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Endocrine-related Cancer Jan 2024It is now apparent that growth hormone (GH), an anterior pituitary hormone predominantly regulating postnatal somatic growth and metabolism, is also expressed in... (Review)
Review
It is now apparent that growth hormone (GH), an anterior pituitary hormone predominantly regulating postnatal somatic growth and metabolism, is also expressed in extrapituitary tissues. An extrapituitary synthetic site of GH that has garnered interest is the de novo or enhanced expression of GH in carcinoma or other cancers. In a number of cancers, including carcinoma of the mammary gland, endometrium, liver, prostate, and colon, the expression of GH is independently associated with more advanced clinicopathologic parameters of the cancer. In some of these cancers, tumor human growth hormone (hGH) expression portends worse survival outcomes for patients. Functionally, tumor-derived hGH exerts both autocrine and paracrine functions on carcinoma cells and cancer-associated stroma. Expression of autocrine/paracrine hGH in cancer drives tumor growth, angiogenesis, metastasis, and resistance to therapy by promotion of cancer cell proliferation, survival, epithelial-to-mesenchymal transition, motility, invasion, cancer stem cell-like behavior, and metastasis. Autocrine/paracrine hGH activates oncogenic signaling pathways and specific transcriptome signatures and enhances the expression of an oncogenic secretome to promote these functions. Hence, extrapituitary expression of GH in cancer promotes cancer progression independent of endocrine hGH, and may be considered as a validated target in oncology.
Topics: Humans; Carcinoma; Epithelial-Mesenchymal Transition; Growth Hormone; Human Growth Hormone
PubMed: 37877767
DOI: 10.1530/ERC-23-0120 -
Best Practice & Research. Clinical... Dec 2023Growth hormone (GH) plays an essential role not only in promoting growth in children, but also in many important metabolic processes in adults. One of the major... (Review)
Review
Growth hormone (GH) plays an essential role not only in promoting growth in children, but also in many important metabolic processes in adults. One of the major metabolic functions of GH is its stimulatory effects on the liver in generating approximately 80% of circulating insulin-like growth factor 1 (IGF-1). Adult growth hormone deficiency (GHD) is an established clinical entity defined as a defect in endogenous GH secretion that is frequently associated with central obesity, loss of muscle mass, decreased bone mass, and impaired quality of life. Nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) are conditions that are often under-recognized in adults with GHD, and accordingly some studies have shown that GH and IGF-1 levels are decreased in patients with NAFLD. Furthermore, it has been reported that it can progress to end-stage liver cirrhosis in some adults and children with GHD. Due to their underlying mechanisms of action, GH and IGF-1 can act on hepatocytes, macrophages, and hepatic stellate cells to mitigate progression to steatosis and fibrosis. It is, thus, important to recognize NAFLD/NASH as important complications in adult and childhood GHD. Therefore, careful and thorough evaluation of NAFLD/NASH in adults with GHD and the consideration for GH replacement therapy is crucial in these patients, together with management of other metabolic risk factors, such as obesity and dyslipidemia. This review will focus on recent reports on the role of GH and IGF-1 in the liver and its clinical significance in the regulation of hepatic function.
Topics: Adult; Child; Humans; Non-alcoholic Fatty Liver Disease; Insulin-Like Growth Factor I; Quality of Life; Growth Hormone; Human Growth Hormone; Dwarfism, Pituitary; Obesity
PubMed: 37643935
DOI: 10.1016/j.beem.2023.101816 -
Best Practice & Research. Clinical... Dec 2023The gut microbiome has been implicated in a variety of neuropathologies with recent data suggesting direct effects of the microbiome on host metabolism, hormonal... (Review)
Review
The gut microbiome has been implicated in a variety of neuropathologies with recent data suggesting direct effects of the microbiome on host metabolism, hormonal regulation, and pathophysiology. Studies have shown that gut bacteria impact host growth, partially mediated through the growth hormone (GH)/insulin-like growth factor 1 (IGF-1) axis. However, no study to date has examined the specific role of GH on the fecal microbiome (FMB) or the changes in this relationship following a traumatic brain injury (TBI). Current literature has demonstrated that TBI can lead to either temporary or sustained abnormal GH secretion (aGHS). More recent literature has suggested that gut dysbiosis may contribute to aGHS leading to long-term sequelae now known as brain injury associated fatigue and cognition (BIAFAC). The aGHS observed in some TBI patients presents with a symptom complex including profound fatigue and cognitive dysfunction that improves significantly with exogenous recombinant human GH treatment. Notably, GH treatment is not curative as fatigue and cognitive decline typically recur upon treatment cessation, indicating the need for additional studies to address the underlying mechanistic cause.
Topics: Humans; Dysbiosis; Brain Injuries, Traumatic; Brain Injuries; Human Growth Hormone; Growth Hormone; Fatigue; Insulin-Like Growth Factor I
PubMed: 38000973
DOI: 10.1016/j.beem.2023.101841 -
Best Practice & Research. Clinical... Dec 2023Growth hormone deficiency (GHD) is a common complication of several pituitary and hypothalamic disorders and dependent on the onset of disease. It may have severe... (Review)
Review
Growth hormone deficiency (GHD) is a common complication of several pituitary and hypothalamic disorders and dependent on the onset of disease. It may have severe clinical implications ranging from growth retardation in childhood-onset, to impaired lipid metabolism and increased cardiovascular risk and mortality in adults. GH effectively modulates lipid metabolism at multiple levels and GHD has been associated with an atherogenic lipid profile, that can be reversed by GH replacement therapy. Despite increasing knowledge on the effects of GH on several key enzymes regulating lipid metabolism and recent breakthroughs in the development and wider availability of recombinant GH preparations, several questions remain regarding the replacement therapy in adults with GHD. This review aims to comprehensively summarize the current knowledge on (i) lipid profile abnormalities in individuals with GHD, (ii) proposed mechanisms of action of GH on lipid and lipoprotein metabolism, and (iii) clinical implications of GH replacement therapy in individuals diagnosed with GHD.
Topics: Adult; Humans; Human Growth Hormone; Hypopituitarism; Dwarfism, Pituitary; Dyslipidemias; Lipids; Growth Hormone; Insulin-Like Growth Factor I
PubMed: 37821339
DOI: 10.1016/j.beem.2023.101821 -
Trends in Endocrinology and Metabolism:... Apr 2024Cushing's syndrome (CS) refers to the clinical features of prolonged pathological glucocorticoid excess. About 10-20% of individuals with CS have ectopic CS (ECS), that... (Review)
Review
Cushing's syndrome (CS) refers to the clinical features of prolonged pathological glucocorticoid excess. About 10-20% of individuals with CS have ectopic CS (ECS), that is, an adrenocorticotropin (ACTH)-producing tumour outside the pituitary gland. ACTH-secreting neuroendocrine neoplasia (NENs) can arise from many organs, although bronchial NEN, small cell lung cancer (SCLC), pancreatic NEN, thymic NEN, medullary thyroid cancer (MTC), and pheochromocytoma are the most common. Patients with ECS frequently present with severe hypercortisolism. The risk of life-threatening complications is high in severe cases, unless the hypercortisolism is effectively treated. A good outcome in ECS requires a methodical approach, incorporating prompt diagnosis, tumour localization, control of cortisol excess, and resection of the primary tumour when possible.
Topics: Humans; Cushing Syndrome; Adrenocorticotropic Hormone; Neuroendocrine Tumors; Pituitary Gland; Adrenal Gland Neoplasms
PubMed: 38143211
DOI: 10.1016/j.tem.2023.12.003 -
European Thyroid Journal Jul 2023Thyroid hormone (TH) is indispensable for brain development in utero and during the first 2-3 years of life, and the negative effects of TH deficiency on brain... (Review)
Review
Thyroid hormone (TH) is indispensable for brain development in utero and during the first 2-3 years of life, and the negative effects of TH deficiency on brain development are irreversible. Detection of TH deficiency early in life by neonatal screening allows early treatment, thereby preventing brain damage. Inborn shortage of TH, also named congenital hypothyroidism (CH), can be the result of defective thyroid gland development or TH synthesis (primary or thyroidal CH (CH-T)). Primary CH is characterized by low blood TH and elevated thyroid-stimulating hormone (TSH) concentrations. Less frequently, CH is due to insufficient stimulation of the thyroid gland because of disturbed hypothalamic or pituitary function (central CH). Central CH is characterized by low TH concentrations, while TSH is normal, low or slightly elevated. Most newborn screening (NBS) programs for CH are primarily TSH based and thereby do not detect central CH. Only a few NBS programs worldwide aim to detect both forms of CH by different strategies. In the Netherlands, we have a unique T4-TSH-thyroxine-binding globulin (TBG) NBS algorithm for CH, which enables the detection of primary and central CH. Although the necessity of central CH detection by NBS is still under debate, it has been shown that most central CH patients have moderate-to-severe hypothyroidism instead of mild and that early detection of central CH by NBS probably improves its clinical outcome and clinical care for central CH patients with multiple pituitary hormone deficiency. We are therefore convinced that detection of central CH by NBS is of utmost importance.
Topics: Infant, Newborn; Humans; Congenital Hypothyroidism; Neonatal Screening; Thyrotropin; Thyroxine; Thyroid Hormones
PubMed: 37326450
DOI: 10.1530/ETJ-23-0041 -
Current Biology : CB Jan 2024Aversive stimuli activate corticotropin-releasing factor (CRF)-expressing neurons in the paraventricular nucleus of hypothalamus (PVN neurons) and other brain stress...
Aversive stimuli activate corticotropin-releasing factor (CRF)-expressing neurons in the paraventricular nucleus of hypothalamus (PVN neurons) and other brain stress systems to facilitate avoidance behaviors. Appetitive stimuli also engage the brain stress systems, but their contributions to reward-related behaviors are less well understood. Here, we show that mice work vigorously to optically activate PVN neurons in an operant chamber, indicating a reinforcing nature of these neurons. The reinforcing property of these neurons is not mediated by activation of the hypothalamic-pituitary-adrenal (HPA) axis. We found that PVN neurons send direct projections to the ventral tegmental area (VTA), and selective activation of these projections induced robust self-stimulation behaviors, without activation of the HPA axis. Similar to the PVN cell bodies, self-stimulation of PVN-VTA projection was dramatically attenuated by systemic pretreatment of CRF receptor 1 or dopamine D1 receptor (D1R) antagonist and augmented by corticosterone synthesis inhibitor metyrapone, but not altered by dopamine D2 receptor (D2R) antagonist. Furthermore, we found that activation of PVN-VTA projections increased c-Fos expression in the VTA dopamine neurons and rapidly triggered dopamine release in the nucleus accumbens (NAc), and microinfusion of D1R or D2R antagonist into the NAc decreased the self-stimulation of these projections. Together, our findings reveal an unappreciated role of PVN neurons and their VTA projections in driving reward-related behaviors, independent of their core neuroendocrine functions. As activation of PVN neurons is the final common path for many stress systems, our study suggests a novel mechanism underlying the positive reinforcing effect of stressful stimuli.
Topics: Mice; Animals; Corticotropin-Releasing Hormone; Pituitary Hormone-Releasing Hormones; Hypothalamo-Hypophyseal System; Pituitary-Adrenal System; Hypothalamus; Paraventricular Hypothalamic Nucleus; Dopaminergic Neurons
PubMed: 38215742
DOI: 10.1016/j.cub.2023.12.046 -
European Journal of Endocrinology Aug 2023Data on pre- and postoperative pituitary function in nonfunctioning pituitary adenomas (NFPA) are not consistent. We aimed to investigate pituitary function before and...
OBJECTIVE
Data on pre- and postoperative pituitary function in nonfunctioning pituitary adenomas (NFPA) are not consistent. We aimed to investigate pituitary function before and up to 5 years after transsphenoidal surgery with emphasis on the hypothalamic-pituitary-adrenal axis (HPA).
DESIGN AND METHODS
Data from the Swedish Pituitary Register was used to analyze anterior pituitary function in 838 patients with NFPA diagnosed between 1991 and 2014. Patients who were reoperated or had received radiotherapy were excluded.
RESULTS
Preoperative ACTH, TSH, LH/FSH, and GH deficiencies were reported in 31% (236/755), 39% (300/769), 51% (378/742), and 28% (170/604) of the patients, respectively. Preoperative median tumor volume was 5.0 (2.4-9.0) cm3. Among patients with preoperative, 1 year and 5 years postoperative data on the HPA axis (n = 428), 125 (29%) were ACTH-deficient preoperatively. One year postoperatively, 26% (32/125) of them had recovered ACTH function while 23% (70/303) patients had developed new ACTH deficiency. Thus, 1 year postoperatively, 163 (38%) patients were ACTH-deficient (P < .001 vs. preoperatively). No further increase was seen 5 years postoperatively (36%, P = .096). At 1 year postoperatively, recoveries in the TSH and LH/FSH axes were reported in 14% (33/241) and 15% (46/310), respectively, and new deficiencies in 22% (88/403) and 29% (83/288), respectively.
CONCLUSIONS
Adrenocorticotrophic hormone deficiency increased significantly at 1 year postoperatively. Even though not significant, some patients recovered from or developed new deficiency between 1 and 5 years postoperatively. This pattern was seen in all axes. Our study emphasizes that continuous individual evaluations are needed during longer follow-up of patients operated for NFPA.
Topics: Humans; Pituitary Neoplasms; Hypothalamo-Hypophyseal System; Sweden; Pituitary-Adrenal System; Follicle Stimulating Hormone; Adrenocorticotropic Hormone; Thyrotropin
PubMed: 37551511
DOI: 10.1093/ejendo/lvad104 -
Reproductive Biology and Endocrinology... Aug 2023Artificial sweeteners, used as sugar substitutes have found their ways into almost all the food items due to the notion that they are non-caloric. Aspartame is used in...
BACKGROUND
Artificial sweeteners, used as sugar substitutes have found their ways into almost all the food items due to the notion that they are non-caloric. Aspartame is used in numerous food products throughout the world. The primary users of aspartame include diabetics and calorie conscious people who intend to limit their calorie intake.
METHODS
Female Swiss albino mice were divided into three groups (12 mice each) for the duration of 30 and 60 days consecutively. The treatment groups received 40 mg/kg b. w. aspartame orally. Hormone assays using ELISA and tissue histopathology have been performed along with the fertility assay to access the treatment outcomeon the fertility of treated mice in comparison to controls.
RESULTS
Present study reports that female mice treated with aspartame for 30 and 60 days showed significant reduction in body weight, relative organ weight of (liver and kidney) and gonadosomatic index. These changes were more significantly recorded in 60 days treatment group. Aspartame treated animals for 30 and 60 days showed duration-dependent decrease gonandotropins (follicle stimulating hormone and luteinizing hormone), and steroids (estradiol and progesterone). Moreover, severe histopathological changes, reduction in number of growing follicles, degenerative changes in follicular structure, corona radiata and zonagranulosa were also observed. Besides, histomorphological changes were also observed in the uterine structure including atrophic uterine endometrial glands, contracted endometrial lining, disruption of the endometrial structure and the shapes of blood vessels were also altered.
CONCLUSION
Non-nutritive artificial sweeteners including aspartame negatively impact the function of ovaries and feedback mechanism of reproductive hormones by affecting the hypothalamic-pituitary-gonadal axis. In light of present findings the aspartame negatively impacted the reproductive system of female mice. More studies are required to identify the molecular mechanism and the pathways involved.
Topics: Female; Mice; Animals; Sweetening Agents; Aspartame; Disease Models, Animal; Luteinizing Hormone; Ovary
PubMed: 37580716
DOI: 10.1186/s12958-023-01115-4 -
Pituitary Oct 2023Cushing's disease (CD) results from autonomous adrenocorticotropic hormone (ACTH) secretion by corticotroph adenomas, leading to excessive cortisol production,...
PURPOSE
Cushing's disease (CD) results from autonomous adrenocorticotropic hormone (ACTH) secretion by corticotroph adenomas, leading to excessive cortisol production, ultimately affecting morbidity and mortality. Pasireotide is the only FDA approved tumor directed treatment for CD, but it is effective in only about 25% of patients, and is associated with a high rate of hyperglycemia. Neuromedin B (NMB), a member of the bombesin-like peptide family, regulates endocrine secretion and cell proliferation. Here, we assessed NMB and NMB receptor (NMBR) expression in human corticotroph adenomas and the effects of NMBR antagonist PD168368 on murine and human corticotroph tumors.
METHODS
To investigate NMB and NMBR expression, real-time qPCR and immunostaining on human pathological specimens of corticotroph, non-functional and somatotroph adenomas were performed. The effects of PD168368 on hormone secretion and cell proliferation were studied in vitro, in vivo and in seven patient-derived corticotroph adenoma cells. NMB and NMBR were expressed in higher extent in human corticotroph adenomas compared with non-functional or somatotroph adenomas.
RESULTS
In murine AtT-20 cells, PD168368 reduced proopiomelanocortin (Pomc) mRNA/protein expression and ACTH secretion as well as cell proliferation. In mice with tumor xenografts, tumor growth, ACTH and corticosterone were downregulated by PD168368. In patient-derived adenoma cells, PD168368 reduced POMC mRNA expression in four out of seven cases and ACTH secretion in two out of five cases. A PD168368-mediated cyclin E suppression was also identified in AtT-20 and patient-derived cells.
CONCLUSION
NMBR antagonist represents a potential treatment for CD and its effect may be mediated by cyclin E suppression.
Topics: Animals; Humans; Mice; ACTH-Secreting Pituitary Adenoma; Adenoma; Adrenocorticotropic Hormone; Cyclin E; Growth Hormone-Secreting Pituitary Adenoma; Pituitary ACTH Hypersecretion; Pro-Opiomelanocortin; Receptors, Bombesin; Receptors, G-Protein-Coupled; RNA, Messenger
PubMed: 37642928
DOI: 10.1007/s11102-023-01350-3