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The Journal of Clinical Endocrinology... Jul 2023Central precocious puberty (CPP) classically refers to premature activation of the hypothalamic-pituitary-gonadal axis with onset of sexual development before the age of...
Central precocious puberty (CPP) classically refers to premature activation of the hypothalamic-pituitary-gonadal axis with onset of sexual development before the age of 8 years in girls and 9 years in boys. A decrease in the age of thelarche has been reported over the past several decades; however, the tempo of pubertal progression can be slower and adult height may not be adversely affected in many of the girls who experience thelarche at 6-8 years. Outside of this secular trend in the development itself, the past several decades have also brought about advances in diagnosis and management. This includes the widespread use of an ultrasensitive luteinizing hormone assay, decreasing the need for stimulation testing and a better understanding of the genetics that govern the onset of puberty. Additionally, management of CPP using gonadotropin-releasing hormone analogs (GnRHas) has changed with the advent of new longer-acting formulations. Emerging long-term outcomes of GnRHa administration with regards to obesity, cardiovascular risk factors and fertility are reassuring. Despite these advancements, clinical care in CPP is hampered by the lack of well-designed controlled studies, and management decisions are frequently not supported by clear practice guidelines. Data in boys with CPP are limited and this article focuses on the diagnosis and management of CPP in girls, particularly, in those who present with thelarche at the age of 6-8 years.
Topics: Female; Male; Humans; Child; Gonadotropin-Releasing Hormone; Puberty, Precocious; Sexual Development; Fertility; Heart Disease Risk Factors; Follicle Stimulating Hormone
PubMed: 36916130
DOI: 10.1210/clinem/dgad081 -
American Journal of Obstetrics and... Mar 2024Oxytocin is a peptide hormone that plays a key role in regulating the female reproductive system, including during labor and lactation. It is produced primarily in the... (Review)
Review
Oxytocin is a peptide hormone that plays a key role in regulating the female reproductive system, including during labor and lactation. It is produced primarily in the hypothalamus and secreted by the posterior pituitary gland. Oxytocin can also be administered as a medication to initiate or augment uterine contractions. To study the effectiveness and safety of oxytocin, previous studies have randomized patients to low- and high-dose oxytocin infusion protocols either alone or as part of an active management of labor strategy along with other interventions. These randomized trials demonstrated that active management of labor and high-dose oxytocin regimens can shorten the length of labor and reduce the incidence of clinical chorioamnionitis. The safety of high-dose oxytocin regimens is also supported by no associated differences in fetal heart rate abnormalities, postpartum hemorrhage, low Apgar scores, neonatal intensive care unit admissions, and umbilical artery acidemia. Most studies reported no differences in the cesarean delivery rates with active management of labor or high-dose oxytocin regimens, thereby further validating its safety. Oxytocin does not have a predictable dose response, thus the pharmacologic effects and the amplitude and frequency of uterine contractions are used as physiological parameters for oxytocin infusion titration to achieve adequate contractions at appropriate intervals. Used in error, oxytocin can cause patient harm, highlighting the importance of precise administration using infusion pumps, institutional safety checklists, and trained nursing staff to closely monitor uterine activity and fetal heart rate changes. In this review, we summarize the physiology, pharmacology, infusion regimens, and associated risks of oxytocin.
Topics: Pregnancy; Infant, Newborn; Humans; Female; Oxytocin; Oxytocics; Labor, Induced; Labor, Obstetric; Cesarean Section
PubMed: 37460365
DOI: 10.1016/j.ajog.2023.06.041 -
Frontiers in Endocrinology 2023Adrenal insufficiency encompasses a group of congenital and acquired disorders that lead to inadequate steroid production by the adrenal glands, mainly glucocorticoids,... (Review)
Review
Adrenal insufficiency encompasses a group of congenital and acquired disorders that lead to inadequate steroid production by the adrenal glands, mainly glucocorticoids, mineralocorticoids and androgens. These may be associated with other hormone deficiencies. Adrenal insufficiency may be primary, affecting the adrenal gland's ability to produce cortisol directly; secondary, affecting the pituitary gland's ability to produce adrenocorticotrophic hormone (ACTH); or tertiary, affecting corticotrophin-releasing hormone (CRH) production at the level of the hypothalamus. Congenital causes of adrenal insufficiency include the subtypes of Congenital Adrenal Hyperplasia, Adrenal Hypoplasia, genetic causes of Isolated ACTH deficiency or Combined Pituitary Hormone Deficiencies, usually caused by mutations in essential transcription factors. The most commonly inherited primary cause of adrenal insufficiency is Congenital Adrenal Hyperplasia due to 21-hydroxylase deficiency; with the classical form affecting 1 in 10,000 to 15,000 cases per year. Acquired causes of adrenal insufficiency can be subtyped into autoimmune (Addison's Disease), traumatic (including haemorrhage or infarction), infective (e.g. Tuberculosis), infiltrative (e.g. neuroblastoma) and iatrogenic. Iatrogenic acquired causes include the use of prolonged exogenous steroids and post-surgical causes, such as the excision of a hypothalamic-pituitary tumour or adrenalectomy. Clinical features of adrenal insufficiency vary with age and with aetiology. They are often non-specific and may sometimes become apparent only in times of illness. Features range from those related to hypoglycaemia such as drowsiness, collapse, jitteriness, hypothermia and seizures. Features may also include signs of hypotension such as significant electrolyte imbalances and shock. Recognition of hypoglycaemia as a symptom of adrenal insufficiency is important to prevent treatable causes of sudden deaths. Cortisol has a key role in glucose homeostasis, particularly in the counter-regulatory mechanisms to prevent hypoglycaemia in times of biological stress. Affected neonates particularly appear susceptible to the compromise of these counter-regulatory mechanisms but it is recognised that affected older children and adults remain at risk of hypoglycaemia. In this review, we summarise the pathogenesis of hypoglycaemia in the context of adrenal insufficiency. We further explore the clinical features of hypoglycaemia based on different age groups and the burden of the disease, focusing on hypoglycaemic-related events in the various aetiologies of adrenal insufficiency. Finally, we sum up strategies from published literature for improved recognition and early prevention of hypoglycaemia in adrenal insufficiency, such as the use of continuous glucose monitoring or modifying glucocorticoid replacement.
Topics: Child; Adult; Infant, Newborn; Humans; Adolescent; Hydrocortisone; Adrenal Hyperplasia, Congenital; Blood Glucose Self-Monitoring; Blood Glucose; Adrenal Insufficiency; Glucocorticoids; Adrenocorticotropic Hormone; Hypoglycemia; Iatrogenic Disease
PubMed: 38053731
DOI: 10.3389/fendo.2023.1198519 -
ELife Jul 2023The hypothalamus-pituitary-adrenal (HPA) axis is activated in response to inflammation leading to increased production of anti-inflammatory glucocorticoids by the...
The hypothalamus-pituitary-adrenal (HPA) axis is activated in response to inflammation leading to increased production of anti-inflammatory glucocorticoids by the adrenal cortex, thereby representing an endogenous feedback loop. However, severe inflammation reduces the responsiveness of the adrenal gland to adrenocorticotropic hormone (ACTH), although the underlying mechanisms are poorly understood. Here, we show by transcriptomic, proteomic, and metabolomic analyses that LPS-induced systemic inflammation triggers profound metabolic changes in steroidogenic adrenocortical cells, including downregulation of the TCA cycle and oxidative phosphorylation, in mice. Inflammation disrupts the TCA cycle at the level of succinate dehydrogenase (SDH), leading to succinate accumulation and disturbed steroidogenesis. Mechanistically, IL-1β reduces SDHB expression through upregulation of DNA methyltransferase 1 (DNMT1) and methylation of the promoter. Consequently, increased succinate levels impair oxidative phosphorylation and ATP synthesis and enhance ROS production, leading to reduced steroidogenesis. Together, we demonstrate that the IL-1β-DNMT1-SDHB-succinate axis disrupts steroidogenesis. Our findings not only provide a mechanistic explanation for adrenal dysfunction in severe inflammation, but also offer a potential target for therapeutic intervention.
Topics: Mice; Animals; Succinic Acid; Proteomics; Glucocorticoids; Adrenocorticotropic Hormone; Inflammation
PubMed: 37449973
DOI: 10.7554/eLife.83064 -
Psychoneuroendocrinology Nov 2023Famine and starvation have punctuated the evolutionary past of the human species. As such, we have developed hormonal responses to undernutrition that minimize energy... (Review)
Review
Famine and starvation have punctuated the evolutionary past of the human species. As such, we have developed hormonal responses to undernutrition that minimize energy expenditure on processes that are not critical for the survival of the individual, such as reproduction. In this review, we discuss neuroendocrine adaptations to starvation including hypogonadotropic hypogonadism, growth hormone resistance, hypercortisolemia, and the downregulation of the hypothalamic-pituitary-thyroid axis. We review the time-course of these adaptations by describing studies involving the short-term fasting of healthy individuals as well as studies describing the hormonal changes in states of chronic undernutrition, using individuals with anorexia nervosa as a model of chronic starvation. Lastly, we review representative clinical effects of chronic undernutrition.
Topics: Humans; Anorexia Nervosa; Neurosecretory Systems; Hypogonadism; Human Growth Hormone; Malnutrition
PubMed: 37573628
DOI: 10.1016/j.psyneuen.2023.106365 -
Nature Communications Sep 2023The immunomodulatory effects of ultraviolet B (UVB) radiation in human diseases have been described. Whether type 2 lung inflammation is directly affected by solar...
The immunomodulatory effects of ultraviolet B (UVB) radiation in human diseases have been described. Whether type 2 lung inflammation is directly affected by solar ultraviolet (UV) radiation is not fully understood. Here, we show a possible negative correlation between solar UVB radiation and asthmatic inflammation in humans and mice. UVB exposure to the eyes induces hypothalamus-pituitary activation and α-melanocyte-stimulating hormone (α-MSH) accumulation in the serum to suppress allergic airway inflammation by targeting group 2 innate lymphoid cells (ILC2) through the MC5R receptor in mice. The α-MSH/MC5R interaction limits ILC2 function through attenuation of JAK/STAT and NF-κB signaling. Consistently, we observe that the plasma α-MSH concentration is negatively correlated with the number and function of ILC2s in the peripheral blood mononuclear cells (PBMC) of patients with asthma. We provide insights into how solar UVB radiation-driven neuroendocrine α-MSH restricts ILC2-mediated lung inflammation and offer a possible strategy for controlling allergic diseases.
Topics: Humans; Animals; Mice; alpha-MSH; Immunity, Innate; Leukocytes, Mononuclear; Lymphocytes; Asthma; Inflammation; Lung
PubMed: 37699899
DOI: 10.1038/s41467-023-41319-1 -
Frontiers in Endocrinology 2023Copeptin is cleaved from the same precursor as arginine vasopressin and is released in equimolar amounts with arginine vasopressin from the posterior pituitary in... (Review)
Review
Copeptin is cleaved from the same precursor as arginine vasopressin and is released in equimolar amounts with arginine vasopressin from the posterior pituitary in response to the same stimuli. Its level of stability in the blood, quick and simple analysis, and ease of automation make it much easier to analyze than arginine vasopressin, thereby offering a suitable alternative to measuring arginine vasopressin in endocrine disorders. Research has demonstrated the suitability of copeptin in adults for the differentiation of arginine vasopressin resistance and arginine vasopressin deficiency from primary polydipsia, in addition to the early identification of arginine vasopressin deficiency following pituitary surgery; however, further research is still required in the Syndrome of Inappropriate Antidiuretic Hormone (SIADH) and the pediatric population.
Topics: Child; Adult; Humans; Diabetes Insipidus, Neurogenic; Glycopeptides; Arginine Vasopressin; Arginine
PubMed: 37859988
DOI: 10.3389/fendo.2023.1230045 -
Nature Reviews. Endocrinology Dec 2023Traditional textbook physiology has ascribed unitary functions to hormones from the anterior and posterior pituitary gland, mainly in the regulation of effector hormone... (Review)
Review
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.
Topics: Humans; Pituitary Hormones; Pituitary Gland; Prolactin; Adipose Tissue; Brain
PubMed: 37715028
DOI: 10.1038/s41574-023-00894-5 -
International Journal of Molecular... Nov 2023Human sexual and reproductive development is regulated by the hypothalamic-pituitary-gonadal (HPG) axis, which is primarily controlled by the gonadotropin-releasing... (Review)
Review
Human sexual and reproductive development is regulated by the hypothalamic-pituitary-gonadal (HPG) axis, which is primarily controlled by the gonadotropin-releasing hormone (GnRH) acting on its receptor (GnRHR). Dysregulation of the axis leads to conditions such as congenital hypogonadotropic hypogonadism (CHH) and delayed puberty. The pathophysiology of GnRHR makes it a potential target for treatments in several reproductive diseases and in congenital adrenal hyperplasia. GnRHR belongs to the G protein-coupled receptor family and its GnRH ligand, when bound, activates several complex and tissue-specific signaling pathways. In the pituitary gonadotrope cells, it triggers the G protein subunit dissociation and initiates a cascade of events that lead to the production and secretion of the luteinizing hormone (LH) and follicle-stimulating hormone (FSH) accompanied with the phospholipase C, inositol phosphate production, and protein kinase C activation. Pharmacologically, GnRHR can be modulated by synthetic analogues. Such analogues include the agonists, antagonists, and the pharmacoperones. The agonists stimulate the gonadotropin release and lead to receptor desensitization with prolonged use while the antagonists directly block the GnRHR and rapidly reduce the sex hormone production. Pharmacoperones include the most recent GnRHR therapeutic approaches that directly correct the misfolded GnRHRs, which are caused by genetic mutations and hold serious promise for CHH treatment. Understanding of the GnRHR's genomic and protein structure is crucial for the most appropriate assessing of the mutation impact. Such mutations in the GNRHR are linked to normosmic hypogonadotropic hypogonadism and lead to various clinical symptoms, including delayed puberty, infertility, and impaired sexual development. These mutations vary regarding their mode of inheritance and can be found in the homozygous, compound heterozygous, or in the digenic state. GnRHR expression extends beyond the pituitary gland, and is found in reproductive tissues such as ovaries, uterus, and prostate and non-reproductive tissues such as heart, muscles, liver and melanoma cells. This comprehensive review explores GnRHR's multifaceted role in human reproduction and its clinical implications for reproductive disorders.
Topics: Female; Male; Humans; Receptors, LHRH; Puberty, Delayed; Hypogonadism; Gonadotropin-Releasing Hormone; Luteinizing Hormone; Follicle Stimulating Hormone; Klinefelter Syndrome
PubMed: 37958948
DOI: 10.3390/ijms242115965 -
Endocrine-related Cancer Oct 2023Anti-Müllerian hormone (AMH) is produced and secreted by granulosa cells of growing follicles, and its main role is to inhibit the recruitment of primordial follicles,... (Review)
Review
Anti-Müllerian hormone (AMH) is produced and secreted by granulosa cells of growing follicles, and its main role is to inhibit the recruitment of primordial follicles, reduce the sensitivity of follicles to follicle-stimulating hormone (FSH), and regulate FSH-dependent preantral follicle growth. It has become an effective indicator of ovarian reserve in clinical practice. Research on AMH and its receptors in recent years has led to a better understanding of its role in breast cancer. AMH specifically binds to anti-Müllerian hormone receptor II (AMHRII) to activate downstream pathways and regulate gene transcription. Since AMHRII is expressed in breast cancer cells and triggers apoptosis, AMH/AMHRII may play an important role in the occurrence, treatment, and prognosis of breast cancer, which needs further research. The AMH level is a potent predictor of ovarian function after chemotherapy in premenopausal breast cancer patients older than 35 years, either for ovarian function injury or ovarian function recovery. Moreover, AMHRII has the potential to be a new marker for the molecular typing of breast cancer and a new target for breast cancer treatment, which may be a link in the downstream pathway after TP53 mutation.
Topics: Female; Humans; Anti-Mullerian Hormone; Breast Neoplasms; Ovarian Follicle; Granulosa Cells; Follicle Stimulating Hormone
PubMed: 37410375
DOI: 10.1530/ERC-23-0060