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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.

Abstract Context Silent pituitary adenomas are anterior pituitary tumors with hormone synthesis but without signs or symptoms of hormone hypersecretion. They have been increasingly recognized and represent challenging diagnostic issues. Evidence Acquisition A comprehensive literature search was performed using MEDLINE and EMBASE databases from January 2000 to March 2018 with the following key words: (i) pituitary adenoma/tumor and nonfunctioning; or (ii) pituitary adenoma/tumor and silent. All titles and abstracts of the retrieved articles were reviewed, and recent advances in the field of silent pituitary adenomas were summarized. Evidence Synthesis The clinical and biochemical picture of pituitary adenomas reflects a continuum between functional and silent adenomas. Although some adenomas are truly silent, others will show some evidence of biochemical hypersecretion or could have subtle clinical signs and, therefore, can be referred to as clinically silent or “whispering” adenomas. Silent tumors seem to be more aggressive than their secreting counterparts, with a greater recurrence rate. Transcription factors for pituitary cell lineages have been introduced into the 2017 World Health Organization guidelines: steroidogenic factor 1 staining for gonadotroph lineage; PIT1 (pituitary-specific positive transcription factor 1) for growth hormone, prolactin, and TSH lineage, and TPIT for the corticotroph lineage. Prospective studies applying these criteria will establish the value of the new classification. Conclusions A concise review of the clinical and pathological aspects of silent pituitary adenomas was conducted in view of the new World Health Organization classification of pituitary adenomas. New classifications, novel prognostics markers, and emerging imaging and therapeutic approaches need to be evaluated to better serve this unique group of patients. We present a concise review of the clinical and pathological aspects of silent pituitary adenomas in view of the new World Health Organization classification of pituitary adenomas.

Abstract Context Few data exist about the clinical course of acromegaly, surgical and medical outcomes in patients with GH- and prolactin cosecreting pituitary adenomas (GH&PRL-PAs). Nevertheless, some series described a more aggressive clinic-radiological behavior than in growth hormone–secreting pituitary adenomas (GH-PAs). Objective This work aims to evaluate differences in clinical presentation and in surgical outcomes between GH-PAs and GH&PRL-PAs. Methods A multicenter retrospective study was conducted of 604 patients with acromegaly who underwent pituitary surgery. Patients were classified into 2 groups according to serum PRL levels at diagnosis and immunohistochemistry (IHC) for PRL: a) GH&PRL-PAs when PRL levels were above the upper limit of normal (ULN) and IHC for GH and PRL was positive or PRL levels were greater than 100 ng/dL and PRL IHC was not available (n = 130) and b) GH-PA patients who did not meet the previously mentioned criteria (n = 474). Results GH&PRL-PAs represented 21.5% (n = 130) of patients with acromegaly. The mean age at diagnosis was lower in GH&PRL-PAs than in GH-PAs (P < .001). GH&PRL-PAs were more frequently macroadenomas (90.6% vs 77.4%; P = .001) and tended to be more invasive (33.6% vs 24.7%; P = .057) than GH-PAs. Furthermore, they had presurgical hypopituitarism more frequently (odds ratio 2.8; 95% CI, 1.83-4.38). Insulin-like growth factor ULN levels at diagnosis were lower in patients with GH&PRL-PAs (median 2.4 [interquartile range (IQR) 1.73-3.29] vs 2.7 [IQR 1.91-3.67]; P = .023). There were no differences in the immediate (41.1% vs 43.3%; P = .659) or long-term postsurgical acromegaly biochemical cure rate (53.5% vs 53.1%; P = .936) between groups. However, there was a higher incidence of permanent arginine-vasopressin deficiency (AVP-D) (7.3% vs 2.4%; P = .011) in GH&PRL-PA patients. Conclusion GH&PRL-PAs are responsible for 20% of acromegaly cases. These tumors are more invasive, larger, and cause hypopituitarism more frequently than GH-PAs and are diagnosed at an earlier age. The biochemical cure rate is similar between both groups, but patients with GH&PRL-PAs tend to develop permanent postsurgical AVP-D more frequently.

Amyloids are highly organized cross-β-sheet-rich protein or peptide aggregates that are associated with pathological conditions including Alzheimer's disease and type II diabetes. However, amyloids may also have a normal biological function, as demonstrated by fungal prions, which are involved in prion replication, and the amyloid protein Pmel17, which is involved in mammalian skin pigmentation. We found that peptide and protein hormones in secretory granules of the endocrine system are stored in an amyloid-like cross-β-sheet-rich conformation. Thus, functional amyloids in the pituitary and other organs can contribute to normal cell and tissue physiology.

About 30% of patients with active acromegaly experience paradoxically increased growth hormone (GH) secretion during the diagnostic oral glucose tolerance test (OGTT). Endogenous glucose-dependent insulinotropic polypeptide (GIP) is implicated in this paradoxical secretion. We used the GIP receptor (GIPR) antagonist GIP(3-30)NH2 to test the hypothesis that GIP mediates this paradoxical response when GIPR is abundantly expressed in somatotropinomas. A total of 25 treatment-naive patients with acromegaly were enrolled. Each patient underwent one OGTT during simultaneous placebo infusion and one OGTT during a GIP(3-30)NH2 infusion. Blood samples were drawn at baseline and regularly after infusions to measure GH. We assessed pituitary adenoma size by magnetic resonance imaging and GIPR expression by immunohistochemistry on resected somatotropinomas. For mechanistic confirmation, we applied in vitro and ex vivo approaches. The main outcome measure was the effect of GIP(3-30)NH2 on paradoxical GH secretion during OGTT as a measure of GIP involvement. In 4 of 7 patients with paradoxical GH secretion, GIP(3-30)NH2 infusion completely abolished the paradoxical response (P = .0003). Somatotrophs were available from 3 of 4 of these patients, all showing abundant GIPR expression. Adenoma size did not differ between patients with and without paradoxical GH secretion. Of 25 patients with acromegaly, 7 had paradoxical GH secretion during OGTT, and pharmaceutical GIPR blockade abolished this secretion in 4. Corresponding somatotroph adenomas abundantly expressed GIPR, suggesting a therapeutic target in this subpopulation of patients. In vitro and ex vivo analyses confirmed the role of GIP and the effects of the antagonist.

Abstract Context Congenital combined pituitary hormone deficiency (cCPHD) is the loss of ≥2 pituitary hormones caused by congenital factors. Objective We aimed to estimate the national incidence of cCPHD diagnosed before age 18 years and in subgroups. Methods Patients with cCPHD were identified in the Danish National Patient Registry and Danish hospital registries in the period 1996-2020. Hospital files were reviewed and incidences calculated using background population data. Incidence was the main outcome measure. Results We identified 128 patients with cCPHD; 88 (68.8%) were males. The median (range) age at diagnosis was 6.2 (0.01-19.0) years. The median (25th;75th percentile) number of hormone deficiencies at diagnosis was 3 (3; 4) at <1 year vs 2 (2; 2) at 1-17 years, P < .0001. Abnormal pituitary magnetic resonance imaging findings were seen in 70.3% (83/118). For those born in Denmark aged <18 years at diagnosis (n = 116/128) the estimated national incidence (95% CI) of cCPHD was 10.34 (7.79-13.72) per 100 000 births, with an annual incidence rate of 5.74 (4.33-7.62) per million. In subgroup analysis (diagnosis <1 vs 1-17 years), the incidence was highest in the 1-17 years subgroup, 7.97 (5.77-11.00) vs 1.98 (1.39-2.84) per 100 000 births, whereas the annual incidence rate was highest at <1 year, 19.8 (13.9-28.4) vs 4.69 (3.39-6.47) per million births. Conclusion cCPHD had the highest incidence rate and the most hormone deficiencies in those diagnosed at <1 year. The incidence was highest in the 1-17 years age group, underscoring the need for multiple pituitary hormone investigations throughout childhood and adolescence in children with only 1 hormone deficiency.

The prostate gland is an endocrine-sensitive organ responding to multiple stimuli. Its development and function are regulated by multiple hormones (i.e. steroids such as androgens, estrogens and glucocorticoids) but also by other key hormonal systems such as those comprised by insulin-like growth factor 1 and insulin, which are sourced by different tissues [e.g. testicles/adrenal-gland/adipose-tissue/liver/pancreas, etc.). Particularly important for the endocrine control of prostatic pathophysiology and anatomy are hormones produced and/or secreted by different cell types of the pituitary gland [growth-hormone, luteinizing-hormone, follicle-stimulating hormone, and prolactin, oxytocin, arginine-vasopressin and melanocyte-stimulating hormone], which affect prostate gland function either directly or indirectly under physiological and pathophysiological conditions [e.g. metabolic dysregulation (e.g. obesity), and prostate transformations (e.g. prostate cancer)]. This review summarizes the impact of all pituitary hormone types on prostate gland under these diverse conditions including in vivo and in vitro studies.

Traditional textbook physiology has ascribed unitary functions to hormones from the anterior and posterior pituitary gland, mainly in the regulation of effector hormone secretion from endocrine organs. However, the evolutionary biology of pituitary hormones and their receptors provides evidence for a broad range of functions in vertebrate physiology. Over the past decade, we and others have discovered that thyroid-stimulating hormone, follicle-stimulating hormone, adrenocorticotropic hormone, prolactin, oxytocin and arginine vasopressin act directly on somatic organs, including bone, adipose tissue and liver. New evidence also indicates that pituitary hormone receptors are expressed in brain regions, nuclei and subnuclei. These studies have prompted us to attribute the pathophysiology of certain human diseases, including osteoporosis, obesity and neurodegeneration, at least in part, to changes in pituitary hormone levels. This new information has identified actionable therapeutic targets for drug discovery.This Review discusses newly discovered functions of pituitary hormones on bone, adipose tissue and the brain. Mechanisms of pituitary hormone actions on somatic organs and neural function are outlined. The role of dysregulated pituitary hormone function in multiple diseases and the potential for targeting ligands and receptors therapeutically are discussed.

Sexual size dimorphism (SSD) refers to the phenomenon where males and females of the same species exhibit differences in overall or partial body size, and it is widespread among mammals, birds, reptiles, and fish. Notably, this dimorphism is significantly influenced by the sexually dimorphic secretion of growth hormone (gh), a key pituitary-derived growth regulator. Commonly, the secretion of gh is positively regulated by glucagon family members such as growth hormone-releasing hormone (ghrh) and adenylate cyclase-activating polypeptide 1 (adcyap1). To explore the stimulators for pituitary hormones (especially gh) in the teleost, we performed genome-wide identification and functional characterization of the glucagon family on Chinese tongue sole (Cynoglossus semilaevis) that exhibits typical female-biased sexual size dimorphism. Four members of adcyap1/vasoactive intestinal polypeptide(vip)/ghrh family and ten members of their receptor family were identified. Expression pattern analysis revealed high expression of adenylate cyclase-activating polypeptide 1b (adcyap1b) and its receptors in the brain. Moreover, two alternative splice variants for the adcyap1b gene were discovered, resulting from the skipping of exon 4. Following the acquisition of the two eukaryotic recombinant protein splice variants (ADCYAP1b_tv1 and ADCYAP_tv2) from HEK 293T cells, incubation experiments were conducted using C. semilaevis pituitary cell line. The results demonstrated that both variants promoted the expression of gh, pro-opiomelanocortin (pomc), and corticoliberin (crh), but ADCYAP1b_tv1 had a significantly stronger effect and uniquely stimulated prolactin (prl) and somatolactin (sl). This study demonstrates a functional divergence between the two ADCYAP1b splice variants in teleosts, with ADCYAP1b_tv1 acting as a more potent and versatile pituitary hormone stimulator. Further research on their receptor-binding affinity and downstream signaling pathways would be valuable for exploring the mechanism underlying sexual size dimorphism.

The neural mechanisms underlying memory regulation during sleep are not yet fully understood.We found that melanin concentrating hormone–producing neurons (MCH neurons) in the hypothalamus actively contribute to forgetting in rapid eye movement (REM) sleep. Hypothalamic MCH neurons densely innervated the dorsal hippocampus. Activation or inhibition of MCH neurons impaired or improved hippocampus-dependent memory, respectively. Activation of MCH nerve terminals in vitro reduced firing of hippocampal pyramidal neurons by increasing inhibitory inputs.Wake- and REM sleep–active MCH neurons were distinct populations that were randomly distributed in the hypothalamus. REM sleep state–dependent inhibition of MCH neurons impaired hippocampus-dependent memory without affecting sleep architecture or quality. REM sleep–active MCH neurons in the hypothalamus are thus involved in active forgetting in the hippocampus.