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In recent years, the adverse effects of cadmium (Cd 2+ ) on aquatic systems have attracted much attention because Cd 2+ can induce endocrine disorders and toxicity in aquatic organisms at low levels. However, its effects on the thyroid system in native fish in Lhasa are still unclear. In the present study, Schizopygopsis younghusbandi larvae were exposed to Cd 2+ (0.25, 2.5, 25 or 250 μg/L) for 7 or 14 days to determine its toxic effects on thyroid function. The results showed that whole-body total T4 and T3 levels were significantly decreased, which was accompanied by the significant upregulation of the expression of the dio1 and dio2 genes after exposure to Cd 2+ for 7 or 14 days. Genes related to thyroid hormone synthesis (crh and tshβ) were upregulated after both 7 and 14 days of Cd 2+ exposure, possibly due to the negative feedback regulation of the hypothalamic-pituitary-thyroid (HPT) axis caused by a decrease in thyroid hormone. In addition, survival rates and body lengths were reduced after treatment with Cd 2+ . This suggests that Cd 2+ caused developmental toxicity in Schizopygopsis younghusbandi larvae. An integrated assessment of biomarker response (IBR) showed that there were dose-dependent and time-dependent effects of Cd 2+ exposure on Schizopygopsis younghusbandi larvae. Schizopygopsis younghusbandi larvae were sensitive to Cd 2+ , which caused adverse effects at a concentration as low as 2.5 μg/L. In summary, the results indicated that Cd 2+ causes thyroid disruption and developmental toxicity in Schizopygopsis younghusbandi larvae and that wild Schizopygopsis younghusbandi larvae living in the Lhasa River are at potential ecological risk., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interest or personal relationship that could have appeared to influence the work reported in this paper., (Copyright © 2020. Published by Elsevier Inc.)

Introduction: Craniopharyngiomas (CPs) are benign histological tumors that may develop at different positions along the hypothalamic-pituitary axis. Their close, heterogenous relationship to the hypothalamus makes surgical removal challenging even though this remains the primary treatment strategy., Areas Covered: This article presents a critical overview of the pathological and clinical concepts regarding CPs that should be considered when planning treatment. Thus, we have performed a comprehensive review of detailed CP reports published between 1839 and 2020., Expert Opinion: CP surgery should pursue maximal tumor resection while minimizing the risk of injuring the hypothalamus. Therefore, surgical strategies should be individualized for each patient. Accurate assessment of presenting symptoms and preoperative MRI has proven useful to predict the type of CP-hypothalamus relationship that will be found during surgery. CPs with dense and extensive adhesions to the hypothalamus should be highly suspected when MRI shows the hypothalamus positioned around the mid-third of the tumor and an amputated upper portion of the pituitary stalk. Symptoms related to functional impairment of the infundibulo-tuberal area of the third ventricle floor, such as obesity/hyperphagia, Fröhlich's syndrome, diabetes insipidus, and/or somnolence, also indicate risky CP-hypothalamic adhesions. In these cases, limited tumor removal is strongly advocated followed by radiation therapy.

Backgrounds Limitations in the evaluation of the pituitary size and changes according to pubertal status make its validity questionable. Recently, in a small-scale study, pons ratio (PR) has been suggested as a more sensitive tool for diagnosis and etiological evaluation of growth hormone deficiency (GHD). The aim of the study is to evaluate the diagnostic value of PR in the diagnosis of GHD. Methods We retrospectively evaluated the pituitary magnetic resonance imaging (MRI) of 133 patients with a diagnosis of GHD. Primary axis (PA) was assigned as a line crossing the mid-sagittal dorsum sella and fourth ventricle. PR was defined as the pons height above the PA divided by total pons height. The PR of patients with GHD was compared to subjects without GHD. Results Study included 133 patients with GHD and 47 controls. In total, 121 (91%) patients had isolated GHD and 12 (9%) patients had multiple pituitary hormone deficiency. The PR of the patient group (mean: 0.32 ± 0.89; range: 0.14-0.63) was significantly higher than controls (mean: 0.26 ± 0.067; range 0.19-0.44) (p: 0.000). The optimal cut-off value of PR for GHD diagnosis was 0.27 (sensitivity 71% specificity 56%). There was a negative correlation between anterior pituitary height (APH)-SDS and PR (p: 0.002; r: -0.27). APH was increased, but PR remained unchanged in pubertal patients (p: 0.089). Conclusions PR measurement is a noninvasive, practical method with a cost-benefit clinical value. As it is not affected by pubertal status, PR is potentially a more sensitive tool for evaluation of pituitary gland in GHD patients compared to APH.

Background: Cranial radiotherapy (cRT) can induce hormonal deficiencies as a consequence of significant doses to the hypothalamic-pituitary (HP) axis. In contrast to profound endocrinological follow-up data from survivors of childhood cancer treated with cRT, little knowledge exists for adult cancer patients., Methods: A systematic search of the literature was conducted using the PubMed database and the Cochrane library offering the basis for our debate of the relevance of HP axis impairment after cRT in adult cancer patients. Against the background of potential relevance for patients receiving whole brain radiotherapy (WBRT), a particular focus was set on the temporal onset of hypopituitarism and the radiation dose to the HP axis., Results: Twenty-eight original papers with a total of 1728 patients met the inclusion criteria. Radiation doses to the HP area ranged from 4 to 97 Gray (Gy). Hypopituitarism incidences ranged from 20 to 93% for adult patients with nasopharyngeal cancer or non-pituitary brain tumors. No study focused particularly on hypopituitarism after WBRT. The onset of hypopituitarism occurred as early as within the first year following cRT (range: 3 months to 25.6 years). However, since most studies started follow-up evaluation only several years after cRT, early onset of hypopituitarism might have gone unnoticed., Conclusion: Hypopituitarism occurs frequently after cRT in adult cancer patients. Despite the general conception that it develops only after several years, onset of endocrine sequelae can occur within the first year after cRT without a clear threshold. This finding is worth debating particularly in respect of treatment options for patients with brain metastases and favorable survival prognoses.

Background: Diabetes is a devastating metabolic disease that causes long-term damage to various organs. An important leading complication of diabetes is a degenerative effect on the reproductive system including infertility and gonadal dysfunction. This study aimed to evaluate the effects of experimental type I and II diabetes on the levels of luteinizing hormone (LH), follicle-stimulating hormone (FSH), and testosterone., Methods: Male Wistar rats were randomly divided into four separate groups: (1) type I diabetes (T1DM), (2) type II diabetes (T2DM), (3) cetrorelix acetate-treated nondiabetic control group, and (4) normal untreated group (n = 6). T1DM was experimentally induced by a single injection of alloxan (135 mg/kg) while T2DM was induced by feeding the animals with drinking water enriched with fructose (10%). Cetrorelix acetate (100 mg/kg, intraperitoneal for 1 week) treatment group was used as a positive control. All rats were killed and blood and testes were collected after 8 weeks of the study. The effects of induced diabetes on the levels of blood glucose and insulin were assessed. The levels of sex hormones and insulin were determined by radioimmunoassay. Histological staining was used to check abnormal patterns of testicular morphology, the diameter of seminiferous tubules, testicular diameter, and germinal layer thickness., Results: A significant reduction in the testosterone, FSH, and LH levels were observed in T1DM, T2DM, and also in cetrorelix acetate-treated groups. Analysis of testicular histology sections revealed significantly reduced thickness of cell layer in T1DM and cetrorelix acetate-treated groups compared with the T2DM group. In T2DM, the cell numbers, the thickness of cell layer, the diameter of seminiferous tubules, and weight of testicles were slightly increased. In contrast, total tubules of empty seminiferous increased significantly in T1D and cetrorelix treated groups compared with the control group., Conclusion: Overall, diabetes can induce hypothalamus-pituitary-gonad axis dysfunction, affects hormonal secretion, and causes histological damage to testes, collectively leading to deleterious effects on male fertility., (© 2019 Wiley Periodicals, Inc.)

Purpose: Traumatic brain injury (TBI) is one of the most common causes of mortality and long-term disability and it is associated with an increased prevalence of neuroendocrine dysfunctions. Post-traumatic hypopituitarism (PTHP) results in major physical, psychological and social consequences leading to impaired quality of life. PTHP can occur at any time after traumatic event, evolving through various ways and degrees of deficit, requiring appropriate screening for early detection and treatment. Although the PTHP pathophysiology remains to be elucitated, on the basis of proposed hypotheses it seems to be the result of combined pathological processes, with a possible role played by hypothalamic-pituitary autoimmunity (HPA). This review is aimed at focusing on this possible role in the development of PTHP and its potential clinical consequences, on the basis of the data so far appeared in the literature and of some results of personal studies on this issue., Methods: Scrutinizing the data so far appeared in literature on this topic, we have found only few studies evaluating the autoimmune pattern in affected patients, searching in particular for antipituitary and antihypothalamus autoantibodies (APA and AHA, respectively) by simple indirect immunofluorescence., Results: The presence of APA and/or AHA at high titers was associated with an increased risk of onset/persistence of PTHP., Conclusions: HPA seems to contribute to TBI-induced pituitary damage and related PTHP. However, further prospective studies in a larger cohort of patients are needed to define etiopathogenic and diagnostic role of APA/AHA in development of post-traumatic hypothalamic/pituitary dysfunctions after a TBI.

Purpose: Traumatic brain injury most commonly affects young adults under the age of 35 and frequently results in reduced quality of life, disability, and death. In long-term survivors, hypopituitarism is a common complication., Results: Pituitary dysfunction occurs in approximately 20-40% of patients diagnosed with moderate and severe traumatic brain injury giving rise to growth hormone deficiency, hypogonadism, hypothyroidism, hypocortisolism, and central diabetes insipidus. Varying degrees of hypopituitarism have been identified in patients during both the acute and chronic phase. Anterior pituitary hormone deficiency has been shown to cause morbidity and increase mortality in TBI patients, already encumbered by other complications. Hypopituitarism after childhood traumatic brain injury may cause treatable morbidity in those survivors. Prospective studies indicate that the incidence rate of hypopituitarism may be ten-fold higher than assumed; factors altering reports include case definition, geographic location, variable hospital coding, and lost notes. While the precise pathophysiology of post traumatic hypopituitarism has not yet been elucidated, it has been hypothesized that, apart from the primary mechanical event, secondary insults such as hypotension, hypoxia, increased intracranial pressure, as well as changes in cerebral flow and metabolism may contribute to hypothalamic-pituitary damage. A number of mechanisms have been proposed to clarify the causes of primary mechanical events giving rise to ischemic adenohypophysial infarction and the ensuing development of hypopituitarism., Conclusion: Future research should focus more on experimental and clinical studies to elucidate the exact mechanisms behind post-traumatic pituitary damage. The use of preventive medical measures to limit possible damage in the pituitary gland and hypothalamic pituitary axis in order to maintain or re-establish near normal physiologic functions are crucial to minimize the effects of TBI.

Background: This study aimed to detect changes in hormone levels in the hypothalamic-pituitary-ovarian axis in Sprague-Dawley (SD) rats with hypothyroidism, and identify differences in the pregnancy and abortion rates of female adult rats. The potential role of gonadotropin releasing hormone (GnRH) as the link between the hypothalamic-pituitary-ovarian axis and reproductive function regulated by thyroid hormones was also investigated., Methods: Female SD rats (n = 136) were causally classified into two groups: the normal-drinking-water group (n = 60) and the 0.05% propylthiouracil-drinking-water group (PTU 2 mg/kg/day, n = 76) to establish an adult rat model of hypothyroidism (6 weeks). Female and male rats at a ratio of 1:2 were used to establish a hypothyroidism pregnancy model. GnRH mRNA and GnRH receptor (GnRHR) expression in rats was detected using real time quantitative PCR(qRT-PCR) and immunohistochemistry, respectively., Results: The abortion rate differed significantly between the hypothyroidism pregnancy group and the normal pregnancy group (P < 0.05). No significant differences were found in the distribution of the GnRHR among the five nuclei (hypothalamic arcuate nucleus, hypothalamic ventromedial nucleus, hypothalamic anterior nucleus, paraventricular nucleus of the hypothalamus, and ventral premammillary nucleus) of the hypothalamus and ovary (P > 0.05). Hypothyroidism had no significant effect on GnRH mRNA expression in the hypothalamic-pituitary-ovarian axis in the four groups (normal control group, normal pregnancy group, hypothyroidism pregnancy group, and hypothyroidism group) (P > 0.05)., Conclusions: Hypothyroidism had an adverse impact on pregnancy in rats and may affect the distribution of pituitary GnRHR, whereas it did not obviously affect the distribution of GnRHR in the nuclei of the hypothalamus and ovary. Hypothyroidism had no effect on GnRH mRNA expression.

This review summarized different studies reporting the presence of autoantibodies reacting against cells of the pituitary (APAs) and/or hypothalamus (AHAs). Both APAs and AHAs have been revealed through immunofluorescence using different kinds of substrates. Autoantibodies against gonadotropic cells were mainly found in patients affected by cryptorchidism and hypogonadotropic hypogonadism while those against prolactin cells were found in different kinds of patients, the majority without pituitary abnormalities. APAs to growth hormone (GH) cells have been associated with GH deficiency while those against the adrenocorticotropic cells have distinguished central Cushing's disease patients at risk of incomplete cure after surgical adenoma removal. AHAs to vasopressin cells have identified patients at risk of developing diabetes insipidus. APAs have been also found together with AHAs in patients affected by idiopathic hypopituitarism, but both were also present in different kinds of patients without abnormalities of the hypothalamic-pituitary axis. Despite some data being promising, the clinical use of pituitary and hypothalamus autoantibodies is still limited by the low diagnostic sensitivity, irreproducibility of the results, and the absence of autoantigen/s able to discriminate the autoimmune reaction involving the pituitary or the hypothalamus from the other autoimmune states., Competing Interests: The authors declare no conflict of interest.

Purpose: Hypothalamic-pituitary axis is susceptible to radiotherapy, causing endocrine disorders to childhood cancer survivors. We conducted a systematic review in order to assess the radiation-induced toxicity that leads to hormone secretion abnormalities and their severity in children with brain tumors., Methods: The data were collected by relevant studies on PubMed and EMBASE. Articles up to December 2016 were included. We selected studies which focused on children patients (<18 yr old) with brain tumors treated with radiotherapy and the consequences for their endocrine system., Results: Growth hormone (GH) deficiency was the most common post-irradiation abnormality among children cancer survivors, followed by gonadotrophin (GT), thyroid stimulating hormone (TSH), corticotropin (ACTH) and prolactin (PRL) disorders., Conclusions: The age of the patient, total radiotherapy dose, number of fractions, fraction size and the duration of treatment seem to determine the severity of these disturbances.

At the beginning of the twentieth century, the hypothalamus was known merely as an anatomical region of the brain lying beneath the thalamus. An increasing number of clinicopathological reports had shown the association of diabetes insipidus and adiposogenital dystrophy (Babinski-Fröhlich's syndrome), with pituitary tumors involving the infundibulum and tuber cinereum, two structures of the basal hypothalamus. The French physicians Jean Camus (1872-1924) and Gustave Roussy (1874-1948) were the first authors to undertake systematic, controlled observations of the effects of localized injuries to the basal hypothalamus in dogs and cats by pricking the infundibulo-tuberal region (ITR) with a heated needle. Their series of surgical procedures, performed between 1913 and 1922, allowed them to claim that both permanent polyuria and adiposogenital dystrophy were symptoms caused by damage to the ITR. Their results challenged the dominant doctrine of hypopituitarism as cause of diabetes insipidus and adiposogenital dystrophy that derived from the experiments performed by Paulescu and Cushing a decade earlier. With their pioneering research, Camus and Roussy influenced the experimental work on the hypothalamus performed by Percival Bailey and Frederic Bremer at Cushing's laboratory, confirming the hypothalamic origin of these symptoms in 1921. More importantly, they provided the foundations for the physiological paradigm of Neuroendocrinology, the hypothalamus' control over the endocrine secretions of the pituitary gland, as well as over water balance and fat metabolism. This article aims to credit Camus and Roussy for their groundbreaking, decisive contributions to postulate the hypothalamus being the brain region in control of endocrine homeostasis and energy metabolism.

Hypopituitarism is an uncommon and under-investigated endocrine disorder in old age since signs and symptoms are unspecific and, at least in part, can be attributed to the physiological effects of aging and related co-morbidities. Clinical presentation is often insidious being characterized by non-specific manifestations, such as weight gain, fatigue, low muscle strength, bradipsychism, hypotension or intolerance to cold. In these circumstances, hypopituitarism is a rarely life-threatening condition, but evolution may be more dramatic as a result of pituitary apoplexy, or when a serious condition of adrenal insufficiency suddenly occurs. Clinical presentation depends on the effects that each pituitary deficit can cause, and on their mutual relationship, but also, inevitably, it depends on the severity and duration of the deficit itself, as well as on the general condition of the patient. Indeed, indications and methods of hormone replacement therapy must include the need to normalize the endocrine profile without contributing to the worsening of intercurrent diseases, such as those of glucose and bone metabolism, and the cardiovascular system, or to the increasing cancer risk. Hormonal requirements of elderly patients are reduced compared to young adults, but a prompt diagnosis and appropriate treatment of pituitary deficiencies are strongly recommended, also in this age range.

Despite being proposed as a promising antifouling and chemopreventive agent, the environmental risks of 3,3'-diindolylmethane (DIM) are scarcely investigated. Therefore, this study used adult marine medaka (Oryzias melastigma) as a model organism to examine the toxicological effects and underlying mechanism of DIM throughout the hypothalamus-pituitary-gonadal-liver (HPGL) axis following 28 days of exposure to low DIM concentrations (0 and 8.46 μg/L). The results showed that altered gene transcription in the hypothalamus, pituitary, and gonads contributed to the great imbalance in hormone homeostasis. The lowered estradiol (E2)/testosterone (T) and E2/11-keto-testosterone (11-KT) ratios in female plasma resulted in decreased synthesis and levels of vitellogenin (VTG) and choriogenin in the liver and plasma, and vice versa in males. Subsequently, VTG and choriogenin deficiency blocked the reproductive function of the ovary as indicated by decreased fecundity and offspring viability, whereas in male medaka, DIM mainly targeted the liver and induced severe vacuolization. Proteomic profiling of plasma revealed that the sex-specific susceptibility to DIM could be attributed to the increased detoxification and oxidative defense in males. Overall, this study identified the endocrine disruption and reproductive impairment potency of DIM and first elucidated its mechanisms of action in medaka. The differential responses to DIM (estrogenic activities in the male but antiestrogenic activities in the female) provided sensitive biomarkers characteristic of each sex. Considering the chemical stability and potent endocrine disturbance at low concentration, the application of DIM either as an antifouling or chemopreventive agent should be approached with caution in marine environments.

Purpose: Hypothalamic-pituitary (HP) neurosarcoidosis (NS) accounts for 0.5 % cases of sarcoidosis and 1 % of HP masses. Correlative data on endocrine and neurological outcomes is lacking., Methods: Retrospective case series and literature review of presentation, treatment and outcome of HP NS., Results: Our series includes 4 men, ages 34-59, followed for a median of 7.3 years (range 1.5-17). All had optic neuropathy, multiple pituitary hormone abnormalities (PHAs) and other organ involvement by sarcoidosis (lung, sino-nasal, brain/spine and facial nerve). Two patients had central diabetes insipidus and one impaired thirst with polydipsia. After treatment with high-dose glucocorticoids, optic neuropathy improved in one case and stabilized in the others. After treatment, HP lesions improved radiologically, but PHAs persisted in all cases. Review of four published series on HP NS in addition to ours yielded 46 patients, age 37 ± 11.8 years, 65 % male. PHAs consisted of anterior hypopituitarism (LH/FSH 88.8 %, TSH 67.4 %, GH 50.0 %, ACTH 48.8 %), hyperprolactinemia (48.8 %) and diabetes insipidus (65.2 %). PHAs were the first sign of disease in 54.3 % patients. Vision problems occurred in 28.3 % patients, but optic neuropathy was not well documented in previous series. Most patients (93.5 %) received high-dose glucocorticoids followed by taper; 50 % also received other immunomodulators, including methotrexate, mycophenolate mofetil, cyclosporine, azathioprine, infliximab and hydrochloroquine. Only 13 % patients showed improvement in PHAs. All-cause mortality was 8.7 %., Conclusion: HP NS is a serious disease requiring multidisciplinary treatment and lifelong follow-up. Prospective multicentric studies are needed to determine a more standardized approach to HP NS and outline predictors of disease outcome.

Purpose: We sought to characterize the magnetic resonance imaging (MRI) findings in patients with Kallmann syndrome (KS)., Materials and Methods: Fourteen patients with KS and a comparison group of 20 matched people with normal MRI were analyzed with optimized voxel-based morphometry. Coronal T1- and T2-weighted images from the anterior margin of the frontal sinus to the hypothalamus were obtained. The olfactory sulci, bulbs, and bundles were assessed as normal, hypoplastic, or absent. The pituitary gland was also evaluated., Results: Four of the 14 patients came from 1 family. Ten patients had low levels of GnRH and gonadal hormone, 11 had hyposmia, and 3 had anosmia. On MRI, the olfactory bulbs (OBs) and bundles were absent bilaterally in 8 patients. Two patients exhibited absence of the OBs and bundles on the left and hypoplasia on the right. Four patients displayed bilateral hypoplastic OBs and bundles. The olfactory sulci were absent in 5 and hypoplastic in 9 of these patients. The anterior pituitary was hypoplastic in 6 patients., Conclusions: Kallmann syndrome has distinctive features on MRI. Magnetic resonance imaging may aid in the diagnosis of KS in patients with ambiguous clinical findings.

The Uniform Determination of Death Act (UDDA) states that an individual is dead when "all functions of the entire brain" have ceased irreversibly. However, it has been questioned whether some functions of the hypothalamus, particularly osmoregulation, can continue after the clinical diagnosis of brain death (BD). In order to learn whether parts of the hypothalamus can continue to function after the diagnosis of BD, we performed 2 separate systematic searches of the MEDLINE database, corresponding to the functions of the posterior and anterior pituitary. No meta-analysis is possible due to nonuniformity in the clinical literature. However, some modest generalizations can reasonably be drawn from a narrative review and from anatomic considerations that explain why these findings should be expected. We found evidence suggesting the preservation of hypothalamic function, including secretion of hypophysiotropic hormones, responsiveness to anterior pituitary stimulation, and osmoregulation, in a substantial proportion of patients declared dead by neurological criteria. We discuss several possible explanations for these findings. We conclude by suggesting that additional clinical research with strict inclusion criteria is necessary and further that a more nuanced and forthright public dialogue is needed, particularly since standard diagnostic practices and the UDDA may not be entirely in accord., (© The Author(s) 2014.)

Purpose: Infundibulo-tuberal syndrome groups endocrine, metabolic and behavioral disturbances caused by lesions involving the upper neurohypophysis (median eminence) and adjacent basal hypothalamus (tuber cinereum). It was originally described by Henri Claude and Jean Lhermitte in 1917, in a patient with a craniopharyngioma. This study investigates the clinical, pathological and surgical evidence verifying the infundibulo-tuberal syndrome caused by craniopharyngiomas (CPs)., Methods: A systematic retrospective review of craniopharyngiomas reported in French literature between 1705 and 1973 was conducted. A total of 128 well described reports providing a comprehensive clinical and pathological description of the tumors were selected. This series represents the historical French cohort of CPs reported in the pre-CT/MRI era., Results: Three major syndromes caused by CPs were categorized: pituitary syndrome (35%), infundibulo-tuberal syndrome (52%) and hypothalamic syndrome (49%). CP topography was significantly related to the type of syndrome described (p < 0.001). Infundibulo-tuberal syndrome occurred in CPs which replaced or invaded the third ventricle floor. In contrast, the majority of sellar/suprasellar CPs growing below the third ventricle showed a pituitary syndrome (82%). Cases with hypothalamic syndrome were characterized by anatomical integrity of the pituitary gland and stalk (p = 0.033) and occurred predominantly in adults older than 41 years old (p < 0.005). Among infundibulo-tuberal symptoms, abnormal somnolence was not related with the presence of hydrocephalus. All squamous-papillary CPs presented psychiatric disturbances (p < 0.001)., Conclusion: This historical CP cohort evidences a clinical-topographical correlation between the patient's type of syndrome and the anatomical structures involved by the tumor along the hypophysial-hypothalamic axis.

Age-related peculiarities of the adaptation of the hypothalamo-hypophyseo-adrenal system (HHAS) to the effect of heterotypic stress was studied experimentally in the context of stress-associated behavioral reactions. Young (3 month old), mature (6 month old) and aging (12 month old) Sprague Dawley rats (total number of animals equal to 36) were exposed to chronic heterotypic stressors for 7 days with the subsequent testing of their behavioral responses. Histological changes were studied in the hypothalamus, pituitary and adrenal glands as compared to age-matched control; immunohistochemical reactions were performed to demonstrate CRF, ACTH, ED1, PCNA and caspase-3 with subsequent image analysis. In the aging organism, as compared to young and mature animals, the degree of HHAS activation indicated the dissociation in its central part and adaptive desensitization prevention, typical to young and mature animals. Specifically, in the aging animals exposed to stress, high hypothalamic CRF expression was noted in association with relatively low hypophyseal ACTH expression and high level of adrenal activity. Reduced HHAS plasticity in the aging animals as compared to that in the other age groups, corresponded to their behavioral changes, demonstrating the reduced capacity of the aging organism to adapt to the exposure of unpredictably changing stressors.

Background: Despite rendering serum free thyroxine (FT4) and thyrotropin (TSH) within the normal population ranges broadly defined as euthyroidism, many patients being treated for hyperthyroidism and hypothyroidism persistently experience subnormal well-being discordant from their pre-disease healthy euthyroid state. This suggests that intra-individual physiological optimal ranges are narrower than laboratory-quoted normal ranges and implies the existence of a homeostatic set point encoded in the hypothalamic-pituitary-thyroid (HPT) axis that is unique to every individual., Methods: We have previously shown that the dose-response characteristic of the hypothalamic-pituitary (HP) unit to circulating thyroid hormone levels follows a negative exponential curve. This led to the discovery that the normal reference intervals of TSH and FT4 fall within the 'knee' region of this curve where the maximum curvature of the exponential HP characteristic occurs. Based on this observation, we develop the theoretical framework localizing the position of euthyroid homeostasis over the point of maximum curvature of the HP characteristic., Results: The euthyroid set points of patients with primary hypothyroidism and hyperthyroidism can be readily derived from their calculated HP curve parameters using the parsimonious mathematical model above. It can be shown that every individual has a euthyroid set point that is unique and often different from other individuals., Conclusions: In this treatise, we provide evidence supporting a set point-based approach in tailoring euthyroid targets. Rendering FT4 and TSH within the laboratory normal ranges can be clinically suboptimal if these hormone levels are distant from the individualized euthyroid homeostatic set point. This mathematical technique permits the euthyroid set point to be realistically computed using an algorithm readily implementable for computer-aided calculations to facilitate precise targeted dosing of patients in this modern era of personalized medicine.

Objective: Langerhans cell histiocytosis (LCH) is a rare idiopathic disease that is characterized by clonal proliferation of Langerhans histiocytes in various parts of the body. These atypical cells have been found to infiltrate single or multiple organs, including bone, lungs, liver, spleen, lymph nodes, and skin. Central nervous system invasion in LCH patients has rarely been reported, especially in the adult population., Methods and Results: We describe three histopathologically confirmed cases of adult LCH that involves both the pituitary stalk and hypothalamus, and report our limited experience of such cases in this location that has been treated with CyberKnife radio surgery., Conclusion: The treatment goal of controlling lesion growth is achieved by CyberKnife radiosurgery in this case series. All patients tolerated the treatment well without obvious complications., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Background: Pituitary stalk interruption syndrome (PSIS) may induce an isolated growth hormone (GH) deficiency or multiple hypothalamic-pituitary (HP) deficiencies. Patients with multiple HP deficiencies, primarily those with adrenocorticotropin (ACTH) deficiency, are at increased risk of morbidity and mortality. Our objective was to identify the factors influencing each symptom and the MRI features of the syndrome to enhance its diagnosis and genetic analysis., Methods: This study was a retrospective, single-center, case-cohort study of 53 patients with PSIS who had reached pubertal age., Results: Patients were classified as having an isolated GH deficiency (n = 24, Group 1) or HP deficiencies (n = 29, Group 2); of these, 19 had complete HP deficiency, and 10 had GH deficiency associated with TSH (n = 4), TSH and ACTH (n = 3), TSH and gonadotropin (n = 1) deficiencies or amenorrhea (n = 2). The following features were less frequent in Group 1 than in Group 2: breech presentation (4% vs 35%, P = 0.008), hypoglycemia (0% vs 59%, P<0.00001), micropenis (13% vs 69%, P<0.003), hypothalamic origin (0% vs 52%, P<0.000001), ophthalmic malformation (8% vs 38%, P<0.02) and psychomotor delay (0% vs 31%, P<0.004). The frequencies of all other malformations were similar in both groups (37% vs 59%). A visible pituitary stalk was characteristic of patients belonging to Group 1 (P<0.0002). The GH peak was greater in Group 1 than in Group 2 (P<0.0003), as was the anterior pituitary height (P = 0.01)., Conclusion: The factors that best discriminate patients with multiple HP deficiencies from those with an isolated GH deficiency are breech presentation, hypoglycemia, and micropenis. No patient with an isolated GH deficiency had psychomotor delay, but associated malformations and/or syndromes, with the exception of ophthalmic disorders, occurred with similar frequencies in both groups. We have also shown that each of the above characteristics is associated with a given HP deficiency and/or malformation/syndrome in the majority of cases.

We analyzed forensic autopsy findings of 66 consecutive patients with fatal closed head injury who survived up to 48 days after trauma to ascertain the causal factors and the time course of development of posttraumatic pituitary lesions. Pituitary lesions were identified in 27 patients. In patients with pituitary lesions, posterior lobe hemorrhage was observed in 21 patients, followed by anterior lobe hemorrhage in 10 patients and anterior lobe infarct in 7 patients. Comparisons between patients with and without pituitary lesions showed that falls and subdural hematoma were significantly frequent in patients with pituitary lesions. Immunohistochemistry of neurophysin showed increased immunoreactivity in the hypothalamus of patients with pituitary lesions and brain edema, providing morphologic evidence of pituitary dysfunction. Hemorrhage in the anterior or posterior lobe was identifiable in patients with short survival periods, whereas infarct in the anterior lobe appeared in patients surviving at least 14 hours. These data further our understanding of the mechanisms of pituitary dysfunctions and help in the estimation of the survival period after head trauma.

This morphological, morphometric, and immunohistochemical study of the myocardium, adrenal gland, and hypothalamus included 50 corpses of men aged from 25-49 years deceased by reason of acute coronary failure associated with coronary heart disease. The commonest lesions in the myocardium were contractures (54.3 +/- 3.5% [51.2; 57.8%]), cyclic deformation (44.7 +/- 6.3% [38.2; 51.4%]), and dissociation of cardiomyocytes (61.2 +/- 2.3% [56.3; 64.8%]). The sinoatrial and atrioventricular nodes of the heart contained large amounts of adrenaline-positive cells (45.6 +/- 4.5% [40.1; 48.7%]) and 34.2 +/- 2.9% [31.2; 37.4%]). The equally large numbers of adrenaline-positive cells were detected in the adrenal medulla (67.2 +/- 6.8% [61.9; 74.3%]). The arcuate, supraoptic, and paraventricular nuclei of the hypothalamus underwent reversible changes of neutron content (the degree of damage 25.6 +/- 4.8% [21.2; 29.8%]) and contained large amounts of noradrenaline-positive and dopamine-positive neural cells (54.2 +/- 3.6% [51.4; 59.3%]) and 28.7 +/- 2.1% [23.4; 31.7%]) respectively. It is concluded that the morphometric and immunohistochemical changes detected in the present study can be used as the additional forensic medical criteria for diagnostics of death from acute coronary failure associated with coronary heart disease.

Volumetric differences of the hypothalamus and/or the pituitary gland tend to support involvement of the HPA axis in psychotic disorders. These structures were manually outlined in 154 schizophrenia patients and 156 matched healthy comparison subjects by MRI brain images. Linear regression analyses were performed to investigate differences in volume between groups. Moreover, the effects of illness duration and type of medication were investigated. No significant differences were found between patients and healthy controls in volumes of the hypothalamus and pituitary gland. In addition, there were no differences in volumes between patients with short and long illness duration. There was a trend towards patients receiving typical antipsychotic medication at the time of scanning having larger pituitary volumes than patients receiving atypical medication. These findings indicate that volume decreases in brain structures important for the normal functioning of the HPA axis are not present, either in recent-onset or chronically ill patients.

Purpose: The purpose of this study is to assess the relationship between magnetic resonance images (MRI) of the hypothalamic-pituitary (H-P) region and response to recombinant human growth hormone (rhGH) treatment in short children with growth hormone deficiency, basing on changes of auxologic parameters, as well as to answer the question if MRI may serve for selecting and monitoring the rhGH responders., Patients and Methods: The study group comprised 85 children treated with rhGH, aged 7.3-18.7 years, followed for the mean period of 3.2 years (range, 2.1-9.5 years). Auxologic parameters (height deficit hSDS, deviation from the mid-parental height hSDS-mpSDS, bone delay index bone age/chronological age ratio (BA/CA)) were assessed before, during and at the end of rhGH treatment; growth velocity was calculated before and during rhGH therapy. Parameters were correlated with the MRI of the H-P region., Results: Structural anomalies of the H-P region were found in 22 (25.9%) children: empty sella syndrome (ESS) in 12 (14.1%) patients, ectopic posterior pituitary (EPP) in ten (11.8%). Patients' height deficit and their deviation from parental height before rhGH therapy was significantly greater in the EPP group (median hSDS = -3.8; hSDS-mpSDS = -2.5), bone age delay was the greatest in the ESS group (median BA/CA = 0.69), after therapy - in the EPP group (median BA/CA = 0.82). Growth velocity improved in the first year of the rhGH therapy in all groups; however, the most significant acceleration was observed in the EPP group (median delta hSDS = 0.9), then stabilised and was comparable in all groups., Conclusions: MRI may be helpful in predicting response to the rhGH treatment, providing midline abnormalities are taken into account.

We report four cases of adult-onset Langerhans cell histiocytosis (LCH) with central nervous system (CNS) lesions in the hypothalamic-pituitary region. The first clinical symptoms were diabetes insipidus (two patients), hypothyroidism (one patient), and decreased libido/erectile dysfunction (one patient). Diagnosis was delayed as the CNS lesion was not initially suspected to be secondary to LCH, with a median time from symptom onset to treatment of 3.0 (range <1-5.3) years. In three patients, the tumor mass was effectively reduced by chemotherapy; however, all patients continue to exhibit hypopituitarism. Early diagnosis and initiation of treatment are required to improve the outcome of CNS-LCH in adult patients.

Purpose: Chronic pituitary dysfunction is increasingly recognized as a sequela of traumatic brain injury (TBI). Our aim was to rule out any late morphometric changes of the pituitary gland and hypothalamus in survivors of TBI during childhood requiring intensive care., Methods: We assessed morphometric abnormalities of the sella region and hypothalamus in patients who sustained TBI during childhood. The patients showed no clinical hormonal dysfunction at the acute phase and pituitary hormone levels at the time of our study were within normal limits. From the 18 enrolled patients in the magnetic resonance study, five were removed due to morphological changes or anatomical variations. We studied the MRI of 13 male survivors (mean age 27 years, mean time after trauma 20 years) and compared them to 13 male control subjects who were matched in terms of age (mean age, 26 years), education and ethnicity. Analyses of the pituitary gland and sella on a midsagittal T2- and T1-weighted image were performed. We used voxel-based morphometry (VBM), an unbiased MRI morphometric method to investigate hypothalamic region in this group of patients., Results: There was only a trend towards a reduced pituitary gland width in the patient group compared to controls. However, no significant morphological and morphometric abnormality was seen and VBM showed no hypothalamic grey matter loss., Conclusion: In the absence of hormonal dysfunction, no persisting morphometric changes of the pituitary gland and hypothalamus were seen in survivors of childhood TBI requiring intensive care.

In this article the epidemiology, pathophysiology, clinical presentation, investigation, management, and prognosis of hypopituitarism and hypothalamic dysfunction, arising from skull base pathologies and treatment of these conditions, are reviewed and discussed. The clinical question: "What is the consequence of pituitary hypofunction in young patients (ie, craniopharyngioma)?" is answered based on information provided in the review., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Objective: To evaluate the effect of hypothalamic/pituitary radiation (HPT RT) dose on the occurrence of first pregnancy., Design: Retrospective cohort study of childhood cancer 5-year survivors (CCS) diagnosed between 1970 and 1986 before 21 years of age at one of 26 North American pediatric cancer treatment centers., Setting: Self-administered questionnaire., Patient(s): A total of 3,619 female CCS who participated in the Childhood Cancer Survivor Study and received no or scatter (≤0.1 Gy) radiation to the ovaries and 2,081 female siblings (Sibs) of the participants., Intervention(s): None., Main Outcome Measure(s): Self-reported pregnancy events., Result(s): As a group, CCS were as likely to report being pregnant as Sibs (hazard ratio 1.07, 95% confidence interval 0.97-1.19). Multivariable models showed a significant decrease in the risk of pregnancy with HPT RT doses≥22 Gy compared with those CCS receiving no HPT RT., Conclusion(s): These results support the hypothesis that exposures of 22-27 Gy HPT RT may be a contributing factor to infertility among female CCS., (Copyright © 2011 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Poorly controlled type1 diabetes is associated with hormonal imbalances and increased cell death in different tissues, including the pituitary, hypothalamus and cerebellum. In the pituitary, lactotrophs are the cell population with the greatest increase in cell death, whereas in the hypothalamus and cerebellum astrocytes are most highly affected. Insulin treatment can delay, but does not prevent, diabetic complications. As ghrelin and growth hormone (GH) secretagogues are reported to prevent apoptosis in different tissues, and to modulate glucose homeostasis, a combined hormonal treatment may be beneficial. Hence, we analyzed the effect of insulin and GH-releasing peptide 6 (GHRP-6) on diabetes-induced apoptosis in the pituitary, hypothalamus and cerebellum of diabetic rats. Adult male Wistar rats were made diabetic by streptozotocin injection (65 mg/kg ip) and divided into four groups from diabetes onset: those receiving a daily sc injection of saline (1 ml/kg/day), GHRP-6 (150 μg/kg/day), insulin (1-8U/day) or insulin plus GHRP-6 for 8 weeks. Control non-diabetic rats received saline (1 ml/kg/day). Diabetes increased cell death in the pituitary, hypothalamus and cerebellum (P<0.05). In the pituitary, insulin treatment prevented diabetes-induced apoptosis (P<0.01), as well as the decline in prolactin and GH mRNA levels (P<0.05). In the hypothalamus, neither insulin nor GHRP-6 decreased diabetes-induced cell death. However, the combined treatment of insulin+GHRP-6 prevented the diabetes induced-decrease in glial fibrillary acidic protein (GFAP) levels (P<0.05). In the cerebellum, although insulin treatment increased GFAP levels (P<0.01), only the combined treatment of insulin+ GHRP-6 decreased diabetes-induced apoptosis (P<0.05). In conclusion, insulin and GHRP-6 exert tissue specific effects in STZ-diabetic rats and act synergistically on some processes. Indeed, insulin treatment does not seem to be effective on preventing some of the diabetes-induced alterations in the central nervous system., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Tubercular meningitis (TBM) is the most dreaded form of extra pulmonary tuberculosis associated with high morbidity and mortality. Various hypothalamic pituitary hormonal abnormalities have been reported to occur years after recovery from disease but there are no systematic studies in the literature to evaluate the pituitary hypothalamic dysfunction in patients with TBM at the time of presentation. Therefore, the present study was designed to evaluate hypothalamic pituitary abnormalities in newly diagnosed patients with TBM. Patient case series. This prospective study included 75 untreated adult patients with TBM diagnosed as "definite", "highly probable" and "probable" TBM by Ahuja's criteria and in clinical stage 1, 2 or 3 at the time of presentation to hospital. Basal hormonal profile was measured by electrochemilumniscence technique for serum cortisol, luetinizing hormone (LH), follicular stimulating hormone (FSH), prolactin (PRL), thyrotropin (TSH), free tri-iodothyronine (fT3), and free thyroxine (fT4). All patients were subjected to MRI to image brain and hypothalamic pituitary axis and CT for adrenal glands. Thirty-two (42.7%) cases showed relative or absolute cortisol insufficiency. Twenty-three (30.7%) cases showed central hypothyroidism and 37 (49.3%) cases had hyperprolactinemia. No patient had evidence of diabetes insipidus. Multiple hormone deficiency was seen in 22 (29.3%) cases. MRI of hypothalamic pituitary axis using dynamic scanning and thin cuts revealed abnormalities in 10 (13.3%) of the cases. CT adrenal gland was normal in all the patients. Tubercular meningitis is associated with both hormonal and structural abnormalities in the hypothalamic pituitary axis at the time of diagnosis.

Objectives: To determine the factors affecting the development of pituitary and hypothalamic lesions after fatal closed head injury., Materials: Thirty-four patients with severe closed head injury succumbing to the effects of brain trauma before or during admission, whether managed conservatively or surgically, formed the study group. Clinical parameters, injury to death interval, radiologic data, and management details were taken into consideration. Autopsy was performed within 48 hours of death; hypothalamus and pituitary were carefully removed and evaluated for the presence of lesions on hematoxylin and eosin and immunohistochemical staining., Results: Patients were categorized into early death group (n = 11, those succumbing before/on admission) and late death group (n = 23, those succumbing after admission). Histopathologic evaluation of pituitary revealed capsular hemorrhages in 50%, posterior pituitary hemorrhage in 25%, anterior pituitary infarct in 21.8%, and anterior pituitary hemorrhage in 6.2% patients. Hypothalamic hemorrhage was observed in 65.2% patients and infarcts in 17.3%. Lesions in hypothalamus and pituitary were significantly related to the presence of ventricular compression on computed tomography scan and survival of >24 hours after injury (p < 0.05). Capsular hemorrhage, anterior pituitary hemorrhage, and posterior pituitary hemorrhage were present in 40%, 10%, and 30% of the patients in the early death group when compared with 54.5%, 4.5%, and 22.7% of the patients in the late death group. Anterior pituitary infarcts were present in 10% of the patients with early deaths and 27.3% patients in the late death group. Hypothalamic hemorrhages were present in 44.4% of patients in early death and 78.6% in late death groups. Hypothalamic infarcts (40%) were present in the late death group only. Two patients (25%) in the early death group and 11 (84.6%) in the late death group had lesions in pituitary as well as hypothalamus (p < 0.05)., Conclusions: Presence of ventricular compression on computed tomography scan and survival >24 hours after severe head injury has a significant correlation with the development of hypothalamic and pituitary lesions. Secondary insults account for a proportion of pituitary and hypothalamic lesions after trauma, which may be amenable to prevention by early intervention to treat raised intracranial pressure (ICP)/herniation.

Context: Idiopathic hypogonadotropic hypogonadism (IHH) with normal smell (normosmic IHH) or anosmia (Kallmann syndrome) is associated with defects in the production or action of GnRH. Accordingly, most IHH patients respond to physiological pulsatile GnRH replacement by normalizing serum LH, FSH, and testosterone (T) levels and achieving gametogenesis; some patients, however, show atypical responses. Interestingly, several IHH-associated genes are expressed in multiple compartments of the hypothalamic-pituitary-gonadal axis., Objective: The aim of the study was to investigate whether the clinical, biochemical, or genetic characteristics of IHH men with atypical responses to GnRH indicate alternative or additional defects in the hypothalamic-pituitary-gonadal axis., Subjects: We studied 90 IHH men undergoing long-term pulsatile GnRH treatment over 30 yr., Design and Setting: We conducted a retrospective study of response to GnRH at a Clinical Research Center., Interventions: Physiological regimens of pulsatile s.c. GnRH were administered for at least 12 months. Dose-response studies using i.v. GnRH pulses assessed the pituitary LH response., Main Outcome Measures: We measured serum T, LH, FSH, and inhibin B levels, sperm in ejaculate, and determined the sequence of IHH-associated genes., Results: Twenty-six percent of subjects displayed atypical responses to GnRH: 1) 10 remained hypogonadotropic and hypogonadal, demonstrating pituitary and testicular defects; 2) eight achieved spermatogenesis and normal T but only with hypergonadotropism, indicating impaired testicular responsiveness to gonadotropins; and 3) five remained azoospermic despite achieving adult testicular volumes and normal hormonal profiles, suggesting primary defects in spermatogenesis. Mutations were identified only in KAL1 across groups., Conclusion: In addition to hypothalamic GnRH deficiency, IHH men can have primary pituitary and/or testicular defects, which are unmasked by GnRH replacement.

The relationship of the stress response to the pathogenesis of alopecia areata (AA) was investigated by subjecting normal and skin graft-induced, AA-affected C3H/HeJ mice to light ether anesthesia or restraint stress. Plasma corticosterone (CORT), adrenocorticotropic hormone (ACTH), and estradiol (E2) levels were determined by RIA, whereas gene expression in brains, lymphoid organs, and skin was measured by quantitative RT-PCR for corticotropin-releasing hormone (Crh), arginine vasopressin (Avp), proopiomelanocortin (Pomc), glucocorticoid receptor (Nr3c1), mineralocorticoid receptor (Nr3c2), corticotropin-releasing hormone receptor types 1 and 2 (Crhr1, Crhr2), interleukin-12 (Il12), tumor necrosis factor-alpha (Tnf alpha), and estrogen receptors type-1 (Esr1) and type-2 (Esr2). AA mice had a marked increase in hypothalamic-pituitary-adrenal (HPA) tone and activity centrally, and peripherally in the skin and lymph nodes. There was also altered interaction between the adrenal and gonadal axes compared with that in normal mice. Stress further exacerbated changes in AA mouse HPA activity both centrally and peripherally. AA mice had significantly blunted CORT and ACTH responses to acute ether stress (physiological stressor) and a deficit in habituation to repeated restraint stress (psychological stressor). The positive correlation of HPA hormone levels with skin Th1 cytokines suggests that altered HPA activity may occur as a consequence of the immune response associated with AA.

Posttraumatic hypopituitarism is the failure of the hypothalamic-pituitary axis secondary to traumatic brain injury. It can clinically present as decreased muscle mass, concentration, libido, and fertility. It can also present as increased fatigue, depression, and cognitive deficits. In addition, electrolyte abnormalities such as hyponatremia can occur in hypopituitarism. As a result of heightened awareness of posttraumatic hypopituitarism, it is a phenomenon that is becoming more commonly diagnosed. Posttraumatic hypopituitarism is a diagnosis based on clinical evaluation, laboratory testing, and neuroimaging. Of the radiological techniques, magnetic resonance imaging is the preferred technique to image the pituitary gland. This article contains coronal and sagittal magnetic resonance imaging of the posterior fossa, illustrating the normal hypothalamus and pituitary gland as well as adjacent structures. The sequential enhancement pattern of the normal pituitary gland is consistent with its vascular supply. A colored illustration was created to display the vascular supply to the hypothalamus, pituitary stalk, and pituitary gland.

Objective: Reassessment of GH status after the attainment of adult height has important clinical implications in the diagnosis and prognosis of GH deficiency (GHD) in adulthood. The current GH threshold for biochemical definition of GHD in young adults is still a subject of debate., Design: To investigate the role of pharmacological stimulation tests compared with spontaneous 12-h nocturnal GH secretion in the diagnosis of permanent GHD in young adults with childhood-onset GHD., Patients: Forty-five young adults (25 males, 20 females) with childhood-onset GHD, height standard deviation score (SDS) -1.1 +/- 1.3 and body mass index (BMI) SDS 1.0 +/- 1.6, were re-evaluated at the age of 19.8 +/- 2.7 years. Sixteen subjects showed a normal pituitary gland on magnetic resonance imaging (MRI), while in 29, consistent structural hypothalamic-pituitary abnormalities were found. GH secretion was assessed by means of an insulin tolerance test (ITT) and a 12-h spontaneous nocturnal profile as well as by IGF-I assessment. The results were compared with those of 43 healthy controls., Results: Mean 12-h spontaneous nocturnal GH secretion was < 3.1 microg/l (the lowest limit of the normal range) in 36 (80%) of the subjects and > 3.1 microg/l in nine (20%). Of these 36 patients, 29 (80%) had abnormal MRI findings and 20 (55%) had multiple pituitary hormone deficiencies (MPHD). All nine subjects with mean spontaneous GH secretion > 3.1 microg/l had a normal pituitary MRI, isolated GHD and a peak GH response to ITT > 5 microg/l. There was a discordance in 14 patients (31%), who showed a peak GH response to ITT > 5 microg/l but a reduced spontaneous GH secretory capacity; 10 had structural hypothalamic-pituitary abnormalities on MRI., Conclusions: Although the ITT provides valuable information and proves to be a sensitive index of permanent GHD, the results of this study emphasize the potential diagnostic value of assessment of 12-h spontaneous GH secretion in young adults with childhood-onset GHD.

Intracerebroventricular administration of oxytocin reduces anxiety behavior and hypothalamo-pituitary-adrenal (HPA) responses to stress in female rats. Similar changes are seen in late-pregnant rats, and oxytocin-sensitive pathways may mediate these effects. This study investigated anxiety behavior and stress responses using a gonadal steroid model of late pregnancy, which is known to increase endogenous oxytocin expression. Compared with continuous progesterone treatment, 3-d withdrawal of progesterone after 11-d treatment of ovariectomized rats with estradiol and progesterone resulted in increased binding of the oxytocin receptor ligand [(125)I]d(CH(2))(5)[Tyr(Me)(2),Thr(4),Tyr-NH(2)(9)]ornithine vasotocin in selective forebrain regions, including the ventrolateral septum and ventromedial hypothalamus. Behavior in the elevated plus-maze indicated that progesterone withdrawal had an anxiolytic effect, and this was associated with lower levels of c-fos mRNA expression in the ventral hippocampus, an area previously shown to be sensitive to oxytocin. In other groups of animals, the plasma corticosterone response to a psychological stress (10 min of 114 dB white noise) was significantly attenuated by this steroid manipulation. Furthermore, simultaneous infusion of the selective oxytocin receptor antagonist desGlyNH(2), d(CH(2))(5)[Tyr(Me)(2),Thr(4)]OVT during the period of progesterone withdrawal reversed this attenuation of noise-induced HPA activation, indicating a role for endogenous oxytocin in this effect. Thus, mimicking the steroid profile of late pregnancy leads to a reduction in anxiety behavior and attenuates HPA activity induced by mild stress. These effects appear to be mediated through the involvement of central oxytocin neurotransmission.

A number of transcription factors have been implicated in the development of the hypothalamo-neurohypophysial system (HNS). Null mutations for these factors caused severe defects in proliferation, migration and survival during early embryogenesis. While they have informed about early events of HNS developments no insights in mechanisms of late development and maturation of this major peptidergic system have been obtained as yet. In a screen for adult-expressed homeobox genes we identified Uncx4.1 as a gene expressed in adult and embryonic magnocellular neurons of the (HNS). Null mutation of Uncx4.1 left these neurons viable and able to express neuropeptides. However, the connectivity of magnocellular neurons with posterior pituitary elements was compromised. As a consequence neuronal fibres traversed to the adenohypophysis. The penetrance of this phenotype was about 50%. The data show a selective role of Uncx4.1 in controlling the development of connections of hypothalamic neurons to pituitary elements, allowing central neurons to reach the peripheral blood circulation and to deliver hormones for control of peripheral functions.

Estrogen receptor-alpha (ER alpha) levels in gonadotropes are increased during the follicular phase of the ovine estrous cycle, a time of increased frequency of pulsatile secretion of GnRH and elevated plasma estrogen levels. In the present study, our first aim was to determine which of these factors causes the rise in the number of gonadotropes with ER alpha. Ovariectomized hypothalamo-pituitary disconnected ewes (n = 4-6) received the following treatments: 1) no treatment, 2) injection (im) of 50 microg estradiol benzoate (EB), 3) pulses (300 ng iv) of GnRH every 3 h, 4) GnRH treatment as in group 3 and EB treatment as in group 2, 5) increased frequency of GnRH pulses commencing 20 h before termination, and 6) GnRH treatment as in group 5 with EB treatment. These treatments had predictable effects on plasma LH levels. The number of gonadotropes in which ER alpha was present (by immunohistochemistry) was increased by either GnRH treatment or EB injection, but combined treatment had the greatest effect. Immunohistochemistry was also performed to detect phosphorylated cAMP response element binding protein (pCREB) and Fos protein in gonadotropes. The number of gonadotropes with Fos and with pCREB was increased only in group 6. We conclude that either estrogen or GnRH can up-regulate ER alpha in pituitary gonadotropes. On the other hand, during the period of positive feedback action of estrogen, the appearance of pCREB and Fos in gonadotropes requires the combined action of estrogen and increased frequency of GnRH input. This suggests convergence of signaling for GnRH and estrogen.

Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis is a commonly recognized feature of many pathological conditions. Abnormal adrenal responses to experimental manipulation have been well documented in patients suffering from chronic fatigue syndrome, anorexia nervosa and major depression. Yet no defect of any single organ, gland or brain region has been identified as a cause of these abnormalities. The disruption of the HPA axis that occurs in these conditions can be understood if an interfering factor is present in these patients. Evidence indicates that this interfering factor is adrenocorticotropin hormone (ACTH) autoantibodies. Chronic high levels of ACTH autoantibodies will significantly disrupt the HPA axis and force the body to compensate for an impaired cortisol response. The resulting effect of chronic ACTH autoantibody interference is the manifestation of adrenocortical insufficient symptoms and psychological disturbances. Some symptoms of chronic fatigue syndrome, anorexia nervosa and major depression, such as anxiety, are the adverse effects of mechanisms compensating for less effective ACTH due to autoantibodies. Furthermore, these patients engage in extraordinary behaviors, such as self-injury, to increase their cortisol levels. When this compensation is inadequate, symptoms of adrenocortical insufficiency appear. Corticosteroid supplements have been demonstrated to be an effective treatment for chronic fatigue syndrome, anorexia nervosa and major depression. It allows the patients to have the corticosteroids they require for daily functioning and daily stressors. This therapy will relieve the patients of their symptoms of adrenocortical insufficiency and permit their cortisol-stimulating mechanisms to operate at levels that will not cause pathological problems.

Introduction: We report the magnetic resonance imaging (MRI) of a case of Langerhans cell histiocytosis in the pituitary. Isolated central nervous system involvement is uncommon., Case Report: An eighteen-years old female patient who had an acute onset of central diabetes insipidus because of the Langerhans cell histiocytosis. The MRI evidenced a lesion in the hypothalamic-pituitary axis. The hyperintensity in the posterior pituitary lobe, which is seen in normal subjects on T1-weighted images, was absent. The pituitary stalk was thickened and enhanced homogeneously following contrast administration. During the follow-up, the infundibullar lesion extended to the hypothalamic region and other systemic manifestations appeared. Diagnosis of Langerhans cell histiocytosis was confirmed by lung biopsy. After radiotherapy and chemotherapy, MRI showed regression of the hypothalamic-pituitary lesion., Conclusion: The combination of these findings, although nonspecific of Langerhans cell histiocytosis, should nevertheless prompt further studies, including chest films, bone scanning and temporal bone computerized tomography in order to narrow the differential diagnosis.

A comprehensive morphological-and-histochemical study of neuroendocrinal internals in cases of ethanol poisonings was undertaken. Actual forensic medical materials were used (62 cadavers) to make morphometry examinations of the hypothesis and adrenal glands. Besides, the distribution of alcohol dehydrogenase and acetaldehyde dehydrogenase was investigated in the mediatory differential brain sections, i.e. cerebellum, locus coeruleus, dorsal raphe nucleus, hypothalamus and adrenal glands. A differential distribution of ethanol-oxidizing enzymes as well as their changes in ethanol lethal poisoning were established; additionally, a variety of morphological signs were defined, which enable the differential diagnosis of a death reason in acute alcoholic intoxication.

Objective: The purpose of the present study was to investigate whether lifelong secretion of high levels of GH, characteristic of Laron syndrome, leads to an increase in the size of the pituitary gland., Methods: Eleven patients (six females, five males) with Laron syndrome underwent magnetic resonance imaging of the pituitary region with a system operating at 0.5 T. There were nine adults aged 36-68 Years and two children, a 4-Year-old boy and a 9-Year-old girl. The latter patient had been treated with IGF-I (150-180 mg/kg per day) since the age of 3 Years; all the other patients were untreated. The height of the adenohypophysis was measured on the sagittal images and compared with reference values for age and sex., Results: The height of the adenohypophysis was within the normal range for age and gender in all patients, except for one male, who had a small gland. No congenital anomalies of the pituitary-hypothalamic region were detected., Conclusion: Despite the lifelong high levels of GH, no pituitary hypertrophy was detected. The anatomy of the pituitary-hypothalamic region in Laron syndrome is normal.

Background: Disturbances in the GH/IGF-I axis are reported in 25-60% of short children born small for gestational age (SGA). We hypothesized that these abnormalities might be related to abnormalities in the pituitary region. Therefore, the results of magnetic resonance imaging (MRI) of short SGA children were compared to MRI results of other groups of short children and to normal controls., Patients and Methods: MRI was performed in four groups of short children: SGA children without GH deficiency (SGA group; n = 17), SGA children with isolated GH deficiency (SGA + IGHD group; n = 10), non-SGA children with isolated GH deficiency (IGHD group; n = 24) and non-SGA children with multiple pituitary hormone deficiencies (MPHD group; n = 15). MRI was also performed in children with normal stature (control group; n = 13). Pituitary height (PH) and thickness of the pituitary stalk (PS) were measured and their relationship with the maximum GH peak during a GH stimulation test, serum IGF-I and IGFBP-3 levels was evaluated., Results: Short SGA children either with or without IGHD did not show major anatomical abnormalities in the hypothalamic-pituitary region in contrast to 58% of the non-SGA IGHD children and 87% of the MPHD children who had anatomical abnormalities. PH in SGA children without GHD was normal whereas it was significantly lower in SGA children with IGHD. The lowest PHs were measured in non-SGA children with MPHD. A moderate decrease in PH was associated with significantly lower maximum serum GH peaks and lower serum IGF-I and IGFBP-3 levels., Conclusion: Measuring PHs in children with less severe GHD, who underwent MRI as part of the diagnostic process, might support the diagnosis of GHD even in the absence of anatomical abnormalities. Our study demonstrates that there is no indication to perform MRI of the pituitary region in short children born SGA without GHD.

Langerhans cell histiocytosis (LCH) is a rare disorder in which granulomatous deposits occur at multiple sites within the body, but which often involves the hypothalamo-pituitary axis (HPA). Although diabetes insipidus (DI) is a well recognized complication, the frequency of anterior pituitary and other nonendocrine hypothalamic (NEH) involvement has not been well defined, particularly in adult patients with the disease. We have evaluated the frequency and progression of LCH-related anterior pituitary and other NEH dysfunction and their responses to treatment in 12 adult patients with histologically proven LCH and DI. They were followed up for a median of 11.5 yr (range, 3-28 yr) after the diagnosis of DI was made. Study evaluations comprised clinical (including formal psychometric assessment where appropriate), basal and dynamic pituitary function tests, and radiology with computed tomography and/or magnetic resonance imaging scanning. Eleven patients received systemic treatment, and 5 patients received external beam radiotherapy confined to the HPA. The median age at diagnosis of DI was 34 yr (range, 2-47 yr); DI was the presenting symptom in four patients, whereas the remaining eight each developed DI 1-20 yr (median, 2 yr) after the diagnosis of LCH. Eight patients developed one or more anterior pituitary hormonal deficiencies at a median of 4.5 yr (range, 2-22 yr) after the diagnosis of DI: GH deficiency developed in eight patients (median, 2 yr; range, 2-22 yr), FSH-LH deficiency in 7 patients (median, 7 yr; range, 2-22 yr), and TSH and ACTH deficiency in five patients (median, 10 yr; range, 3-16 and 3-19 yr), respectively; five patients developed panhypopituitarism. In addition, seven patients with anterior pituitary dysfunction also developed symptoms of other NEH dysfunctions at a median of 10 yr (range, 1-23 yr): five morbid obesity (body mass index, >35), five short term memory deficits, four sleeping disorders, two disorders of thermoregulation, and one adipsia. All patients developed disease outside of the hypothalamus during the course of the study, and no fluctuation of disease activity in the HPA region was noted. Radiological examination of the HPA was abnormal in each of the eight patients with anterior pituitary involvement and in the seven patients with NEH dysfunction (one or more abnormalities): seven had thickening of the infundibulum, and one had hypothalamic and thalamic signal changes. All patients who had a magnetic resonance imaging scan had absence of the bright spot of the posterior pituitary on the T1-weighted sequences, and in four patients with DI and normal anterior pituitary function this was the only abnormality. The five patients who received radiotherapy to the HPA achieved a partial or complete radiological response, and there was no evidence of tumor progression in this region. No form of therapy, including chemotherapy, improved any established hormonal deficiencies or symptoms of NEH. In summary, in our adult patients with hypothalamic LCH and DI, anterior pituitary hormonal deficiencies developed in 8 of 12 patients; these occurred over the course of 20 yr. They were frequently accompanied by structural changes of the HPA, although these were often subtle in nature. In addition, symptoms of NEH dysfunction developed in up to 90% of such patients and complicated management. Radiotherapy may be useful in achieving local control of tumor, but established anterior, posterior pituitary, and other NEH dysfunctions do not improve in response to current treatment protocols. Patients with LCH and DI, particularly those with multisystem disease and a structural lesion on radiology, should undergo regular and prolonged endocrine assessment to establish anterior pituitary deficiency and provide appropriate hormonal replacement.