Diagnosing and treating anterior pituitary hormone deficiency in pediatric patients.

Hypopituitarism, or the failure to secrete hormones produced by the anterior pituitary (adenohypophysis) and/or to release hormones from the posterior pituitary (neurohypophysis), can be congenital or acquired. When more than one pituitary hormone axis is impaired, the condition is known as combined pituitary hormone deficiency (CPHD). The deficiency may be primarily due to a hypothalamic or to a pituitary disorder, or concomitantly both, and has a negative impact on target organ function. This review focuses on the pathophysiology, diagnosis and management of anterior pituitary hormone deficiency in the pediatric age. Congenital hypopituitarism is generally due to genetic disorders and requires early medical attention. Exposure to toxicants or intrauterine infections should also be considered as potential etiologies. The molecular mechanisms underlying the fetal development of the hypothalamus and the pituitary are well characterized, and variants in the genes involved therein may explain the pathophysiology of congenital hypopituitarism: mutations in the genes expressed in the earliest stages are usually associated with syndromic forms whereas variants in genes involved in later stages of pituitary development result in non-syndromic forms with more specific hormone deficiencies. Tumors or lesions of the (peri)sellar region, cranial radiation therapy, traumatic brain injury and, more rarely, other inflammatory or infectious lesions represent the etiologies of acquired hypopituitarism. Hormone replacement is the general strategy, with critical periods of postnatal life requiring specific attention.

Perioperative fluctuation and overall evaluation of adenohypophyseal hormone secretion in patients with nonfunctioning pituitary adenoma.

OBJECTIVE: Perioperative adenohypophyseal hormone assessment can improve therapeutic strategies and be used to evaluate the prognosis of pituitary adenomas. An individual hormone level does not entirely reflect the pituitary gland. Thus, this study aimed to analyze perioperative hormonal changes and propose a normalized method to facilitate overall assessment of the adenohypophysis. METHODS: The authors retrospectively analyzed 89 male patients with nonfunctioning pituitary adenoma (NFPA) who underwent transsphenoidal surgery. Preoperative clinical data, imaging data, and perioperative hormone levels of the anterior pituitary gland were evaluated. Hormone values were rescaled using minimum-maximum normalization. The sum of the normalized hormone levels was defined as the total hormonal rate (THR). RESULTS: Preoperative findings indicated correlations among different adenohypophyseal hormones. Luteinizing hormone (p = 0.62) and adrenocorticotropic hormone (p = 0.89) showed no significant changes after surgery, but growth hormone levels increased (p < 0.001). On the contrary, the levels of thyroid-stimulating hormone (p < 0.001), follicle-stimulating hormone (p = 0.02), and prolactin (p < 0.001) decreased. THR indicated a significant postoperative reduction in adenohypophyseal function (p = 0.04). Patients with postoperative hypopituitarism had significantly lower THR than those without (p = 0.003), with an area under the curve of 0.66. For NFPAs that presented with normal preoperative hormone levels, THR was a good clinical predictor of immediate postoperative hypopituitarism, with an area under the curve of 0.74. CONCLUSIONS: The normalized synthesis index of hormones is a novel and clinically valuable method used to reflect adenohypophyseal secretion. Compared with individual hormones, these results indicated that THR can facilitate the analysis of general hormone levels despite various fluctuations in adenohypophyseal hormones. THR may also contribute to the effective prediction of short-term surgery-induced hypopituitarism.

The silent variants of pituitary tumors: demographic, radiological and molecular characteristics.

INTRODUCTION: Tumors of the anterior pituitary gland (PTs) are mostly benign tumors with a low prevalence, which has nevertheless increased with advances in brain radiology techniques. Nearly half of PTs are not associated with a clinical endocrine syndrome. These tumors have been indistinctly named non-functioning pituitary adenomas (NFPAs) or silent pituitary tumors (SPTs) and the mechanisms of silencing are not fully known. AIM: To study the frequency and characterize the silent variant of PTs in a large local series, and to assess their pituitary adenohypophyseal gene expression. METHODS: This observational, cross-sectional study was performed in a Pituitary Tumor Center of Excellence and involved 268 PTs. After identifying the different subtypes according to the immunohistochemical (IHC) expression of adenohypophyseal hormones, we studied their gene expression by RT-qPCR. RESULTS: We found that silent tumors were larger and more invasive, but not more proliferative than their functional counterparts. The RT-qPCR complements the IHC typification of PTs, reducing the proportion of null-cell subtype. Finally, some silent PT subtype variants showed lower specific adenohypophyseal hormone gene expression than their functional counterparts, which may contribute to the absence of endocrine manifestations. CONCLUSIONS: This paper highlights the importance of identifying the silent variant of the PTs subtypes. As expected, silent tumors were larger and more invasive than their functioning counterparts. However, there was no difference in the proliferation activity between them. Finally, the lower specific gene expression in the silent than in the functioning counterparts of some PTs subtypes gives insights into the silencing mechanisms of PTs.

Prevalence of low lean mass in patients with adult growth hormone deficiency with or without low-dose growth hormone therapy.

OBJECTIVE: The importance of muscle mass has been emphasized in various studies, and growth hormone (GH) deficiency is tightly associated with lean mass loss. Therefore, we aimed to investigate the prevalence of low lean mass in patients with adult growth hormone deficiency (AGHD) who received or did not receive GH therapy. METHODS: In this retrospective study, we included patients diagnosed with AGHD by using the insulin tolerance test (ITT) in our hospital. Patients without completed follow-up data were excluded, and data for 56 patients were analysed. Twenty-six patients who had received GH therapy for more than 6 months, based on the medical record, were included in the GH group and received recombinant human growth hormone (rhGH) at a dose of 0.5 IU/d. Thirty patients who had not previously received GH treatment were included in the non-GH group. Many anthropometric and blood biochemical indicators were measured. Body composition was measured on a dual-energy X-ray-absorptiometry (DXA) scanner. Low lean mass was defined as a skeletal muscle index (SMI) <7.0 kg/m2 in males or 5.7 kg/m2 in females. Statistical analyses were performed using GraphPad Prism 5.0. RESULTS: Compared to the non-GH group, the patients who received GH therapy had significantly lower total cholesterol (TC), low-density lipoprotein cholesterol (LDL-c) and fasting plasma glucose (FPG). The percentage of patients with low lean mass in GH and non-GH groups was 30.77% and 60%, respectively. The percentage of total lean was lower in the GH group than in the non-GH group, but the difference in total lean mass was not statistically significant. Conversely, patients with GH treatment had significantly lower fat mass and percentage than non-GH-treated patients (P < 0.05). The GH group had significantly higher serum levels of both IGF-1 and IGFBP3. Moreover, both IGF-1 and IGFBP3 were significantly correlated with SMI (r2  = 0.275, P = 0.003, and r2  = 0.138, P = 0.005, respectively). CONCLUSIONS: Our data showed that AGHD patients who received low-dose GH treatment had a lower prevalence of low lean mass than those who did not receive GH treatment. Patients with GH treatment had significantly lower cardiovascular risk factors, especially the lipid profile.

[A Pediatric Case of Xanthogranuloma in the Suprasellar Region Detected by a Severe Short Stature after 6 Years Growth Failure].

Here we report a case of a 12-year-old girl who was referred to our department because of marked short stature of more than -5 SD below the median. Although her growth failure began suddenly at 6 years of age, she never had an examination because she had no other symptoms. Brain MRI examination suggested a tumor in the suprasellar region, and endocrine examination revealed combined pituitery hormone deficiency due to the tumor. Before surgery, the supplementation with hydrocortisone and levothyroxine was initiated. The pathological diagnosis of the surgically removed tumor was xanthogranuloma. The pattern of her growth curve showed a growth failure with sudden onset, which is a typical pattern of short stature secondary to pituitary disfunction including growth hormone deficiency associated with brain tumors. This case suggests that growth failure could be the only symptom in pediatric cases with brain tumors. Improved awareness regarding the association of growth failure with brain tumors is needed for earlier diagnosis and treatment. Furthermore, the growth curves should be carefully evaluated in regular health examinations at school.

Alteration of ghrelin/obestatin ratio in adolescence with polycystic ovarian syndrome.

Ghrelin, an endoggenous for the growth hormone secretagogue receptor, has been shown to participate in the regulation of energy homeostasis and pituitary hormone secretion. Obestatin, encoded by the same gene as ghrelin, is described as a physiological opponent of ghrelin. Ghrelin and obestatin are altered in polycystic ovary syndrome (PCOS), which is characterized by insulin resistance and pituitary hormone secretion disorder. The aim of this study was to evaluate ghrelin/obestatin imbalance in relation to insulin resistance and pituitary hormone in adolescence with PCOS. This restrospective case-control study included 33 adolescence with PCOS and 38 control adolescence. Ghrelin and obestatin concentrations in serum were determined by RIA, and the serum fasting glucose and Insulin were determined by the glucose oxidase color method and INS-EASIA. The serum LH and FSH were measured by highly specific hemiluminescence immunoassays. We found that the serum ghrelin levels and ghrelin/obestatin ratio were significant lower in PCOS group than in control group, and the serum obestatin levels were significant higher in PCOS group than in control group. The ghrelin/obestatin ratios were negatively correlation with LH/FSH ratio and insulin resistant index in PCOS group. The findings of this study suggest that ghrelin/obestatin imbalance may play a role in pathogenesis of adolescent PCOS.

[Clinical characteristics of central diabetes insipidus: a retrospective analysis of 230 cases].

Objective: To evaluate the clinical characteristics and etiologies of central diabetes insipidus (CDI). Methods: The clinical data of 230 patients with CDI in the Department of Endocrinology of Chinese PLA General Hospital from 2008 June to 2014 December were collected and analyzed retrospectively. Results: The three most common causes of CDI were idiopathic CDI, lymphocytic hypophysitis and intracranial germ cell tumors. Among all the CDI, the idiopathic CDI accounted for 37.48%. There were significant differences in age onset and gender distribution among the different causes of CDI. The patients with intracranial germ cell tumors [age of onset(19.2±10.2) years] were younger than the other types of CDI. Germ cell tumors patients were more common in male, and lymphocytic hypophysitis patients were more common in female. The most frequent abnormality of anterior pituitary in patients with CDI was growth hormone deficiency, followed by hypogonadism, adrenal insufficiency and hypothyroidism. The dysfunction of thyroid axis and adrenal axis in patients with germ cell tumor was more common than those in patients with idiopathic and lymphocytic hypophysitis. Conclusions: The most common causes of central diabetes insipidus were idiopathic CDI, lymphocytic hypophysitis and intracranial germ cell tumors. There were differences in age of onset, gender distribution and abnormal production of anterior pituitary hormones among all causes of CDI patients.

Hypopituitarism.

Hypopituitarism refers to deficiency of one or more hormones produced by the anterior pituitary or released from the posterior pituitary. Hypopituitarism is associated with excess mortality, a key risk factor being cortisol deficiency due to adrenocorticotropic hormone (ACTH) deficiency. Onset can be acute or insidious, and the most common cause in adulthood is a pituitary adenoma, or treatment with pituitary surgery or radiotherapy. Hypopituitarism is diagnosed based on baseline blood sampling for thyroid stimulating hormone, gonadotropin, and prolactin deficiencies, whereas for ACTH, growth hormone, and antidiuretic hormone deficiency dynamic stimulation tests are usually needed. Repeated pituitary function assessment at regular intervals is needed for diagnosis of the predictable but slowly evolving forms of hypopituitarism. Replacement treatment exists in the form of thyroxine, hydrocortisone, sex steroids, growth hormone, and desmopressin. If onset is acute, cortisol deficiency should be replaced first. Modifications in replacement treatment are needed during the transition from paediatric to adult endocrine care, and during pregnancy.

The incidence of anterior pituitary hormone deficiencies in patients with microprolactinoma and idiopathic hyperprolactinaemia.

INTRODUCTION: Patients with microprolactinoma and idiopathic hyperprolactinaemia are not generally considered to be at risk of hypopituitarism and are therefore not routinely screened for this abnormality. In our clinical practice, we have observed a number of patients with nonmacroadenomatous hyperprolactinaemia to have anterior pituitary hormone deficits. AIMS: We aimed to establish the frequency and clinical significance of anterior pituitary hormone deficiencies, comparing patients with radiologically proven microprolactinomas and patients with idiopathic hyperprolactinaemia. STUDY DESIGN: We retrospectively examined the casenotes of 206 patients with hyperprolactinaemia from our centre. Patients who did not fit the profile of surgically naïve microprolactinoma or idiopathic hyperprolactinaemia or who had incomplete data were excluded, resulting in a study group of 56 patients. RESULTS: A total of 35 patients with MRI evidence of microprolactinoma were identified, three (8.57%) of whom had one or more anterior pituitary hormone deficiencies. A total of 21 patients with MRI-negative idiopathic hyperprolactinaemia were identified, nine (42%) of whom had one or more anterior pituitary hormone deficiencies (P<.01). Only one patient in the MRI-positive group had deficiency that required hormone replacement, in contrast six patients in the MRI-negative group had deficiencies that were of clinical significance and which required hormone replacement. SUMMARY: This study shows a clinically significant incidence of anterior pituitary hormone deficiency in patients with idiopathic hyperprolactinaemia. The authors recommend that dynamic pituitary assessment should be considered routinely in this patient group. A prospective study would be required to assess the underlying cause for these abnormalities, as they suggest a nontumour pan-pituitary process.

Clinical presentation and outcome of children with central diabetes insipidus associated with a self-limited or transient pituitary stalk thickening, diagnosed as infundibuloneurohypophysitis.

OBJECTIVE: Despite lymphocytic or autoimmune infundibuloneurohypophysitis (INH) is an increasingly recognized aetiology in children with central diabetes insipidus (CDI); clinical data on epidemiology (clinical evolution, predisposing factors, complications), diagnosis and management of this entity are limited and mostly based on published case reports. The aim of this study was to gain a broader insight in the natural history of this disease by analysing the clinical presentation, radiological pituitary stalk changes, associated autoimmunity and hormonal deficiencies in children with CDI and a self-limiting or transient stalk thickening (ST), diagnosed as autoimmune infundibuloneurohypophysitis, during the last 15 years in four Belgian university hospitals. DESIGN AND PATIENTS: The medical files of nine CDI patients with a ST at initial presentation and no signs of Langerhans cell histiocytosis or germinoma at presentation and/or during follow-up of more than 1.5 years were reviewed. RESULTS: Age at presentation ranged from 3 to 14 years. Two patients had a positive family history of autoimmunity. Three children presented with associated growth failure, two with nausea and one with long-standing headache. Median maximal diameter of the stalk was 4.6 mm (2.7-10 mm). Four patients had extra-pituitary brain anomalies, such as cysts. One patient had central hypothyroidism, and another had a partial growth hormone deficiency at diagnosis. Within a mean follow-up of 5.4 (1.5-15) years, stalk thickening remained unchanged in two patients, regressed in one and normalized in six children. CDI remained in all, while additional pituitary hormone deficiencies developed in only one patient. CONCLUSIONS: In this series of children INH with CDI as initial presentation, CDI was permanent and infrequently associated with anterior pituitary hormone deficiencies, despite a frequent association with nonstalk cerebral lesions.

Primary lymphocytic hypophysitis: Clinical characteristics and treatment of 50 cases in a single centre in China over 18 years.

OBJECTIVE: Primary lymphocytic hypophysitis (LYH) is rare, and it is often evaluated in a small case series. This study aimed to describe the diagnosis and treatment of primary LYH in a larger cohort. DESIGN: A retrospective study of the diagnosis and treatment of primary LYH was conducted at Peking Union Medical College Hospital from 1999 to 2016. PATIENTS: Fifty patients (28 histologically diagnosed and 22 clinically-diagnosed) were eligible for inclusion. MEASUREMENTS: Clinical, endocrine, pathological and imaging findings; therapies and outcomes were assessed. Ordinal logistic regression analysis was used to evaluate the association between the clinical parameters and outcomes (eg, improvements in pituitary function, regression of lesion size on MRI and disease recurrence). RESULTS: Central diabetes insipidus (CDI) (72.0%) was the most common endocrine dysfunction. Hypogonadotropic hypogonadism was the most frequently observed (60.0%) manifestation of anterior pituitary dysfunction; adrenal insufficiency was the third most common (26.0%) manifestation; and IGF-1 axis defects were the least frequent (22.0%). Thickening of the pituitary stalk was the most frequent (96.0%) imaging finding, and 78.0% of the patients exhibited both intrasellar and suprasellar expansion. Pharmacological dose of glucocorticoids was identified to be significantly associated with increased odds of anterior pituitary function improvement. No observed covariates were significantly associated with improvement of CDI and recurrence. CONCLUSION: The sequence of anterior pituitary deficiencies in Chinese primary LYH patients was atypical (LH/FSH>TSH>ACTH>IGF-1 axis deficiency). A pharmacological dose of glucocorticoids was significantly associated with the improved anterior pituitary insufficiency.

Rasd1 is an estrogen-responsive immediate early gene and modulates expression of late genes in rat anterior pituitary cells.

Dexamethasone-induced Ras-related protein 1 (Rasd1) is a member of the Ras superfamily of monomeric G proteins that have a regulatory function in signal transduction. Here we investigated the role of Rasd1 in regulating estrogen-induced gene expression in primary cultures of rat anterior pituitary cells. Rasd1 mRNA expression in anterior pituitary cells decreased after treatment with forskolin or serum and increased after treatment with 17ß-estradiol (E2). Increases in Rasd1 mRNA expression occurred as early as 0.5 h after E2 treatment, peaked at 1 h and were sustained for as long as 96 h. This rapid and profound increase in Rasd1 mRNA expression induced by E2 was also seen in GH4C1 cells, an estrogen receptor-positive somatolactotroph cell line. Among pituitary estrogen-responsive late genes studied, basal mRNA expression of Pim3 and Igf1 genes was decreased by RNA interference-mediated knockdown of Rasd1 expression, whereas basal expression of the Giot1 gene was increased. Moreover, Rasd1 knockdown enhanced stimulation of Pim3 mRNA expression and attenuated inhibition of Fosl1 mRNA expression 24 h after E2 treatment. These changes in mRNA expression were accompanied by enhanced activity of promoters containing CRE, AP-1 and SRE binding sequences. These results suggest that Rasd1 is an estrogen-responsive immediate early gene and modulates E2 induction of at least several late genes in anterior pituitary cells.

Relationship of each anterior pituitary hormone deficiency to the size of non-functioning pituitary adenoma in the hospitalized patients.

Non-functioning pituitary adenoma (NFPA) is often associated with hypopituitarism. Diagnosis of hypopituitarism is important because of its poor prognosis and low quality of life. Among hypopituitarism, it is difficult to diagnose secondary adrenocortical insufficiency and GH deficiency without hormone stimulation test. Therefore, the aim of our study was to identify patients with NFPA who require more careful endocrinological examination. We examined the relationship between NFPA size and the prevalence of each hypopituitarism or the response of each anterior pituitary hormone by insulin tolerance test, LHRH test and TRH test. We studied 63 patients with NFPA admitted for evaluation of pituitary function and surgical indication. They were classified three groups by tumor diameter. The prevalence of GH deficiency, male secondary hypogonadism, secondary hypothyroidism and PRL deficiency were higher in the group of larger tumor diameter (p<0.0001, p<0.05, p<0.05 and p<0.05, respectively). However, that of secondary adrenocortical insufficiency only tended to be higher (p=0.07). In the group with small NFPA (less than 20 mm), the prevalence of secondary adrenocortical insufficiency was 38% although those of GH deficiency, male secondary hypogonadism, secondary hypothyroidism and PRL deficiency were 0%, 0% and 8% and 9%, respectively. Anterior pituitary hormone responses except TSH had significantly negative correlation with tumor diameter (ACTH: r=-0.40, GH: r=-0.57, LH: r=-0.69, FSH: r=-0.46, PRL: r=-0.36). The results suggested physicians should proactively suspect GH deficiency, male secondary hypogonadism and secondary hypothyroidism in patients with larger NFPA. On the other hand, adrenocortical function should be examined even in patients with small NFPA.

Dynamics of anterior pituitary immunoreactive gonadotrophs in moulted hens supplemented with protein, symbiotic and probiotics.

The present work delineates redistribution patterns of the hormone-producing cells of the anterior pituitary, after the phase of moulting. Two hundred single comb White Leghorn hens at the end of their first production cycle (Age = 70 week) were purchased from the commercial poultry farm and were induced to moult by high-dietary zinc (3 g/kg feed/day) after 1 week of acclimatization, at the experimental research station, Department of Physiology and Pharmacology, University of Agriculture, Faisalabad. The moulted birds were equally (n = 50) and randomly allocated to their respective groups as G1 (control; CP (Crude protein) 16%, no supplement), G2 (CP18%, no other supplement), G3 (CP16%, symbiotic at does rate of 85 mg/l in drinking water daily) and G4 (CP16%, probiotic at dose rate of 85 mg/l in drinking water daily). Ten birds were slaughtered in each group at 5% and at peak of post-moult production stage to collect their pituitary glands. An earlier post-moult production recovery, sustained and lengthier production span was seen in the G2 as compared to all other groups. The lowest production and an earlier production decline were seen in G1. The cell diameter and area of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) gonadotroph increased (p ≤ 0.01) in G2 and G3 as compared to G1. The FSH gonadotroph nucleus diameter and area did increase (p ≤ 0.01) in G2 and G3, while LH gonadotroph nucleus diameter and area decreased (p ≤ 0.01) in G2 and G3 as compared to G1. The increased FSH and LH gonadotroph diameter in protein and symbiotic supplemented birds is accountable for the increased egg production in these groups.

The somatotropic axis and longevity in mice.

The somatotropic signaling pathway has been implicated in aging and longevity studies in mice and other species. The physiology and lifespans of a variety of mutant mice, both spontaneous and genetically engineered, have contributed to our current understanding of the role of growth hormone and insulin-like growth factor I on aging-related processes. Several other mice discovered to live longer than their wild-type control counterparts also exhibit differences in growth factor levels; however, the complex nature of the phenotypic changes in these animals may also impact lifespan. The somatotropic axis impacts several pathways that dictate insulin sensitivity, nutrient sensing, mitochondrial function, and stress resistance as well as others that are thought to be involved in lifespan regulation.

Relationship between pituitary stalk (PS) visibility and the severity of hormone deficiencies: PS interruption syndrome revisited.

CONTEXT: Pituitary stalk interruption syndrome (PSIS) is a rare cause of combined pituitary hormone deficiency characterized by a triad shown in pituitary imaging, yet it has never been evaluated due to the visibility of pituitary stalk (PS) in imaging findings. OBJECTIVE: The major objective of the study was to systematically describe the disease including clinical presentations, imaging findings and to estimate the severity of anterior pituitary hormone deficiency based on the visibility of the PS. METHODS: This was a retrospective study including 74 adult patients with PSIS in Shanghai Clinical Center for Endocrine and Metabolic Diseases between January 2010 and June 2014. Sixty had invisible PS according to the findings on MRI, while the rest had a thin or intersected PS. Basic characteristics and hormonal status were compared. RESULTS: Of the 74 patients with PSIS, age at diagnosis was 25 (22-28) years. Absent pubertal development (97·3%) was the most common presenting symptom, followed by short stature. Insulin tolerance test (ITT) and gonadotrophin-releasing hormone (GnRH) stimulation test were used to evaluate the function of anterior pituitary. The prevalence of isolated deficiency in growth hormone (GH), gonadotrophins, corticotrophin and thyrotrophin were 100%, 97·2%, 88·2% and 70·3%, respectively. Although the ratio of each deficiency did not vary between patients with invisible PS and with visible PS, panhypopituitarism occurred significantly more frequent in patients with invisible PS. Patients with invisible PS had significantly lower levels of luteinizing hormone (LH), follicle stimulation hormone (FSH) and hormones from targeted glands including morning cortisol, 24-h urine free cortisol, free triiodothyronine (FT3), free thyroxine (FT4) and testosterone (T) in male than patients with visible PS. Moreover, patients with invisible PS had lower peak LH and FSH in GnRH stimulation test, and higher peak cortisol in ITT while peak GH remained unchanged between two groups. CONCLUSIONS: The prevalence of multiple anterior pituitary hormone deficiency was high in adult patients with PSIS. And more importantly, we found the visibility of PS shown on MRI might be an indication of the severity of PSIS.

[Sheehan's syndrome--a forgotten disease with 100 years' history]. / Zespól Sheehana--zapomniana choroba ze stuletnia historia.

Although named after Harold Sheehan, postpartum ischemic pituitary necrosis was reported for the first time 100 years ago in Przeglad Lekarski by Leon Konrad Glinski. In the majority of cases, the syndrome is a consequence of severe postpartum bleeding episode resulting in severe hypotension or hemorrhagic shock. The frequency of Sheehan's syndrome has decreased in developed countries as a result of improved obstetrical care, but this clinical entity remains a common cause of hypopituitarism in developing countries. The syndrome is characterized by varying degrees of anterior pituitary dysfunction resulting from the deficiency of multiple pituitary hormones. The order of frequency of hormone loss has generally been found to be growth hormone and prolactin, gonadotropins, ACTH and thyrotropin. Women with Sheehan's syndrome exhibit a variety of signs and symptoms including failure to lactate or resume menses, loss of genital and axillary hair, and often occurring long after delivery clinical manifestations of central hypothyroidism and secondary adrenal insufficiency. Diagnosis is based on laboratory studies, including hormone levels and hormone stimulation tests. Treatment of Sheehan's syndrome involves hormone replacement therapy. The aim of this study is to review current knowledge on clinically relevant aspects of this clinical entity and to provide the reader with recommendations concerning its diagnosis and treatment.

Mutations in NFKB2 and potential genetic heterogeneity in patients with DAVID syndrome, having variable endocrine and immune deficiencies.

BACKGROUND: DAVID syndrome is a rare condition combining anterior pituitary hormone deficiency with common variable immunodeficiency. NFKB2 mutations have recently been identified in patients with ACTH and variable immunodeficiency. A similar mutation was previously found in Nfkb2 in the immunodeficient Lym1 mouse strain, but the effect of the mutation on endocrine function was not evaluated. METHODS: We ascertained six unrelated DAVID syndrome families. We performed whole exome and traditional Sanger sequencing to search for causal genes. Lym1 mice were examined for endocrine developmental anomalies. RESULTS: Mutations in the NFKB2 gene were identified in three of our families through whole exome sequencing, and in a fourth by direct Sanger sequencing. De novo origin of the mutations could be demonstrated in three of the families. All mutations lie near the C-terminus of the protein-coding region, near signals required for processing of NFΚB2 protein by the alternative pathway. Two of the probands had anatomical pituitary anomalies, and one had growth and thyroid hormone as well as ACTH deficiency; these findings have not been previously reported. Two children of one of the probands carried the mutation and have to date exhibited only an immune phenotype. No mutations were found near the C-terminus of NFKB2 in the remaining two probands; whole exome sequencing has been performed for one of these. Lym1 mice, carrying a similar Nfkb2 C-terminal mutation, showed normal pituitary anatomy and expression of proopiomelanocortin (POMC). CONCLUSIONS: We confirm previous findings that mutations near the C-terminus of NFKB2 cause combined endocrine and immunodeficiencies. De novo status of the mutations was confirmed in all cases for which both parents were available. The mutations are consistent with a dominant gain-of-function effect, generating an unprocessed NFKB2 super-repressor protein. We expand the potential phenotype of such NFKB2 mutations to include additional pituitary hormone deficiencies as well as anatomical pituitary anomalies. The lack of an observable endocrine phenotype in Lym1 mice suggests that the endocrine component of DAVID syndrome is either not due to a direct role of NFKB pathways on pituitary development, or else that human and mouse pituitary development differ in its requirements for NFKB pathway function.

GFP-expressing S100ß-positive cells of the rat anterior pituitary differentiate into hormone-producing cells.

Some non-endocrine cells in the pituitary anterior lobe are responsible for providing stem/progenitor cells to maintain hormone-producing cells. In particular, cells expressing S100ß protein, a calcium-binding protein, have been hypothesized to be a pituitary cell resource. Accumulating data have revealed that S100ß-positive cells comprise heterogeneous populations and some of them certainly show stem/progenitor characteristics in vivo. Hence, we examine whether S100ß-positive cells have the capacity to differentiate into endocrine cells, by means of in vivo and in vitro experiments on transgenic rats expressing enhanced green fluorescent protein (EGFP) under the control of the S100ß promoter. Immunohistochemistry of the pituitary confirmed that some S100ß-positive cells expressed SOX2 (SRY [sex-determining region Y]-box 2) and had proliferative activity. Dispersed anterior lobe cells were observed by time-lapse microscopy, followed by immunostaining for hormone and pituitary-transcription-factor1 (PIT1). First, the dispersed anterior lobe cells were immunostained by an antibody against SOX2. S100ß-protein co-localizes with SOX2 (about 89 %). Although 44 of 134 S100ß-positive cells traced were proliferative but negative to any hormones, 14 cells were positive for one of the pituitary hormones and/or PIT1, confirming the presence of all types of hormone-producing cells. Notably, GFP-fluorescence appeared in two hormone-positive cells during culture. On the other hand, we observed hormone-producing cells that were not positive for S100ß at the end of the time-lapse study, despite being initially positive. These findings suggest that S100ß-positive cells cultured from the anterior lobe are capable of developing into hormone-producing cells, although this happens relatively infrequently.