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The Journal of Clinical Endocrinology... Apr 2024Hyperandrogenism in women, such as polycystic ovary syndrome, ovarian hyperthecosis, congenital adrenal hyperplasia, and androgen-secreting tumors, are all associated... (Review)
Review
Hyperandrogenism in women, such as polycystic ovary syndrome, ovarian hyperthecosis, congenital adrenal hyperplasia, and androgen-secreting tumors, are all associated with increased prevalence of cardiovascular risk factors that include type 2 diabetes, hypertension, dyslipidemia, and metabolic syndrome. However, it is not clear whether this also implies enhanced risk of cardiovascular disease and mortality. Furthermore, the involvement of obesity and menopausal status for cardiometabolic risk in these women has not been elucidated. Based on the most recent systematic reviews and meta-analyses, this review summarizes the latest scientific evidence. To conclude, hyperandrogenism in premenopausal women is associated with enhanced prevalence of cardiovascular risk factors, as well as increased risk of cardiovascular disease and mortality, independently of body mass index. In contrast, elevated cardiovascular risk factors and increased risk of myocardial infarction and stroke in hyperandrogenic postmenopausal women are dependent on obesity. Furthermore, the overall risk of cardiovascular disease and coronary artery disease in hyperandrogenic postmenopausal women is similar to controls. The reason for a reduced cardiometabolic risk after menopause in hyperandrogenic women compared to nonhyperandrogenic women is not clear. It can be speculated that the difference in endocrine balance and metabolic status between women with and without hyperandrogenism might decrease after menopause because hyperandrogenism usually improves with age, whereas menopausal transition itself is associated with androgen dominance and abdominal obesity. Although we have gained increased knowledge about cardiometabolic risks in women with hyperandrogenism, it must be acknowledged that the quality of data is overall low. More research is needed, especially longer and larger follow-up studies in women with hyperandrogenism of different etiologies and phenotypes.
Topics: Female; Humans; Hyperandrogenism; Androgens; Postmenopause; Diabetes Mellitus, Type 2; Polycystic Ovary Syndrome; Obesity; Myocardial Infarction
PubMed: 37886900
DOI: 10.1210/clinem/dgad590 -
Clinics (Sao Paulo, Brazil) 2023PCOS is an endocrine disorder characterized by chronic anovulation, hyperandrogenism, and polycystic ovaries. Its etiology is uncertain. It is debated whether BPA would... (Review)
Review
PCOS is an endocrine disorder characterized by chronic anovulation, hyperandrogenism, and polycystic ovaries. Its etiology is uncertain. It is debated whether BPA would be a component of the environmental factor in the etiology of PCOS. Contamination by BPA can occur from food packaging (exposure during the diet) and through skin absorption and/or inhalation. It can be transferred to the fetus via the placenta or to the infant via breast milk, and it can be found in follicular fluid, fetal serum, and amniotic fluid. The phenolic structure of BPA allows it to interact with Estrogen Receptors (ERs) through genomic signaling, in which BPA binds to nuclear ERα or Erβ, or through nongenomic signaling by binding to membrane ERs, prompting a rapid and intense response. With daily and constant exposure, BPA's tendency to bioaccumulate and its ability to activate nongenomic signaling pathways can alter women's metabolic and reproductive function, leading to hyperandrogenism, insulin resistance, obesity, atherogenic dyslipidemia, chronic inflammatory state, and anovulation and favoring PCOS. The harmful changes caused by BPA can be passed on to future generations without the need for additional exposure because of epigenetic modifications. Not only high BPA levels can produce harmful effects, but at low levels, BPA may be harmful when exposure occurs during the most vulnerable periods, such as the fetal and neonatal periods, as well as during the prepubertal age causing an early accumulation of BPA in the body. Learning how BPA participates in the pathogenesis of PCOS poses a challenge and further studies should be conducted.
Topics: Pregnancy; Infant, Newborn; Female; Humans; Polycystic Ovary Syndrome; Hyperandrogenism; Anovulation; Phenols
PubMed: 38008036
DOI: 10.1016/j.clinsp.2023.100310 -
Endocrine Journal Oct 2023Optimizing the glucocorticoid dosage has been a major concern in classic 21OHD (21-hydroxylase deficiency) treatment, as it is essential to adjust it meticulously to the... (Review)
Review
Optimizing the glucocorticoid dosage has been a major concern in classic 21OHD (21-hydroxylase deficiency) treatment, as it is essential to adjust it meticulously to the needs of the individual patient. Insufficient glucocorticoid treatment will cause adrenal insufficiency, including life-threatening adrenal crisis, while excess of androgen could cause precocious pubertal growth in children, virilization in female patients, and infertility in male and female adult patients. Meanwhile, overtreatment with glucocorticoids causes iatrogenic Cushing's syndrome which could result in growth impairment, obesity, osteoporosis, and hypertension. The dilemma of 21OHD treatment is that glucocorticoid supplementation therapy at physiological dosage does not sufficiently suppress ACTH, consequently leading to adrenal androgen excess. Accordingly, the window for the appropriate glucocorticoid treatment would have to be substantially narrower than that of other types of adrenal insufficiency without androgen excess, such as adrenal hypoplasia. For the appropriate management of classic 21OHD, the physician has to be well versed in the physiology of the adrenal cortex, growth, and reproductive function. Comprehensive understanding of patients' requirements according to their life stage and sex is essential. Furthermore, female patients with 46,XX need to be cared for as differences in sex development (DSD) with careful psychological management. In this review, we aimed to comprehensively summarize the current status of classic 21OHD treatment, including the initial treatment during the neonatal period, management of adrenal insufficiency, maintenance therapy of each life stage, and the importance of clinical management as DSD for 46,XX female patients. The recently developed agents, Chronocort, and Crinecerfont, are also discussed.
Topics: Adult; Child; Infant, Newborn; Humans; Male; Female; Glucocorticoids; Androgens; Adrenal Hyperplasia, Congenital; Adrenal Insufficiency; Steroid 21-Hydroxylase
PubMed: 37380491
DOI: 10.1507/endocrj.EJ23-0075 -
International Immunopharmacology Dec 2023Hyperandrogenemia and persistent chronic inflammation, two main striking features of polycystic ovary syndrome (PCOS), have been proven involved in follicular dysgenesis...
Hyperandrogenemia and persistent chronic inflammation, two main striking features of polycystic ovary syndrome (PCOS), have been proven involved in follicular dysgenesis in PCOS. However, the association between hyperandrogenism and inflammation activation in PCOS is not fully understood. Excess testosterone(T) induces inflammation and pyroptosis activation in a mouse model of PCOS, leading to ovarian dysfunction and fibrosis. Excessive endoplasmic reticulum (ER) stress is present in ovarian granulosa cells (GCs), testosterone-induced PCOS mouse and cellular models. This study found higher levels of interleukin (IL)-1β, IL-8, IL-17, and IL-18 in the follicular fluid of PCOS patients with hyperandrogenemia undergoing IVF treatment. In addition, pyroptosis in GCs was demonstrated, which was significantly elevated in PCOS patients. To clarify the association of hyperandrogenism, inflammation, and pyroptosis activation in PCOS, dehydroepiandrosterone(DHEA)-treated mouse PCOS model and T-treated KGN cell line were explored for PCOS mechanism. Markers of inflammatory activation and pyroptosis were significantly increased after DHEA treatment in mice and T treatment in KGN cells. In addition, ER stress sensor proteins were increased simultaneously. However, suppression of inflammation by genipin(GP) led to decreased pyroptosis in KGN cells but no variation in ER stress sensor proteins. In contrast, when treated with tauroursodeoxycholic acid(TUDCA) to attenuate ER stress, the markers of inflammatory factors were significantly reduced, accompanied by a reduction in pyroptosis. Our results suggest that persistent hyperandrogenemia of PCOS promotes local inflammatory activation of the ovary, and the imbalanced inflammatory microenvironment leads to pyroptosis of GCs, which is mediated by ER stress activation.
Topics: Humans; Female; Mice; Animals; Polycystic Ovary Syndrome; Hyperandrogenism; Pyroptosis; Testosterone; Inflammation; Dehydroepiandrosterone; Tumor Microenvironment
PubMed: 37918087
DOI: 10.1016/j.intimp.2023.111141 -
Clinical Endocrinology Dec 2023Polycystic ovary syndrome (PCOS) is a complex disorder with diverse metabolic implications. Diagnosis typically relies on oligo-amenorrhoea (OA), hyperandrogenism (HA),... (Observational Study)
Observational Study
OBJECTIVE
Polycystic ovary syndrome (PCOS) is a complex disorder with diverse metabolic implications. Diagnosis typically relies on oligo-amenorrhoea (OA), hyperandrogenism (HA), and polycystic ovarian morphology (PCOM). However, the role of polymenorrhoea in PCOS remains understudied. Additionally, limited information exists regarding metabolic disturbances in women with partial PCOS phenotypes that do not meet diagnostic criteria. This extensive database aims to provide substantial evidence on the metabolic implications of polymenorrhoea and partial PCOS phenotypes.
DESIGN
Prospective observational study.
PATIENTS AND MEASUREMENTS
In this single-centre study, 6463 women with PCOS-like characteristics and 3142 age-matched healthy women were included. The study compared clinical (anthropometry, modified Ferriman Gallwey [mFG] score), hormonal (serum testosterone), and metabolic (plasma glucose, serum lipids, insulin) characteristics between women diagnosed with PCOS, those with partial PCOS phenotypes, and the healthy control group RESULTS: In all, 5174 women met Rotterdam criteria for PCOS diagnosis, while 737 were classified as Pre-PCOS, including HA (n = 538), OA (n = 121), or PCOM (n = 78). Common clinical features included oligomenorrhoea (75.5%), hirsutism (82.9%), obesity (27.2%), hypertension (1.6%), metabolic syndrome (19.6%), and diabetes mellitus (5.6%). Women diagnosed with PCOS, HA only, and OA only exhibited higher average body mass index, plasma glucose levels (both fasting and 2 h after the oral glucose tolerance test), and lipid fractions in comparison to those with PCOM and the healthy controls. However, indices of insulin resistance were similar among women with PCOS, HA, PCOM, and OA, albeit higher than in the healthy controls. The polymenorrhoea subgroup (5.9%) had lower BMI and serum testosterone, but similar mFG score, plasma glucose, insulin, and lipid levels as the oligomenorrhoea subgroup.
CONCLUSION
The metabolic disturbances observed in Pre-PCOS women highlight the need to reassess diagnostic criteria. Including the polymenorrhoea subcategory in PCOS criteria is recommended due to similar metabolic dysfunctions as the oligomenorrhoea group.
Topics: Female; Humans; Polycystic Ovary Syndrome; Oligomenorrhea; Blood Glucose; Hyperandrogenism; Insulin; Testosterone; Lipids
PubMed: 37656656
DOI: 10.1111/cen.14964 -
Experimental and Clinical Endocrinology... Oct 2023Adrenal tumors are generally rare in children and can be a part of familial cancer syndrome. This research was conducted to examine the clinical outcomes,...
OBJECTIVE
Adrenal tumors are generally rare in children and can be a part of familial cancer syndrome. This research was conducted to examine the clinical outcomes, histopathological results, and genetic etiologies of adrenal tumors in children and adolescents.
METHODS
Thirty-one children and adolescents with adrenal tumors were included. Data on clinical outcomes and endocrine and radiologic results were retrospectively analyzed. Molecular analysis was conducted in select patients according to their phenotype and family history.
RESULTS
The median age at diagnosis was 7.9 years (range: 0.8-17.8 years) with 5.1±1.8 cm of maximum tumor diameter. Adrenal adenoma (n=7), carcinoma (n=5), borderline (n=2), isolated micronodular adrenocortical disease (n=2), pheochromocytoma (n=8), paraganglioma (n=3), and ganglioneuroma (n=4) are all pathological diagnoses. The most common presenting symptom was excess production of adrenocortical hormones (n=15), including virilization and Cushing syndrome. Non-functioning adrenocortical tumors were found in a patient with congenital adrenal hyperplasia. Genetic etiologies were identified in (n=5), (n=4), and (n=1). Patients with mutations in were young (1.5±0.5 years) and had large masses (6.1±2.3 cm).
CONCLUSIONS
This study describes clinical outcomes and the pathological spectrum of adrenal tumors in children and adolescents. Adrenocortical tumors mostly presented with an excess of the adrenocortical hormone. Patients with genetic defects presented at a young age and large size of tumors, necessitating genetic testing in patients at a young age.
Topics: Humans; Child; Adolescent; Infant; Child, Preschool; Retrospective Studies; Adrenal Cortex Neoplasms; Adrenocortical Adenoma; Cushing Syndrome; Adrenal Gland Neoplasms
PubMed: 37437600
DOI: 10.1055/a-2127-9292 -
Medicine Dec 2023Polycystic ovary syndrome (PCOS) is a complex disorde7r influenced by genetic, neuroendocrine, metabolic, environmental, and lifestyle factors. This paper delves into... (Review)
Review
Polycystic ovary syndrome (PCOS) is a complex disorde7r influenced by genetic, neuroendocrine, metabolic, environmental, and lifestyle factors. This paper delves into the increasingly recognized role of gut microbiota dysbiosis in the onset and progression of PCOS. Utilizing advances in next-generation sequencing and metabolomics, the research examines the intricate interaction between the gut microbiota and the central nervous system via the gut-brain axis. The paper highlights how disruptions in gut microbiota contribute significantly to PCOS by modulating the release of gut-brain peptides and activating inflammatory pathways. Through such mechanisms, gut microbiota dysbiosis is implicated in hyperandrogenism, insulin resistance, chronic inflammation, and metabolic disorders associated with PCOS. While the relationship between gut microbiota and PCOS has begun to be elucidated, this paper underscores the need for further research to identify specific bacterial strains and their metabolic byproducts as potential therapeutic targets. Therefore, comprehensive studies are urgently needed to understand and fundamentally treat the pathophysiological processes of PCOS, offering valuable insights for future treatment and prevention strategies.
Topics: Female; Humans; Polycystic Ovary Syndrome; Gastrointestinal Microbiome; Dysbiosis; Hyperandrogenism; Insulin Resistance
PubMed: 38115365
DOI: 10.1097/MD.0000000000036075 -
The American Journal of Pathology Dec 2023Pregnancy-related problems have been linked to impairments in maternal uterine spiral artery (SpA) remodeling. The mechanisms underlying this association are still...
Pregnancy-related problems have been linked to impairments in maternal uterine spiral artery (SpA) remodeling. The mechanisms underlying this association are still unclear. It is also unclear whether hyperandrogenism and insulin resistance, the two common manifestations of polycystic ovary syndrome, affect uterine SpA remodeling. We verified previous work in which exposure to 5-dihydrotestosterone (DHT) and insulin (INS) in rats during pregnancy resulted in hyperandrogenism, insulin intolerance, and higher fetal mortality. Exposure to DHT and INS dysregulated the expression of angiogenesis-related genes in the uterus and placenta and also decreased expression of endothelial nitric oxide synthase and matrix metallopeptidases 2 and 9, increased fibrotic collagen deposits in the uterus, and reduced expression of marker genes for SpA-associated trophoblast giant cells. These changes were related to a greater proportion of unremodeled uterine SpAs and a smaller proportion of highly remodeled arteries in DHT + INS-exposed rats. Placentas from DHT + INS-exposed rats exhibited decreased basal and labyrinth zone regions, reduced maternal blood spaces, diminished labyrinth vascularity, and an imbalance in the abundance of vascular and smooth muscle proteins. Furthermore, placentas from DHT + INS-exposed rats showed expression of placental insufficiency markers and a significant increase in cell senescence-associated protein levels. Altogether, this work demonstrates that increased pregnancy complications in polycystic ovary syndrome may be mediated by problems with uterine SpA remodeling, placental functionality, and placental senescence.
Topics: Humans; Rats; Pregnancy; Female; Animals; Placenta; Polycystic Ovary Syndrome; Hyperandrogenism; Uterus; Arteries; Dihydrotestosterone; Insulin; Uterine Artery
PubMed: 37689383
DOI: 10.1016/j.ajpath.2023.08.008 -
Biomedicine & Pharmacotherapy =... Nov 2023Polycystic ovarian syndrome (PCOS) is the most common endocrine and metabolic disorder in women of childbearing age, with ovulatory dysfunction, hyperandrogenism, and... (Review)
Review
Polycystic ovarian syndrome (PCOS) is the most common endocrine and metabolic disorder in women of childbearing age, with ovulatory dysfunction, hyperandrogenism, and polycystic ovarian morphology (PCOM) as the clinical features. Androgen excess, insulin resistance, obesity, adipose tissue dysfunction, ovulatory dysfunction, and gut microbiota dysbiosis are the main pathological features and pathogenesis of PCOS and are related to systemic chronic low-grade inflammation and chronic ovarian tissue inflammation in PCOS. With the advances in immune-endocrine interaction studies, research on the role of immune cells in the occurrence and development of PCOS is gradually increasing. As the core of innate immunity, macrophages play an indispensable role in systemic inflammatory response. Meanwhile, they are involved in maintaining the stability and function of the ovary as the most abundant immune cells in ovarian tissue. Studies in humans and mice have found that the polarization of macrophages into M1 type plays multiple roles in the pathogenesis of PCOS. This review describes the distribution characteristics of macrophage subpopulations in patients and animal models with PCOS, discusses the role of macrophage-related metabolic inflammation in PCOS, and summarizes the relationship between macrophages and PCOS-related pathological features and its possible mechanisms, to further understand the pathogenesis of PCOS and reveal the role of macrophages in it. In addition, research on immune-endocrine interactions can also provide direction for finding new therapeutic targets for PCOS.
Topics: Female; Humans; Mice; Animals; Polycystic Ovary Syndrome; Hyperandrogenism; Insulin Resistance; Macrophages; Inflammation
PubMed: 37716116
DOI: 10.1016/j.biopha.2023.115470 -
Clinical Endocrinology Aug 2023Patients with salt-wasting congenital adrenal hyperplasia (SW-CAH) usually show pronounced impairment of aldosterone secretion and, therefore, also require... (Review)
Review
Patients with salt-wasting congenital adrenal hyperplasia (SW-CAH) usually show pronounced impairment of aldosterone secretion and, therefore, also require mineralocorticoid replacement. While a lot of research and discussion focusses on the glucocorticoid therapy in SW-CAH to replace the missing cortisol and to control adrenal androgen excess, very little research is dealing with mineralocorticoid replacement. However, recent data demonstrated an increased cardiovascular risk in adult CAH patients urging to reflect also on the current mineralocorticoid replacement therapy. In this review, we explain the role and function of the mineralocorticoid receptor, its ligands and inhibitors and its relevance for the therapy of patients with SW-CAH. We performed an extensive literature search and present data on mineralocorticoid therapy in SW-CAH patients as well as clinical advice how to monitor and optimise mineralocorticoid replacement therapy.
PubMed: 37564007
DOI: 10.1111/cen.14959