitary Axis].

The hypothalamus is part of the diencephalon and regulates not only endocrine functions but also various physiological functions, including controlling sleep and wakefulness, eating and drinking, and regulating body temperature. The pituitary gland can be divided into the adenohypophysis and neurohypophysis based on its developmental origin. The hypothalamus and pituitary gland play important roles in maintaining homeostasis by closely coordinating hormones. In the treatment of hypothalamic and pituitary diseases, it is important to understand the functions of the hypothalamus and pituitary gland, preserve hypothalamic function, evaluate the endocrine function, and follow up appropriately throughout life, including hormone replacement without excess or deficiency. Additionally, when interpreting hormone data, it is necessary to understand the factors that influence test values.

A procedure in mice to obtain intact pituitary-infundibulum-hypothalamus preparations: a method to evaluate the reconstruction of hypothalamohypophyseal system.

PURPOSE: The histopathological study of brain tissue is a common method in neuroscience. However, efficient procedures to preserve the intact hypothalamic-pituitary brain specimens are not available in mice for histopathological study. METHOD: We describe a detailed procedure for obtaining mouse brain with pituitary-hypothalamus continuity. Unlike the traditional methods, we collect the brain via a ventral approach. We cut the intraoccipital synchondrosis, transection the endocranium of pituitary, broke the spheno-occipital synchondrosis, expose the posterior edge of pituitary, separate the trigeminal nerve, then the intact pituitary gland was preserved. RESULT: We report an more effective and practical method to obtain continuous hypothalamus -pituitary preparations based on the preserve of leptomeninges. COMPARED WITH THE EXISTING METHODS: Our procedure effectively protects the integrity of the fragile infundibulum preventing the pituitary from separating from the hypothalamus. This procedure is more convenient and efficient. CONCLUSION: We present a convenient and practical procedure to obtain intact hypothalamic-pituitary brain specimens for subsequent histopathological evaluation in mice.

The Pituitary-Adrenal Response to Paradoxical Sleep Deprivation Is Similar to a Psychological Stressor, Whereas the Hypothalamic Response Is Unique.

Stressors of different natures induce activation of the hypothalamic-pituitary-adrenal (HPA) axis at different magnitudes. Moreover, the HPA axis response to repeated exposure is usually distinct from that elicited by a single session. Paradoxical sleep deprivation (PSD) augments ACTH and corticosterone (CORT) levels, but the nature of this stimulus is not yet defined. The purpose of the present study was to qualitatively compare the stress response of animals submitted to PSD to that of rats exposed once or four times to cold, as a physiological stress, movement restraint (RST) as a mixed stressor and predator odour (PRED) as the psychological stressor, whilst animals were submitted for 1 or 4 days to PSD and respective control groups. None of the stressors altered corticotropin releasing factor immunoreactivity in the paraventricular nucleus of the hypothalamus (PVN), median eminence (ME) or central amygdala, compared to control groups, whereas vasopressin immunoreactivity in PSD animals was decreased in the PVN and increased in the ME, indicating augmented activity of this system. ACTH levels were higher after repeated stress or prolonged PSD than after single- or 1 day-exposure and control groups, whereas the CORT response was habituated by repeated stress, but not by 4-days PSD. This dissociation resulted in changes in the CORT : ACTH ratio, with repeated cold and RST decreasing the ratio compared to single exposure, but no change was seen in PRED and PSD groups. Comparing the magnitude and pattern of pituitary-adrenal response to the different stressors, PSD-induced responses were closer to that shown by PRED-exposed rats. In contrast, the hypothalamic response of PSD-exposed rats was unique, inasmuch as this was the only stressor which increased the activity of the vasopressin system. In conclusion, we propose that the pituitary-adrenal response to PSD is similar to that induced by a psychological stressor.

Impact of blue light therapy on plasma adrenocorticotropic hormone (ACTH) and hypertrichosis in horses with pituitary pars intermedia dysfunction.

Blue light therapy can be used in horses to alter the natural photoperiod and inhibit winter hair coat growth. Seasonal increases in ACTH occur in the fall season but are exaggerated in horses with pituitary pars intermedia dysfunction (PPID). Additionally, PPID horses frequently present with hypertrichosis. Thus, blue light therapy was proposed as a potential management tool for hypertrichosis and for investigating the impact of photoperiod manipulation on ACTH. Eighteen PPID horses, aged 18 to 31 yr, from a university-owned research herd were selected and assigned to either the control group (n = 10) or the treatment (blue light therapy) group (n = 8) based on age and clinical history, which included the results of multiple endocrine tests. Consistent daylength of approximately 14.5 h was maintained for the treated horses from July 15 through approximately late October via the extension of natural daylength using wearable masks that provided short wavelength blue light (465 nm) to 1 eye. The control group was exposed to only the natural photoperiod during this time. All horses were housed on the same farm and remained on pasture for the duration of the study. On Day 0, thyrotropin-releasing hormone (TRH) stimulation tests were performed to confirm PPID status; there were no differences between the 2 groups in resting plasma ACTH or plasma ACTH at 10 min after TRH administration. To determine an effect of treatment on ACTH, blood was collected via jugular venipuncture for measurement of ACTH at sequential timepoints over a 16-h period in mid-October. Hair weights were also assessed throughout the study. No differences in resting plasma ACTH were observed between the 2 groups across the seasonal analysis (July and October) or during the 16-h testing. The PPID horses receiving blue light therapy had lighter hair weights compared to the PPID control horses. These results suggest that blue light therapy does not alter ACTH concentrations but could potentially be used as an additional management tool for hypertrichosis in PPID horses. Manipulation of the photoperiod using blue light therapy did not affect seasonal changes in ACTH in this study.

Hypothalamic-Pituitary Autoimmunity and Related Impairment of Hormone Secretions in Chronic Fatigue Syndrome.

CONTEXT: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a severe chronic illness that reduces the quality of life. A potential role of neuroendocrine autoimmune dysfunction has been hypothesized. OBJECTIVE: This work aims to investigate the occurrence of antipituitary (APA) and antihypothalamic (AHA) antibodies and possible related hypothalamic/pituitary dysfunctions in ME/CSF patients. METHODS: This is a case-control study conducted in a university hospital setting (Stanford, California, USA; and Naples, Italy). Thirty women with ME/CSF (group 1) diagnosed according to Fukuda, Canadian, and Institute of Medicine criteria, at Stanford University, were enrolled and compared with 25 age-matched healthy controls. APA and AHA were detected by immunofluorescence; moreover, we investigated hormonal secretions of anterior pituitary and respective target glands. APA and AHA titers both were assessed and the prevalence of pituitary hormone deficiencies was also investigated. RESULTS: Patients in group 1 showed a high prevalence of AHA (33%) and APA (56%) and significantly lower levels of adrenocorticotropin (ACTH)/cortisol, and growth hormone (GH) peak/insulin-like growth factor-1 (IGF-1) vs controls (all AHA/APA negative). Patients in group 1A (13 patients positive at high titers, ≥ 1:32) showed ACTH/cortisol and GH peak/IGF-1 levels significantly lower and more severe forms of ME/CFS with respect to patients in group 1B (7 positive at middle/low titers, 1:16-1:8) and 1C (10 antibody-negative patients). CONCLUSION: Both AHA and/or APA at high titers were associated with hypothalamic/pituitary dysfunction, suggesting that hypothalamic/pituitary autoimmunity may play an important role in the manifestations of ME/CFS, especially in its more severe forms.

Hypothalamitis and pituitary atrophy.

Hypothalamitis is a rare inflammatory disorder involving the hypothalamus and classified as primary, or isolated, and secondary hypothalamitis. Secondary hypothalamitis although very rare is more common than the primary one and may occur in patients affected by autoimmune diseases such as autoimmune hypophysitis, systemic autoimmune diseases, infective diseases in patients affected by immune-deficit, paraneoplastic encephalitis, or in patients treated with immune checkpoint inhibitors. In accordance with the rarity of this disease, diagnosis and management of hypothalamitis prove to be challenging. The diagnosis requires a high index of clinical suspicion. The main symptoms may be: various degrees of hypopituitarism, neuropsychiatric and behavioral disorders, and disturbances of autonomic and metabolic regulation. Magnetic resonance images play a crucial role in the diagnosis of hypothalamitis and in the exclusion of a neoplastic lesion. Therapeutic management should be oriented according to the disease etiology. In most cases, after ruling out infective hypothalamitis, the mainstay of therapy consists of immunosuppressive treatment. Great attention should be paid to hormonal replacement therapy, if partial or total hypopituitarism is present, in particular in patients affected by diabetes insipidus, central hypoadrenalism and hypothyroidism. According to the complexity of this disease, a multidisciplinary approach is strongly advocated to reach an early diagnosis and an integrated therapy.

Antibodies against the pituitary and hypothalamus in boxers.

Traumatic brain injury (TBI), a growing public health problem worldwide, has recently been recognized as one of the leading causes of hypopituitarism. The main causes of TBI-induced pituitary dysfunction are car accidents, falls, violence, sports-related brain injury, and war accidents, including blast-related brain injuries. Car accidents and falls are the most common causes of TBI and pituitary dysfunction among the younger generation and elderly population, respectively. The prevalence of hypopituitarism after TBI is about 30%. GH is the most common hormone lost. The mechanisms underlying hypopituitarism are still unclear; however, recent studies have demonstrated that hypoxic insult, increased intracranial pressure, axonal injury, genetic predisposition, neuroinflammation, and autoimmunity may be responsible for the development of pituitary dysfunction. Neuroendocrine abnormalities are recently described in athletes dealing with contact sports, including boxing and kickboxing, which are characterized by chronic repetitive head trauma. Mild TBI and concussion are accepted in boxing and kickboxing. The positivity of antipituitary and antihypothalamic antibodies is also a significant risk factor in the development of neuroendocrine abnormalities. Autoimmune reaction may also be responsible for the reduction in pituitary volume in boxers with hypopituitarism. In this chapter, the role of autoimmunity in the occurrence of pituitary dysfunction among boxers is discussed.

Hypothalamic-Pituitary Outcome after Treatment for Childhood Craniopharyngioma.

Although childhood-onset craniopharyngioma is a low-grade intracranial tumor with excellent prognosis in terms of overall survival, survivors may suffer from devastating consequences caused by hypothalamic damage. Disease- or treatment-related hypothalamic damage leads to disturbed hunger-satiety and thirst feelings, decreased energy expenditure, behavioral problems, disturbances of circadian rhythm, temperature dysregulation, and pituitary dysfunction. These children are at great risk for developing the metabolic syndrome and comorbidities leading to premature mortality. In this chapter, we shall discuss hypothalamic-pituitary morbidity and outcome of childhood-onset craniopharyngioma patients and future perspectives for improvement.

Requirement of FAT and DCHS protocadherins during hypothalamic-pituitary development.

Pituitary developmental defects lead to partial or complete hormone deficiency and significant health problems. The majority of cases are sporadic and of unknown cause. We screened 28 patients with pituitary stalk interruption syndrome (PSIS) for mutations in the FAT/DCHS family of protocadherins that have high functional redundancy. We identified seven variants, four of which putatively damaging, in FAT2 and DCHS2 in six patients with pituitary developmental defects recruited through a cohort of patients with mostly ectopic posterior pituitary gland and/or pituitary stalk interruption. All patients had growth hormone deficiency and two presented with multiple hormone deficiencies and small glands. FAT2 and DCHS2 were strongly expressed in the mesenchyme surrounding the normal developing human pituitary. We analyzed Dchs2-/- mouse mutants and identified anterior pituitary hypoplasia and partially penetrant infundibular defects. Overlapping infundibular abnormalities and distinct anterior pituitary morphogenesis defects were observed in Fat4-/- and Dchs1-/- mouse mutants but all animal models displayed normal commitment to the anterior pituitary cell type. Together our data implicate FAT/DCHS protocadherins in normal hypothalamic-pituitary development and identify FAT2 and DCHS2 as candidates underlying pituitary gland developmental defects such as ectopic pituitary gland and/or pituitary stalk interruption.

Clinical impact of hypothalamic-pituitary disorders after conformal radiation therapy for pediatric low-grade glioma or ependymoma.

BACKGROUND: To determine the impact of hypothalamic-pituitary (HP) disorders on health outcomes in children and adolescents who received conformal radiation therapy (RT) for central nervous system tumors. PROCEDURE: Cohort study including 355 patients (age ≤25 years at diagnosis) treated with high-dose (50.4-59.4 Gy) RT using photons for low-grade glioma or ependymoma. Patients (median age, 6.4 years at RT) received systematic endocrine follow-up (median duration, 10.1 years; range, 0.1-19.6). Associations between HP disorders and adverse health outcomes were determined by multivariable analysis. RESULTS: Prevalence was 37.2% for growth hormone deficiency (GHD), 17.7% for gonadotropin deficiency (LH/FSHD), 14.9% for thyroid-stimulating hormone deficiency (TSHD), 10.3% for adrenocorticotropic hormone deficiency (ACTHD), and 12.6% for central precocious puberty (CPP). Hypothalamus mean dose ≥ 36 Gy was associated with higher odds of any deficiency. GHD was associated with short stature (OR 2.77; 95% CI 1.34-5.70), low bone mineral density (OR 3.47; 95% CI 1.16-10.40), and TSHD with dyslipidemia (OR 5.54; 95% CI 1.66-18.52). Patients with ACTHD and CPP had lower intelligence quotient scores, and memory scores were impaired in patients with GHD (P = 0.02). Treatment of GHD was not associated with increased risk for tumor recurrence, secondary tumors, or mortality. CONCLUSIONS: HP disorders occur frequently in patients receiving high-dose RT and are related to physical and neurocognitive well-being. Future studies are needed to assess whether further optimization of endocrine management yields better health outcomes.

Langerhans Cell Histiocytosis Involving Second Cervical Vertebra and the Hypothalamus and Pituitary in an Adult.

BACKGROUND: Adult-onset Langerhans cell histiocytosis (LCH) with simultaneous involvement of the high cervical spine and the hypothalamus is rare. CASE DESCRIPTION: We have reported a case of adult-onset LCH in the second cervical vertebra with bony destruction and subsequent diabetes insipidus due to simultaneous involvement of the hypothalamus and pituitary stalk. Magnetic resonance imaging of the hypothalamus and pituitary lesion and immunohistochemistry of the cervical lesion revealed LCH. Posterior fusion of the cervical spine (first, third, and fourth cervical vertebrae) was performed, followed by systemic chemotherapy. The cervical fusion was well maintained, and the patient achieved clinical remission. No new LCH lesion was found during the follow-up of >2 years. CONCLUSIONS: Patients with known LCH of the spine showing new symptoms of diabetes insipidus should be examined for infiltrating lesions of the pituitary stalk or hypothalamus. In cases of severe instability of the spine, surgical treatment should be performed. If multiple and systemic LCH lesions are found, systemic chemotherapy should be administered.

Pituitary society guidance: pituitary disease management and patient care recommendations during the COVID-19 pandemic-an international perspective.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the viral strain that has caused the coronavirus disease 2019 (COVID-19) pandemic, has presented healthcare systems around the world with an unprecedented challenge. In locations with significant rates of viral transmission, social distancing measures and enforced 'lockdowns' are the new 'norm' as governments try to prevent healthcare services from being overwhelmed. However, with these measures have come important challenges for the delivery of existing services for other diseases and conditions. The clinical care of patients with pituitary disorders typically involves a multidisciplinary team, working in concert to deliver timely, often complex, disease investigation and management, including pituitary surgery. COVID-19 has brought about major disruption to such services, limiting access to care and opportunities for testing (both laboratory and radiological), and dramatically reducing the ability to safely undertake transsphenoidal surgery. In the absence of clinical trials to guide management of patients with pituitary disease during the COVID-19 pandemic, herein the Professional Education Committee of the Pituitary Society proposes guidance for continued safe management and care of this population.

Antibodies Against Hypothalamus and Pituitary Gland in Childhood-Onset Brain Tumors and Pituitary Dysfunction.

Purpose: To detect the presence of antipituitary (APA) and antihypothalamus antibodies (AHA) in subjects treated for brain cancers, and to evaluate their potential association with pituitary dysfunction. Methods: We evaluated 63 patients with craniopharyngioma, glioma, and germinoma treated with surgery and/or radiotherapy and/or chemotherapy at a median age of 13 years. Forty-one had multiple pituitary hormone deficiencies (MPHD), six had a single pituitary defect. GH was the most common defect (65.1%), followed by AVP (61.9%), TSH (57.1%), ACTH (49.2%), and gonadotropin (38.1%). APA and AHA were evaluated by simple indirect immunofluorescence method indirect immunofluorescence in patients and in 50 healthy controls. Results: Circulating APA and/or AHA were found in 31 subjects (49.2%) and in none of the healthy controls. In particular, 25 subjects out of 31 were APA (80.6%), 26 were AHA (83.90%), and 20 were both APA and AHA (64.5%). Nine patients APA and/or AHA have craniopharyngioma (29%), seven (22.6%) have glioma, and 15 (48.4%) have germinoma. Patients with craniopharyngioma were positive for at least one antibody in 39.1% compared to 33.3% of patients with glioma and to 78.9% of those with germinoma with an analogous distribution for APA and AHA between the three tumors. The presence of APA or AHA and of both APA and AHA was significantly increased in patients with germinoma. The presence of APA (P = 0.001) and their titers (P = 0.001) was significantly associated with the type of tumor in the following order: germinomas, craniopharyngiomas, and gliomas; an analogous distribution was observed for the presence of AHA (P = 0.002) and their titers (P = 0.012). In addition, we found a significant association between radiotherapy and APA (P = 0.03). Conclusions: Brain tumors especially germinoma are associated with the development of hypothalamic-pituitary antibodies and pituitary defects. The correct interpretation of APA/AHA antibodies is essential to avoid a misdiagnosis of an autoimmune infundibulo-neurohypophysitis or pituitary hypophysitis in patients with germinoma.

Relationships of inflamm-aging with circulating nutrient levels, body composition, age, and pituitary pars intermedia dysfunction in a senior horse population.

Similarly to aged humans, senior horses (≥20 years) exhibit chronic low-grade inflammation systemically, known as inflamm-aging. Inflamm-aging in the senior horse has been characterized by increased circulating inflammatory cytokines as well as increased inflammatory cytokine production by lymphocytes and monocytes in response to a mitogen. Little is currently known regarding underlying causes of inflamm-aging. However, senior horses are also known to present with muscle wasting and often the endocrinopathy pituitary pars intermedia dysfunction (PPID). Despite the concurrence of these phenomena, the relationships inflamm-aging may have with measures of body composition and pituitary function in the horse remain unknown. Furthermore, nutrition has been a focus of research in an attempt to promote health span as well as life span in senior horses, with some nutrients, such as omega-3 fatty acids, having known anti-inflammatory effects. Thus, an exploratory study of a population of n = 42 similarly-managed senior horses was conducted to determine relationships between inflamm-aging and measures of circulating nutrients, body composition, age, and PPID. Serum was collected to determine vitamin, mineral, and fatty acid content. Peripheral blood mononuclear cells were also isolated to determine inflammatory cytokine production of interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α) following stimulation with a mitogen, as well as to determine gene expression of interleukin(IL)-1ß, IL-6, IL-10, IFN-γ, and TNF-α. Serum IL-6 and C-reactive protein were determined by enzyme-linked immunosorbent assay. Whole blood was collected for hematological and biochemical analysis. Body composition was evaluated via ultrasound and muscle scoring for all 42 horses as well as by deuterium oxide dilution for a subset of n = 10 horses. Pituitary function was evaluated by measuring basal adrenocorticotropin hormone concentrations as well as by thyrotropin releasing hormone stimulation testing (to determine PPID status). Results showed various relationships between inflammatory markers and the other variables measured. Most notably, docosadienoic acid (C22:2n6c), docosapentaenoic acid (C22:5n3c), and folate were positively associated with numerous inflammatory parameters (P ≤ 0.05). Although no relationships were found between inflamm-aging and PPID, being positive for PPID was negatively associated with vitamin B12 (P ≤ 0.01). No relationships between inflammation and body composition were found. Even within this senior horse population, age was associated with multiple parameters, particularly with numerous inflammatory cytokines and fatty acids. In summary, inflamm-aging exhibited relationships with various other parameters examined, particularly with certain fatty acids. This exploratory study provides insights into physiological changes associated with inflamm-aging in the senior horse.