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Endocrine Reviews Nov 2023Based on insights obtained during the past decade, the classical concept of an activated hypothalamus-pituitary-adrenocortical axis in response to critical illness is in...
Based on insights obtained during the past decade, the classical concept of an activated hypothalamus-pituitary-adrenocortical axis in response to critical illness is in need of revision. After a brief central hypothalamus-pituitary-adrenocortical axis activation, the vital maintenance of increased systemic cortisol availability and action in response to critical illness is predominantly driven by peripheral adaptations rather than by an ongoing centrally activated several-fold increased production and secretion of cortisol. Besides the known reduction of cortisol-binding proteins that increases free cortisol, these peripheral responses comprise suppressed cortisol metabolism in liver and kidney, prolonging cortisol half-life, and local alterations in expression of 11βHSD1, glucocorticoid receptor-α (GRα), and FK506 binding protein 5 (FKBP51) that appear to titrate increased GRα action in vital organs and tissues while reducing GRα action in neutrophils, possibly preventing immune-suppressive off-target effects of increased systemic cortisol availability. Peripherally increased cortisol exerts negative feed-back inhibition at the pituitary level impairing processing of pro-opiomelanocortin into ACTH, thereby reducing ACTH-driven cortisol secretion, whereas ongoing central activation results in increased circulating pro-opiomelanocortin. These alterations seem adaptive and beneficial for the host in the short term. However, as a consequence, patients with prolonged critical illness who require intensive care for weeks or longer may develop a form of central adrenal insufficiency. The new findings supersede earlier concepts such as "relative," as opposed to "absolute," adrenal insufficiency and generalized systemic glucocorticoid resistance in the critically ill. The findings also question the scientific basis for broad implementation of stress dose hydrocortisone treatment of patients suffering from acute septic shock solely based on assumption of cortisol insufficiency.
Topics: Humans; Hydrocortisone; Critical Illness; Pro-Opiomelanocortin; Hypothalamo-Hypophyseal System; Adrenal Insufficiency; Hypothalamus; Pituitary Diseases; Adrenocorticotropic Hormone; Pituitary-Adrenal System
PubMed: 37409973
DOI: 10.1210/endrev/bnad021 -
Scientific Reports Sep 2023Preoperative homeostasis of sex hormones in testicular germ cell tumor (TGCT) patients is scarcely characterized. We aimed to explore regulation of sex hormones and...
Preoperative homeostasis of sex hormones in testicular germ cell tumor (TGCT) patients is scarcely characterized. We aimed to explore regulation of sex hormones and their implications for histopathological parameters and prognosis in TGCT using a data-driven explorative approach. Pre-surgery serum concentrations of luteinizing hormone (LH), follicle-stimulating hormone (FSH), testosterone (T), estradiol (E2) and prolactin were measured in a retrospective multicenter TGCT cohort (n = 518). Clusters of patients were defined by latent class analysis. Clinical, pathologic and survival parameters were compared between the clusters by statistical hypothesis testing, Random Forest modeling and Peto-Peto test. Cancer tissue expression of sex hormone-related genes was explored in the publicly available TCGA cohort (n = 149). We included 354 patients with pure seminoma and 164 patients with non-seminomatous germ cell tumors (NSGCT), with a median age of 36 years. Three hormonal clusters were defined: 'neutral' (n = 228) with normal sex hormone homeostasis, 'testicle' (n = 91) with elevated T and E2, low pituitary hormones, and finally 'pituitary' subset (n = 103) with increased FSH and LH paralleled by low-to-normal levels of the gonadal hormones. Relapse-free survival in the hormonal subsets was comparable (p = 0.64). Cancer tissue expression of luteinizing hormone- and follicle-stimulating hormone-coding genes was significantly higher in seminomas, while genes of T and E2 biosynthesis enzymes were strongly upregulated in NSGCT. Substantial percentages of TGCT patients are at increased risk of sex hormone dysfunction at primary diagnosis before orchiectomy. TGCT may directly influence systemic hormonal homeostasis by in-situ synthesis of sex hormones.
Topics: Humans; Male; Adult; Neoplasm Recurrence, Local; Testicular Neoplasms; Gonadal Steroid Hormones; Neoplasms, Germ Cell and Embryonal; Luteinizing Hormone; Seminoma; Follicle Stimulating Hormone, Human
PubMed: 37669975
DOI: 10.1038/s41598-023-41915-7 -
Thyroid : Official Journal of the... Jul 2023Thyrotropin-releasing hormone (TRH) neurons in the paraventricular nucleus of the hypothalamus (PVN) have been identified as direct regulators of thyrotropin (TSH) and...
Thyrotropin-releasing hormone (TRH) neurons in the paraventricular nucleus of the hypothalamus (PVN) have been identified as direct regulators of thyrotropin (TSH) and thyroid hormone (TH) levels. They play a significant role in context of negative feedback by TH at the level of TRH gene expression and during fasting when TH levels fall due, in part, to suppression of TRH gene expression. To test these functions directly for the first time, we used a chemogenetic approach and activated PVN TRH neurons in both fed and fasted mice. Next, to demonstrate the signals that regulate the fasting response in TRH neurons, we activated or inhibited agouti-related protein (AgRP)/neuropeptide Y (NPY) neurons in the arcuate nucleus of the hypothalamus of fed or fasted mice, respectively. To determine if the same TRH neurons responsive to melanocortin signaling mediate negative feedback by TH, we disrupted the thyroid hormone receptor beta (TRβ) in all melanocortin 4 receptor (MC4R) neurons in the PVN. Activation of TRH neurons led to increased TSH and TH levels within 2 hours demonstrating the specific role of PVN TRH neurons in the regulation of the hypothalamic-pituitary-thyroid (HPT) axis. Moreover, activation of PVN TRH neurons prevented the fall in TH levels in fasting mice. Stimulation of AgRP/NPY neurons led to a fall in TH levels despite increasing feeding. Inhibition of these same neurons prevented the fall in TH levels during a fast presumably via their ability to directly regulate PVN TRH neurons via, in part, the MC4R. Surprisingly, TH-mediated feedback was not impaired in mice lacking TRβ in MC4R neurons. TRH neurons are major regulators of the HPT axis and the fasting-induced suppression of TH levels. The latter relies, at least in part, on the activation of AgRP/NPY neurons in the arcuate nucleus. Interestingly, present data do not support an important role for TRβ signaling in regulating MC4R neurons in the PVN. Thus, it remains possible that different subsets of TRH neurons in the PVN mediate responses to energy balance and to TH feedback.
Topics: Mice; Animals; Thyrotropin-Releasing Hormone; Thyrotropin; Agouti-Related Protein; Thyroid Gland; Pituitary Hormone-Releasing Hormones; Hypothalamus; Thyroid Hormones; Paraventricular Hypothalamic Nucleus; Neurons
PubMed: 37166378
DOI: 10.1089/thy.2023.0173 -
Reproduction in Domestic Animals =... Sep 2023The hypothalamic-pituitary-gonadal (HPG) axis connects the hypothalamus, pituitary gland, and gonads. The regulation of reproductive processes includes integrating... (Review)
Review
The hypothalamic-pituitary-gonadal (HPG) axis connects the hypothalamus, pituitary gland, and gonads. The regulation of reproductive processes includes integrating various factors from structural functions and environmental conditions in the HPG axis, with the outcome indication of these processes being the pulsatile secretion of gonadotropin-releasing hormone (GnRH) from the hypothalamus. These factors include feed consumption and nutritional condition, sex steroids, season/photoperiod, pheromones, age, and stress. GnRH pulsatile secretion affects the pattern of gonadotropin secretion of follicle-stimulating hormone (FSH) and luteinizing hormone (LH), which then regulates both endocrine function and gamete maturation in the gonads. This regulates gonadotropins and testosterone (T) production. There is evidence that in males, GnRH participates in a variety of host behavioural and physiological processes such as the release of reproductive hormones, progression of spermatogenesis and sperm function, aggressive behaviour, and physiological metabolism. GnRH activates receptors expressed on Leydig cells and Sertoli cells, respectively to stimulate T secretion and spermatogenesis in the testis. Photoperiod affects the reproductive system of the hypothalamic-pituitary axis via rhythmic diurnal melatonin secretion. Increased release of melatonin promotes sexual activity, GnRH production, LH stimulation, and T production. This induces testicular functions, spermatogenesis, and puberty. GnRH reduces the release of LH by the pituitary through the cascade effect and decreases plasma concentration of T. Gut microbiota maintain sex steroid homeostasis and may induce reduction in reproduction productivity. Recently, findings of kisspeptin-neurokinin-dynorphin neuronal network in the brain have resulted in fast advances in how GnRH secretion is controlled. Emerging studies have also indicated that other neuropeptide analogues could be used in control reproduction procedures in various goat and sheep breeds. The Tibetan male sheep and goats reproduce on a seasonal basis and have high reproductive performance. This is a review for the role of GnRH in Tibetan male sheep and goats reproduction. This is intended to enhance reproductive knowledge for understanding the key roles of GnRH relating to male reproductive efficiency of Tibetan sheep or goats.
Topics: Male; Animals; Sheep; Gonadotropin-Releasing Hormone; Melatonin; Goats; Tibet; Semen; Luteinizing Hormone; Reproduction
PubMed: 37492901
DOI: 10.1111/rda.14432 -
Best Practice & Research. Clinical... Dec 2023Growth hormone is among the most common hormones to be deficient in pituitary insult. It can occur either in isolation or combined with other hormone deficiencies.... (Review)
Review
Growth hormone is among the most common hormones to be deficient in pituitary insult. It can occur either in isolation or combined with other hormone deficiencies. Growth hormone deficiency in adults (AGHD) can be due to causes acquired in adulthood or have a childhood-onset etiology, but the former is about three times more common. Usual causes of AGHD include mass effects due to a pituitary tumour, and/or its treatment (surgery, medical therapy, or radiotherapy), or radiotherapy to the head and neck region for non-pituitary lesions. The unusual or lesser-known causes of AGHD, are usually due to non-tumoral etiology and range from vascular and infective to inflammatory and miscellaneous causes. These not only expand the spectrum of AGHD but may also contribute to increased morbidity, adverse metabolic consequences, and mortality due to the primary condition, if unrecognised. The review features these lesser-known and rare causes of AGHD and highlights their clinical and diagnostic implications.
Topics: Adult; Humans; Child; Dwarfism, Pituitary; Hypopituitarism; Growth Hormone; Human Growth Hormone; Pituitary Gland
PubMed: 37704550
DOI: 10.1016/j.beem.2023.101820 -
Endocrinology Aug 2023The anterior pituitary controls key biological processes, including growth, metabolism, reproduction, and stress responses through distinct cell types that each secrete...
The anterior pituitary controls key biological processes, including growth, metabolism, reproduction, and stress responses through distinct cell types that each secrete specific hormones. The anterior pituitary cells show a remarkable level of cell type plasticity that mediates the shifts in hormone-producing cell populations that are required to meet organismal needs. The molecular mechanisms underlying pituitary cell plasticity are not well understood. Recent work has implicated the pituitary stem cell populations and specifically, the mRNA binding proteins of the Musashi family in control of pituitary cell type identity. In this study we have identified the target mRNAs that mediate Musashi function in the adult mouse pituitary and demonstrate the requirement for Musashi function in vivo. Using Musashi RNA immunoprecipitation, we identify a cohort of 1184 mRNAs that show specific Musashi binding. Identified Musashi targets include the Gnrhr mRNA, which encodes the gonadotropin-releasing hormone receptor (GnRHR), and the Fshb mRNA, encoding follicle-stimulating hormone (FSH). Reporter assays reveal that Musashi functions to exert repression of translation of the Fshb mRNA, in addition to the previously observed repression of the Gnrhr mRNA. Importantly, mice engineered to lack Musashi in gonadotropes demonstrate a failure to repress translation of the endogenous Gnrhr and Fshb mRNAs during the estrous cycle and display a significant heterogeneity in litter sizes. The range of identified target mRNAs suggests that, in addition to these key gonadotrope proteins, Musashi may exert broad regulatory control over the pituitary proteome in a cell type-specific manner.
Topics: Mice; Animals; Gonadotrophs; Follicle Stimulating Hormone; Carrier Proteins; Protein Biosynthesis; RNA, Messenger
PubMed: 37477898
DOI: 10.1210/endocr/bqad113 -
Journal of Clinical Research in... Nov 2023Recent reports have indicated the role of the prokineticin receptor 2 gene () in the etiology of pituitary hormone deficiencies, suggesting a potential role for the...
OBJECTIVE
Recent reports have indicated the role of the prokineticin receptor 2 gene () in the etiology of pituitary hormone deficiencies, suggesting a potential role for the PROK2 pathway in pituitary development, in addition to its role in gonadotropin releasing hormone-expressing neuron development. Here, we present the clinical and molecular findings of four patients with mutations.
METHODS
Next-generation targeted sequencing was used to screen 25 genes in 59 unrelated patients with multiple pituitary hormone deficiency (MPHD), isolated growth hormone (GH) deficiency, or idiopathic short stature.
RESULTS
Two different, very rare missense alterations classified as pathogenic (NM_144773.4:c.518T>G; NP_658986.1:p. (Leu173Arg)) and likely pathogenic (NM_144773.4:c.254G>A; NP_658986.1:p.(Arg85His)) were identified in four patients in heterozygous form. Patient 1 and Patient 2 presented with short stature and were diagnosed as GH deficiency. Patient 3 and Patient 4 presented with central hypothyroidism and cryptorchidism and were diagnosed as MPHD. No other pathogenic alterations were detected in the remaining 24 genes related to short stature, MPHD, and hypogonadotropic hypogonadism. Segregation analysis revealed asymptomatic or mildly affected carriers in the families.
CONCLUSION
dominance should be kept in mind as a very rare cause of GH deficiency and MPHD. Expressional variation or lack of penetrance may imply oligogenic inheritance or other environmental modifiers in individuals who are heterozygous carriers.
Topics: Growth Hormone; Pituitary Hormones; Dwarfism, Pituitary; Humans; Pedigree; Male; Female; Infant; Child; Receptors, G-Protein-Coupled; Consanguinity
PubMed: 37338295
DOI: 10.4274/jcrpe.galenos.2023.2023-4-4 -
Endocrine-related Cancer Jul 2023Growth hormone deficiency (GHD) is a common complication in survivors of cancer and patients with tumors of the pituitary region. Growth hormone replacement therapy... (Review)
Review
Growth hormone deficiency (GHD) is a common complication in survivors of cancer and patients with tumors of the pituitary region. Growth hormone replacement therapy (GHT) has proven beneficial effects, including increased growth velocity, positive effects on body composition and skeletal integrity, and increased quality of life. However, due to known pro-proliferative, angiogenic, and anti-apoptotic properties of growth hormone, there are still some concerns about the safety of GHT in survivors. This narrative review aims to provide an overview of the long-term sequelae, and subsequently long-term safety, of GHT in survivors of (childhood) cancer and patients with tumors of the pituitary region. We identified predominantly reassuring results regarding the safety of survivors with GHT, although we must take into account the shortcomings of some studies and limited information on adult cancer survivors. Besides the already increased risk for second neoplasms, recurrences, or mortality in survivors due to host-, disease-, and treatment-related factors, we could not identify an increased risk due to GHT in particular. Therefore, we support the consensus that GHT can be considered in survivors after careful individual risk/benefit analysis and in open discussion with the patients and their families, taking into account the known morbidity of untreated GHD in cancer survivors and the positive effects of GHT.
Topics: Adult; Humans; Child; Quality of Life; Pituitary Neoplasms; Human Growth Hormone; Hypopituitarism; Dwarfism, Pituitary; Growth Hormone; Survivors; Hormone Replacement Therapy
PubMed: 37043373
DOI: 10.1530/ERC-23-0026 -
General and Comparative Endocrinology Sep 2024The gonadotrope cells within the pituitary control vital processes of reproduction by producing follicle stimulating hormone (FSH) and luteinizing hormone (LH). Both... (Review)
Review
The gonadotrope cells within the pituitary control vital processes of reproduction by producing follicle stimulating hormone (FSH) and luteinizing hormone (LH). Both external stimuli and internal regulatory factors contribute to the regulation of gonadotrope development and function. In recent years, growing evidences indicate that microRNAs (miRNAs), which regulate gene expression post-transcriptionally, play critical roles in multiple processes of gonadotrope development and function, including the syntheses of α or β subunits of FSH and LH, the secretion of LH, the regulation of GnRH signaling, and the maintenance of gonadotrope cell kinetics. Here, we review recent advances of miRNAs' expression, functions and mechanisms approached by using miRNA knockout mouse models, in silico analysis and the in vitro cultures of primary pituitary cells and gonadotrope-derived cell lines. By summarizing and discussing different roles of miRNAs in gonadotropes, this minireview helps to gain insights into the complex molecular network in gonadotropes and reproduction.
Topics: Animals; MicroRNAs; Gonadotrophs; Follicle Stimulating Hormone; Mice; Luteinizing Hormone; Pituitary Gland; Humans
PubMed: 38797341
DOI: 10.1016/j.ygcen.2024.114557 -
Best Practice & Research. Clinical... Dec 2023Between 2% and 60% of patients with cured acromegaly may eventually develop growth hormone deficiency. In adults, growth hormone deficiency is associated with abnormal... (Review)
Review
Between 2% and 60% of patients with cured acromegaly may eventually develop growth hormone deficiency. In adults, growth hormone deficiency is associated with abnormal body composition, decreased exercise capacity and quality of life, dyslipidemia, insulin resistance and increased cardiovascular risk. Similar to patients with other sellar lesions, the diagnosis of growth hormone deficiency in adults with cured acromegaly generally requires stimulation testing, with the exception of patients with very low serum insulin-like growth factor I levels and multiple additional pituitary hormone deficiencies. In adults with cured acromegaly, growth hormone replacement may have beneficial effects on body adiposity, muscle endurance, serum lipids and quality of life. Growth hormone replacement is generally well-tolerated. Arthralgias, edema, carpal tunnel syndrome and hyperglycemia may occur in patients with cured acromegaly, as is true of patients with growth hormone deficiency of other etiologies. However, there is evidence of increased cardiovascular risk in some studies of growth hormone replacement in adults with cured acromegaly. More studies are needed to fully establish the beneficial effects and elucidate the risks of growth hormone replacement in adults with cured acromegaly. Until then, growth hormone replacement can be considered in these patients on a case-by-case basis.
Topics: Adult; Humans; Acromegaly; Growth Hormone; Quality of Life; Human Growth Hormone; Hypopituitarism; Dwarfism, Pituitary; Insulin-Like Growth Factor I
PubMed: 37328323
DOI: 10.1016/j.beem.2023.101790