Adrenal Secretion Research Articles

Severe Hyperandrogenism in 46,XX Congenital Adrenal Hyperplasia: Molecular Physiopathology, Late Diagnoses, and Personalized Management.

Congenital Adrenal Hyperplasia (CAH) is a group of autosomal recessive endocrine disorders characterized by alteration in adrenal hormonal secretions. The most common form is caused by CYP21A2 mutations that result in 21-hydroxylase deficiency. Clinical features can vary, from salt-wasting forms, characterized by a lack of mineralocorticoid activity with a risk of perinatal-onset adrenal crises, to "simple-virilizing" forms with sufficient aldosterone secretion, up to milder "non-classical" forms, with a variable grade of hyperandrogenism but no severe hormonal deficiencies. During pregnancy, CAH 46,XX fetuses are exposed to elevated androgen levels, leading to a variable grade of virilization and potential central nervous system effects if untreated. These patients are usually (but not always) assigned female at birth, but some cases may be misdiagnosed and assigned male, potentially inducing fertility, gender identity, and sexual behavior issues in adulthood. In these patients, the benefits and risks of a late gender transition should be carefully evaluated. In this paper, we reviewed the literature concerning the most interesting peculiarities of these conditions.

RGS Proteins in Sympathetic Nervous System Regulation: Focus on Adrenal RGS4.

The sympathetic nervous system (SNS) consists largely of two different types of components: neurons that release the neurotransmitter norepinephrine (NE, noradrenaline) to modulate homeostasis of the innevrvated effector organ or tissue and adrenal chromaffin cells, which synthesize and secrete the hormone epinephrine (Epi, adrenaline) and some NE into the blood circulation to act at distant organs and tissues that are not directly innervated by the SNS. Like almost every physiological process in the human body, G protein-coupled receptors (GPCRs) tightly modulate both NE release from sympathetic neuronal terminals and catecholamine (CA) secretion from the adrenal medulla. Regulator of G protein Signaling (RGS) proteins, acting as guanosine triphosphatase (GTPase)-activating proteins (GAPs) for the Gα subunits of heterotrimeric guanine nucleotide-binding proteins (G proteins), play a central role in silencing G protein signaling from a plethora of GPCRs. Certain RGS proteins and, in particular, RGS4, have been implicated in regulation of SNS activity and of adrenal chromaffin cell CA secretion. More specifically, recent studies have implicated RGS4 in regulation of NE release from cardiac sympathetic neurons by means of terminating free fatty acid receptor (FFAR)-3 calcium signaling and in regulation of NE and Epi secretion from the adrenal medulla by means of terminating cholinergic calcium signaling in adrenal chromaffin cells. Thus, in this review, we provide an overview of the current literature on the involvement of RGS proteins, with a particular focus on RGS4, in these two processes, i.e., NE release from sympathetic nerve terminals & CA secretion from adrenal chromaffin cells. We also highlight the therapeutic potential of RGS4 pharmacological manipulation for diseases characterized by sympathetic dysfunction or SNS hyperactivity, such as heart failure and hypertension.

A-056 Investigating Iodine Contrast Contamination in Cortisol and Aldosterone Samples

Abstract Background Primary aldosteronism (PA) is a condition characterized by hypertension resulting from excess secretion of aldosterone. PA caused by a unilateral aldosterone-producing adenoma can be treated with adrenalectomy but requires diagnosis by adrenal vein sampling (AVS). In this procedure, intravenous cosyntropin is administered to stimulate adrenal cortical secretion, followed by obtaining samples from the right and left adrenal veins and IVC. Laterization index is calculated by obtaining the aldosterone:cortisol ratio for each side, with a ratio cutoff ≥3 is used for confirmation. Iodinated contrast media facilitates visualization of catheter positioning during AVS and sometimes results in contamination of samples, evidenced by abnormal gel separator flotation (i.e. gel above plasma). This study had two aims: 1) to determine at what concentration contrast dye causes gel flotation and 2) discern whether contrast media interferes with our cortisol or aldosterone assays. Methods Gel flotation studies were performed by spiking pooled plasma samples with iohexol contrast media (Omnipaque 240, GE Healthcare) at concentrations ranging from 3%-10% v/v and aliquoting into fresh lithium heparin plasma separator tubes (BD, PSTs). Samples were then centrifuged and visually inspected for abnormal gel flotation. Contrast interference studies were performed using three pools of low (5 µg/dL), medium, (30 µg/dL), and high (55 µg/dL) cortisol concentrations. Sample pools were diluted with 20% contrast media or saline (control) and subsequently mixed at different ratios to create a range of dye concentrations (0.5%-18% v/v). Each mixture was assayed in triplicate for cortisol and aldosterone on a cobas e602 (Roche Diagnostics) and LIAISON XL (DiaSorin) immunoanalyzer, respectively. The total allowable error (TEa) was ±0.4 μg/dL or ±20% for cortisol and ±2 ng/dL or ±20% for aldosterone. Results Flotation of the gel separator was observed at a dye concentration of 4.5% v/v and greater. For the cortisol interference study, the bias was <5% for the three pools at all contrast media concentrations. Aldosterone was also measured in these pools, as bias could affect ratios calculated for PA. Aldosterone interference occurred at contrast dye concentrations ranging from 12%-20% v/v. An average positive bias of 34% was observed in aldosterone samples spiked with contrast media relative to the saline control. Compared to sample pool controls without added saline or dye, measurements for cortisol and aldosterone were 19%-22% and 16-25% lower in media- and saline-spiked samples (20% v/v), respectively, indicating a logical dilution effect. Conclusions Contrast dye contamination of AVS specimens can cause gel flotation in lithium heparin PSTs, preventing their analysis. The presence of contrast media at certain concentrations interfered with the DiaSorin aldosterone assay, leading to falsely elevated results. No cortisol assay interference occurred in the presence of contrast media but results were falsely decreased due to sample dilution. Samples collected during AVS may be contaminated with contrast dye causing gel flotation to occur. This is indicative of a minimum contrast media concentration of 4.5% v/v. Aldosterone:cortisol ratios may be inaccurate due to the positive aldosterone immunoassay bias with contrast media contamination. Care should be taken when reporting and interpreting AVS results with suspected contamination.

Acute rimonabant treatment prevents anhedonia and memory loss in rats submitted to mild restraint stress

Stress-related disorders are becoming increasingly common and are often associated with cognitive impairments. Within this context, the endocannabinoid (ECB) system, particularly the type 1 cannabinoid (CB1) receptor, seems to play a decisive role in restoring body homeostasis. There is consistent evidence in the literature that disrupted CB1-mediated neurotransmission can ultimately contribute to stress-related diseases. Therefore, the present study aimed to evaluate the participation of CB1 receptors in the integrity of stress-induced peripheral and behavioral responses. For this purpose, male adult Wistar rats underwent physical restraint (1 h/day, for 7 days), followed by a single administration of rimonabant (CB1 receptor antagonist, 3 mg/Kg, intraperitonial) at the end of stress protocol. Animals were then subjected to evaluation of neuroendocrine responses, behavioral tests and quantification of Iba-1 (microglial) immunoreactivity in the parvocellular subdivisions of the paraventricular nucleus of the hypothalamus (PVN). No effects of restraint stress or rimonabant administration were detected on body mass variation. However, stress significantly increased adrenal relative mass and corticosterone secretion, and reduced thymus relative size. The stress effects on adrenal size and corticosterone plasma levels were absent in rimonabant-treated rats, but the thymus size was further reduced in the restraint-rimonabant group. Restraint stress also induced anhedonia, a depression-like behavior, and reduced object recognition index, indicating memory recovery impairment. Treatment with the CB1 antagonist significantly reversed stress-induced anhedonia and memory deficit. In the PVN, restraint stress reduced the number of Iba-1 positive cells in the medial parvocellular region of vehicle- but not rimonabant-treated animals. Taken together, these results indicate that the acute inhibition of the CB1-mediated endogenous pathway restores stress-induced depression-like behaviors and memory loss, suggesting a role for endocannabinoids in the neuro-immune-endocrine interplay at both peripheral and hypothalamic levels.

Aldosterone-Cortisol co-secretion in different adrenal tumors: A case series

Primary aldosteronism is the most common cause of endocrine hypertension. It commonly presents as refractory hypertension, carrying an elevated risk of cardiac and renal complications. Concurrent hypercortisolemia exacerbates the susceptibility to metabolic disorders, including obesity, dyslipidemia, abnormal blood glucose levels, and cardiovascular and renal diseases. Among the reported patients with co-secretion of aldosterone, the majority are aldosterone producing adenoma. Cases of bilateral adrenal hyperplasia secreting both aldosterone and cortisol are rarely reported. In this study, we conducted a comparative analysis of the clinical manifestations, laboratory tests, and imaging findings in two cases involving unilateral aldosterone-producing adenomas and bilateral macronodular adrenal hyperplasia respectively. Notably, our patients exhibited a cortisol circadian rhythm during the initial screening, complicating the diagnosis of Cushing's syndrome. The incorporation of early or routine low-dose dexamethasone suppression tests may prove beneficial in identifying co-secretory lesions promptly, assessing the risk of perioperative adrenal insufficiency, and guiding subsequent treatment and prognosis evaluation.

Multiple androgen pathways contribute to the steroid signature of adrenarche

ContextAdrenarche is a normal developmental event in mid-childhood characterized by increasing adrenal androgen secretion. The role of the classic androgen pathway has been well described in adrenarche, but the role of newer active androgens and additional androgen pathways is less clear. ObjectiveTo study the contribution of novel androgens and related steroid biosynthesis pathways to the development of adrenarche, and to identify additional steroid biomarkers of adrenarche. DesignA longitudinal study of children aged 6–8 years at baseline, followed up at ages 8–10 and 14–16 years. A total of 34 children (20 girls) with clinical and/or biochemical signs of adrenarche (cases) and 24 children (11 girls) without these signs (controls) at age 8–10 years were included. Serum steroid profiling was performed by liquid chromatography high-resolution mass spectrometry. Main outcome measuresThirty-two steroids compartmentalized in progestagens, gluco- and mineralocorticoid pathways, and four androgen related pathways, including the classic, backdoor, 11-oxy, and 11-oxy backdoor pathways. ResultsThe classic and 11-oxy androgen pathways were more active, and serum concentrations of main androgens in the classic (dehydroepiandrosterone, dehydroepiandrosterone sulfate, androstenedione and androsterone) and 11-oxy (11β-hydroxyandrostenedione, 11β-hydroxytestosterone, 11-ketoandrostenedione, and 11-ketotestosterone) pathways were higher in cases at ages 6–8 and 8–10 years. Pregnenolone concentrations at adrenarchal age (8–10 years) and cortisol concentrations at adolescence (14–16 years) were higher in cases. 11β-hydroxyandrosterone and 11-ketoandrosterone tended to be higher in cases with clinical signs compared to cases who had only biochemical evidence of adrenarche, albeit they were detected at low levels. In biomarker analyses, calculated steroid ratios with cortisol, cortisone, or 11-deoxycortisone as dividers were better classifiers for adrenarche than single steroids. Among these ratios, androstenedione/cortisone was the best. ConclusionsThe classic and 11-oxy androgen pathways are active in adrenarche. Children with earlier timing of adrenarche have higher serum cortisol levels at late pubertal age, suggesting that early adrenarche might have long-term effects on adrenal steroidogenesis by increasing the activity of the glucocorticoid pathway. Future studies should employ comprehensive steroid profiling to define novel classifiers and biomarkers for adrenarche and premature adrenarche.

PRECOCIOUS PUBERTY: EPIDEMIOLOGY, CLINICAL PRESENTATION, DIAGNOSIS, AND ETIOLOGIES

Precocious puberty, defined as the onset of sexual characteristics before the age of 8 in girls and 9 in boys, can arise from various causes, including central and peripheral mechanisms. While central precocious puberty (CPP) originates from premature activation of the hypothalamic-pituitary axis, peripheral precocious puberty (PPP) results from gonadal or adrenal hormone secretion independent of hypothalamic control. We conducted a retrospective study spanning eight years, from 2015 to 2023, at the Mohamed 6 University Hospital in Marrakech, Morocco, to investigate the epidemiological, clinical findings, laboratory, and etiological aspects of precociuos puberty in 12 children. We found a predominance of CPP, particularly in girls, with breast development being the most common clinical sign. In boys, early puberty typically presented with pubic hair development and increased penile size. Diagnostic evaluation included hormonal assays and imaging studies, with elevated levels of gonadal hormones confirming the diagnosis. CPP was predominantly idiopathic in girls, while traumatic brain injury and CNS lesions were common causes in boys. Adrenal disorders, including congenital adrenal hyperplasia, accounted for PPP cases. Brain imaging was crucial for identifying central lesions, while adrenal imaging aided in diagnosing adrenal pathologies. Despite limitations such as retrospective design and incomplete data, our study emphasizes the importance of early recognition and appropriate diagnostic procedures for children showing signs of early puberty to optimize management and outcomes.

Androgen synthesis cell-specific CREBZF deficiency alters adrenal cortex steroid secretion and develops behavioral abnormalities in adult male mice.

The global challenge of male infertility is escalating, notably due to the decreased testosterone (T) synthesis in testicular Leydig cells under stress, underscoring the critical need for a more profound understanding of its regulatory mechanisms. CREBZF, a novel basic region-leucine zipper transcription factor, regulates testosterone synthesis in mouse Leydig cells invitro; however, further validation through invivo experiments is essential. Our study utilized Cyp17a1-Cre to knock out CREBZF in androgen-synthesis cells and explored the physiological roles of CREBZF in fertility, steroid hormone synthesis, and behaviors in adult male mice. Conditional knockout (cKO) CREBZF did not affect fertility and serum testosterone level in male mice. Primary Leydig cells isolated from CREBZF-cKO mice showed impaired testosterone secretion and decreased mRNA levels of Star, Cyp17a1, and Hsd3b1. Loss of CREBZF resulted in thickening of the adrenal cortex, especially X-zone, with elevated serum corticosterone and dehydroepiandrosterone levels and decreased serum dehydroepiandrosterone sulfate levels. Immunohistochemical staining revealed increased expression of StAR, Cyp11a1, and 17β-Hsd3 in the adrenal cortex of CREBZF-cKO mice, while the expression of AR was significantly reduced. Along with the histological changes and abnormal steroid levels in the adrenal gland, CREBZF-cKO mice showed higher anxiety-like behavior and impaired memory in the elevated plus maze and Barnes maze, respectively. In summary, CREBZF is dispensable for fertility, and CREBZF deficiency in Leydig cells promotes adrenal function in adult male mice. These results shed light on the requirement of CREBZF for fertility, adrenal steroid synthesis, and stress response in adult male mice, and contribute to understanding the crosstalk between testes and adrenal glands.

Effect of Maternal High Fat Diet on the Hypothalamus-Pituitary-Adrenal Gland (HPA) Axis of the Offspring in Sheep

Maternal consumption of a high fat diet (HFD) during pregnancy is associated with metabolic dysfunction and altered HPA axis function in the offspring. These effects are well established in species with short gestation length (e.g., rodents), but less established in species with longer gestation periods more comparable with humans. The objective of the study was to determine the effect of maternal HFD on basal and stimulated cortisol secretion in the offspring at 16 weeks of age in sheep. All experiments were approved by the Institutional Animal Care and Use Committee at Cal Poly Pomona. Pregnant ewes were assigned to control (n=3) and HFD (n=3) groups. The control group was fed farmers best complete ewe and ram pellets. The HFD group was fed the same diet with an additional 30% rumen protected fat (Megalac, Volac Wilmar Feed Ingredients Ltd). After birth lambs were weaned at 12 weeks of age and given free access to control pellet diet with grains. To assess adrenal cortisol secretion at 16 weeks, lambs were infused intravenously with adrenocorticotropic hormone (ACTH; 2 ug/kg cortrosyn in 1 mL saline). Blood samples (1 mL) were taken through the jugular catheter at −30, −15, and 0 min (immediately before) and 5, 15, 30, 60, 90, and 120 min after ACTH administration for measurement of plasma cortisol by ELISA. Data were analyzed by two-way repeated measures ANOVA with a Tukey posthoc test. Basal plasma cortisol tended to be higher in HFD (32±8 ng/mL) than control (13±3 ng/mL) lambs, but this did not reach statistical significance. Plasma cortisol was higher than baseline from 15 to 90 minutes after ACTH administration in all lambs (p<0.05). The increment in plasma cortisol was higher in HFD than control lambs from 15-90 minutes (p<0.05). Accordingly, the maximum increase in plasma cortisol at 60 minutes and was higher in HFD (245±8 ng/mL) than control lambs (121±50 ng/mL p<0.05). These preliminary data suggest that maternal consumption of a high fat diet during pregnancy may increase basal and stimulated activity of the HPA axis in sheep. The study was funded by a Strategic Interdisciplinary Research Grant (SIRG) at California State Polytechnic University, Pomona. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Adrenal G protein-coupled Receptor Kinase (GRK)-2 Downregulation And Regulator of G protein Signaling (RGS)-4 Upregulation Mediate The Sympatholytic Effect Of Dapagliflozin

Dapagliflozin is a sodium/­glucose co-­transporter (SGLT)-­2 inhibitor with beneficial cardiovascular effects independent of its anti­diabetic actions. Among these is sympatholysis, i.e., norepinephrine (NE) lowering, beneficial in chronic human heart failure (HF). Adrenal G protein­-coupled receptor kinase (GRK)-­2 upregulation is a major driver of circulating catecholamine (CA) elevation and sympathetic nervous system (SNS) hyperactivity in HF due to dysregulation of adrenal sympatho-­inhibitory α2­-adrenergic receptors (ARs). On the other hand, we recently reported that Regulator of G protein Signaling (RGS)-­4 inhibits free fatty acid receptor (FFAR)-­3-stimulated NE release from sympathetic neurons, while it is also known to inhibit adrenal CA secretion induced by acetylcholine. Thus, we hypothesized herein that dapagliflozin may lower SNS hyperactivity by enhancing adrenal α2AR and RGS4 functions. We used the rat pheochromocytoma PC12 cell line expressing human α2A­AR, as well as freshly isolated adrenal glands from rats treated with dapagliflozin in vivo. Dapagliflozin treatment for 7 consecutive days (20 mg/kg/d in drinking water) led to a significant reduction in blood circulating NE levels (217±67 pg/ml, n=6), compared to vehicle-­treated rats (363±77 pg/ml, n=6, p<.05), suggesting reduced SNS activity. This was accompanied by reduced GRK2 and tyrosine hydroxylase (TH) mRNA and protein levels in dapagliflozin-­treated vs. vehicle­-treated adrenal glands. In contrast, RGS4 mRNA and protein levels were increased by dapagliflozin ­treatment. Adrenal α2AR density was higher in dapagliflozin- ­vs. vehicle-­treated rats (51.3±7.3 vs. 26.1±8.1 fmol/mg of protein, respectively; n=12 glands from 6 animals per group, p<.05). These results (i.e., GRK2 & TH downregulation with RGS4 upregulation) were completely recapitulated in PC12 cells in culture, treated with 5 μM dapagliflozin (or vehicle) for 24 hours. Importantly, α2AR signaling towards inhibition of CA secretion was markedly enhanced, while the cholinergic agonist carbachol-induced CA secretion was reduced post-­dapagliflozin treatment of PC12 cells. GRK2 overexpression and RGS4 siRNA-mediated knockdown partially reversed dapagliflozin‘s effect on CA secretion, confirming the involvement of GRK2 and RGS4 in dapagliflozin‘s sympatholytic effects in PC12 cells. In conclusion, dapagliflozin exerts adrenal sympatholysis via: a) downregulation of TH, which reduces CA biosynthesis, and GRK2, which reduces α2AR desensitization (i.e., enhances α2AR sympatho-inhibitory signaling); and b) upregulation of RGS4, which directly opposes cholinergic-stimulated CA secretion. 1) NIH/NHLBI #HL155718-01. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Renal Hypokalemia: An Endocrine Perspective.

The majority of disorders that cause renal potassium wasting present with abnormalities in adrenal hormone secretion. While these findings frequently lead patients to seek endocrine evaluation, clinicians often struggle to accurately diagnose these conditions, delaying treatment and adversely impacting patient care. At the same time, growing insight into the genetic and molecular basis of these disorders continues to improve their diagnosis and management. In this review, we outline a practical integrated approach to the evaluation of renal hypokalemia syndromes that are seen in endocrine practice while highlighting recent advances in understanding of the genetics and pathophysiology behind them.

Analysis of Genetic Spectrum in Polycystic Ovary Syndrome- A Review

Polycystic ovary syndrome (PCOS) is increase in an alarming rate since 1935. According to WHO the prevalence rate of PCOS is 3.4% worldwide. Hyperandrogenism, chronic anovulation, small cysts and increase in size of the ovary are the most common diagnostic feature for PCOS. Beside the environmental factors PCOS is highly associated with genetic back up of an individual. So, Different genetic pathways like steroid hormone synthesis , ovarian and adrenal steroidogenesis, gonadotropin action, insulin action and secretion, energy homeostasis , chronic inflammation pathways plays most important role in PCOS progression. Furthermore several report suggested that, some other genes like plasminogen activator inhibitor-1 (PAI-1), HSD3B2 , 17α-hydroxysteroid dehydrogenases, dopamine receptor, IGF107, aldosterone synthetase , paraoxonase, glycogen synthetase, resistin, apoprotein E are also involved in PCOS progression. From different case report it is established that epilepsy and diabetes condition are the two main regulators for PCOS progression. Whereas, epigenetic mechanism is also involved in the pathogenesis of PCOS. Some of the therapeutics is also available for treatment of PCOS but not ensure proper cure. Long-term treatment for PCOS, increases the risk of developing metabolic and cardiovascular abnormalities. So the main aim of this review is to reveal all aspects of genetics mechanism related to PCOS for better understanding of the disease. As well as established a profile of regulatory marker gene for early diagnosis and to develop a better treatment protocol.

THE RELATIONSHIP OF VITAMIN D TOPOLYCYSTIC OVARY SYNDROME (PCOS) TEENAGERS AT KOTO TANGAH PADANG DISTRICT HIGH SCHOOL IN 2022

PCOS is characterized by increased ovarian and adrenal androgen secretion,hyperandrogenic symptoms such as hirsutism, acne and/or alopecia, menstrual irregularities,and polycystic ovaries. The prevalence of PCOS in 2016 was 6−21% of reproductive ageworldwide. PCOS is the most common female endocrine disorder with a prevalence of around4-6% in women of reproductive age in Indonesia. Vitamin D deficiency can increase PCOSsymptoms. The research design was cross-sectional. The study was conducted at SMA N 7,SMA N 8 and SMA N 13 Padang in Koto Tangah District in May-August 2022. The researchsample was high school students who experienced menstrual cycle disorders and were willingto agree to informed consent for the study with a sample size of 59 respondents. Vitamin Dlevels were examined using the 25-Hydroxyvitamin D ELISA Kit. Data were analyzed by chi-square test. The results showed that 86.4% of respondents experienced vitamin D deficiency.Statistically there was a relationship between PCOS in adolescents accompanied byhyperandrogens and vitamin D levels, there was a relationship between PCOS in adolescentsaccompanied by obesity and vitamin D levels, there was no relationship between PCOS inadolescents accompanied by acanthosis nigrican and vitamin D levels, and there was norelationship between PCOS in adolescents accompanied by hyperandrogens, obesity andacanthosis nigrican with vitamin D levels in SMA Koto Tangah District Padang in 2022. Theconclusion of this study is that there is a relationship between PCOS in adolescentsaccompanied by hyperandrogens and vitamin D levels and there is a relationship betweenPCOS in adolescents accompanied by obesity and vitamin D levels. .

An Update on the Genetics of Polycystic Ovary Syndrome

PCOS is a common endocrinopathy among women of reproductive age, with a worldwide prevalence of 8 to 13%, depending on the criteria used for diagnosis. It is characterized by a constellation of features, including oligo/anovulation, clinical and/or biochemical hyperandrogenism, and polycystic ovarian morphology. PCOS is one of the common causes of female infertility. It is also associated with metabolic derangements, including obesity, insulin resistance, and compensatory hyperinsulinemia, which increase the likelihood of developing type 2 diabetes mellitus. Despite extensive research, the etiology of PCOS remains largely unknown. It seems likely that the hypothalamic-pituitary-ovarian axis dysfunction, partial folliculogenesis arrest, insulin resistance, and ovarian and adrenal androgen secretion may play a role in the pathogenesis of PCOS. Familial clustering of the cases of PCOS points to a genetic component linked with it. The initial genetic studies suggest an autosomal dominant pattern of inheritance of the disorder in some families; however, most studies support multifactorial origin. Since PCOS is a complex trait, the typical form of inheritance of PCOS follows a non-Mendelian pattern and involves complex genetic mechanisms. Studies involving linkage and association have suggested a connection between genetic variations and the risk of developing PCOS in certain families or populations. Through genome-wide association studies and next-generation sequencing techniques, several candidate genes have been identified that play a role in the etiopathogenesis of the disorder. Pathogenic variants of various genes such as INSR, IRS1, GHRL, LDLR, MC4R, ADIPOQ, UCP1, UCP2, UCP3, FTO, PCSK9, FBN3, NEIL2, FDFT1, PCSK9, CYP11, CYP17, CYP21, HSD17, STAR, POR, AKR1C3, AMH, AMHR2, INHBA, AR, SHBG, LHR, FSHR, FSH β, SRD5A, GATA4, THADA, YAP1, ERBB2, DENND1A, FEM1B, FDFT1, NEIL2, TCF7L2, etc. in some PCOS cases are linked as underlying etiologic associations. This review aims to provide insight into the current genetic knowledge about PCOS. Discovering the genetic factors and pathways involved in the disorder will help us better comprehend the underlying mechanisms of the disorder.

Peripheral clock gene oscillations are perturbed in neonatal and adult rat offspring raised under adverse limited bedding conditions

Circadian (24-h) rhythms in the suprachiasmatic nucleus (SCN) are established in utero in rodents, but rhythmicity of peripheral circadian clocks appears later in postnatal development. Since peripheral oscillators can be influenced by maternal feeding and behavior, we investigated whether exposure to the adverse environmental conditions of limited bedding (LB) during postnatal life would alter rhythmicity in the SCN, adrenal gland and liver in neonatal (postnatal day PND10), juvenile (PND28) and adult rats. We also examined locomotor activity in adults. Limited bedding increased nursing time and slightly increased fragmentation of maternal behavior. Exposure to LB reduced the amplitude of Per2 in the SCN on PND10. Adrenal clock gene expression (Bmal1, Per2, Cry1, Rev-erbα, Dbp) and corticosterone secretion were rhythmic at all ages in NB offspring, whereas rhythmicity of Bmal1, Cry1 and corticosterone was abolished in neonatal LB pups. Circadian gene expression in the adrenal and liver was well established by PND28. In adults, liver expression of several circadian genes was increased at specific daytimes by LB and the microstructure of locomotor behavior was altered. Thus, changes in maternal care and behavior might provide important signals to the maturing peripheral oscillators and modify, in particular their output functions in the long-term.

Precocious Puberty: Types, Pathogenesis and Updated Management.

Precocious puberty (PP) means the appearance of secondary sexual characters before the age of eight years in girls and nine years in boys. Puberty is indicated in girls by the enlargement of the breasts (thelarche) in girls and in boys by the enlargement of the testes in either volume or length (testicular volume = 4 mL, testicular length = 25 mm, or both). Two types of PP are recognized - namely central PP (CPP) and peripheral PP (PPP). This paper aims to describe the clinical findings and laboratory workup of PP and to illustrate the new trends in the management of precocious sexual maturation. Gonadotropin-releasing hormone (GnRH)-independent type (PPP) refers to the development of early pubertal maturation not related to the central activation of the hypothalamic-pituitary-gonadal (HPG) axis. It is classified into genetic or acquired disorders. The most common forms of congenital or genetic causes involve McCune-Albright syndrome (MAS), familial male-limited PP, and congenital adrenal hyperplasia. The acquired causes include exogenous exposure to androgens, functioning tumors or cysts, and the pseudo-PP of profound primary hypothyroidism. On the other hand, CPP is the most common and it is a gonadotropin-dependent form. It is due to premature maturation of the HPG axis. CPP may occur as genetic alterations, such asMKRN3, DLK1, or KISS1;as a part of mutations in theepigenetic factors that regulate the HPG axis, such as Lin28b and let-7; or as a part of syndromes, central lesions such as hypothalamic hamartoma, and others. A full, detailed history and physical examination should be taken. Furthermore, several investigations should be conducted for both types of PP, including the estimation of serum gonadotropins such as luteinizing and follicle-stimulating hormones and sex steroids, in addition to a radiographic workup and thyroid function tests. Treatment depends on the type of PP: Long-acting GnRHa, either intramuscularly or implanted, is the norm of care for CPP management, while in PPP, especially in congenital adrenal hyperplasia, the goal of management is to suppress adrenal androgen secretion by glucocorticoids. In addition, anastrozole and letrozole - third-generation aromatase inhibitors - are more potent for MAS.

Kinin B1 receptor modulates glucose homeostasis and physical exercise capacity by altering adrenal catecholamine synthesis and secretion

Our group has shown in several papers that kinin B1 receptor (B1R) is involved in metabolic adaptations, mediating glucose homeostasis and interfering in leptin and insulin signaling. Since catecholamines are involved with metabolism management, we sought to evaluate B1R role in catecholamine synthesis/secretion. Using B1R global knockout mice, we observed increased basal epinephrine content, accompanied by decreased hepatic glycogen content and increased glucosuria. When these mice were challenged with maximal intensity exercise, they showed decreased epinephrine and norepinephrine response, accompanied by disturbed glycemic responses to effort and poor performance. This phenotype was related to alterations in adrenal catecholamine synthesis: increased basal epinephrine concentration and reduced norepinephrine content in response to exercise, as well decreased gene expression and protein content of tyrosine hydroxylase and decreased gene expression of dopamine beta hydroxylase and kinin B2 receptor. We conclude that the global absence of B1R impairs catecholamine synthesis, interfering with glucose metabolism at rest and during maximal exercise.

A toddler with testosterone: where did it come from?

Precocious development of secondary sexual characters not involving pulsatile gonadotropin secretion is known as gonadotropin independent precocious puberty or peripheral precocious puberty (PPP). This form of sexual precocity in males can occur due to gonadal, adrenal, or other testosterone secreting tumors (teratomas, hepatomas, and choriocarcinomas), untreated congenital adrenal hyperplasia, testotoxicosis, and familial male limited precocious puberty. We report a case of a 2-year-old boy with PPP caused due to hepatoblastoma. Complete surgical resection of the tumor was done, and the child received cisplatin chemotherapy.

Concurrent and prospective associations between family socioeconomic status, social support and salivary diurnal and hair cortisol in adolescence.

Exposure to socioeconomic adversity is hypothesized to impact hypothalamic-pituitary-adrenal (HPA) axis activity and cortisol secretion, but existing evidence is inconsistent. Yet, few studies have investigated this association using a developmental approach that considers potential protective contextual factors. This study examined the role of stability and changes in family socioeconomic status (SES) in the prediction of multiple cortisol indicators and tested whether social support moderated these associations. Participants were part of a population-based sample of twin pairs recruited at birth. Family SES was assessed in early childhood (ages 0-5) and mid-adolescence (age 14). Social support was assessed at ages 14 and 19. Diurnal cortisol (n = 569) was measured at age 14 at awakening, 30 min later, in the afternoon and evening over four non-consecutive days. Hair cortisol concentration (HCC, n = 704) was measured at age 19. All data were collected before the pandemic and multilevel regression models were conducted to account for the nested data structure. Youth exposed to lower family SES levels in childhood and mid-adolescence had a flatter diurnal slope and higher HCC compared with those who experienced upward socioeconomic mobility in mid-adolescence. Contrastingly, mid-adolescence SES showed no association with the diurnal slope or HCC for youth from higher-SES households in early childhood. Moreover, youth raised in higher-SES families in early childhood had a higher CAR in mid-adolescence if they reported greater social support in mid-adolescence. Social support also moderated the SES-cortisol association in mid-adolescence, with higher-SES youth showing higher awakening cortisol secretion when reporting more social support. Our findings support the hypothesis that early socioeconomic adversity sensitizes HPA axis activity to later socioeconomic disadvantage, which may bear consequences for socioemotional and behavioral functioning.

Adrenal limb thickness is associated with metabolism profiles in patients with diabetes: A cross-sectional study.

The association between adrenal size and metabolic profiles in patients with diabetes mellitus (DM) is unclear. This study was conducted to determine whether the adrenal thickness measured by computed tomography (CT) is correlated with the metabolic profiles of patients with DM. This was a cross-sectional study including 588 Chinese hospitalized patients with DM without comorbidities or medications known to affect adrenal morphology or hormone secretion. Adrenal limb thickness was measured on unenhanced chest CT. Participants were stratified into tertiles according to their total adrenal limb thickness. Linear and logistic regression models were used to estimate the correlations. After adjustment for sex and age, the adrenal thickness was positively associated with body mass index (BMI), waist circumference (WC), urinary albumin/creatinine ratio, and 24-h urinary free cortisol (UFC) and negatively correlated with high-density lipoprotein cholesterol. The sequential equation model (SEM) suggested UFC partially mediated the effect of adrenal limb thickness on WC by 12%. Adrenal thickness, but not UFC, was associated with a higher risk of existing hypertension (odds ratio [OR] = 3.78, 95% confidence interval [CI] 1.58, 9.02) and hyperlipidemia (OR = 2.76, 95% CI 1.03, 7.38), independent of age, gender, BMI, and WC. The adrenal thickness is independently associated with BMI, WC, cortisol levels, urinary albumin/creatinine ratio, hypertension, and dyslipidemia but not glycemic parameters in patients with diabetes. Our study encourages further studies to investigate the role of adrenal physiology in patients with diabetes.