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Molecular and Cellular Endocrinology Jul 2013Alterations of ovarian follicle morphology and function have been well documented in women with PCOS. These include increased numbers of growing preantral follicles,... (Review)
Review
Alterations of ovarian follicle morphology and function have been well documented in women with PCOS. These include increased numbers of growing preantral follicles, failure of follicle growth beyond the mid-antral stage, evidence of granulosa call degeneration, and theca cell hyperplasia. Functional abnormalities include paradoxical granulosa cell hyperresponsiveness to FSH which is clinically linked to ovarian hyperstimulation during ovulation induction. In addition, there is likely a primary theca cell defect that accounts for the majority of excess androgen production in this disorder. The precise mechanisms responsible for altered follicle function are not completely clear. However, several factors appear to influence normal advancement of follicle development as well as impair ovarian steroidogenesis. These include intra- as well as extraovarian influences that distort normal ovarian growth and disrupt steroid production by follicle cells.
Topics: Androgens; Animals; Anti-Mullerian Hormone; Estrogens; Female; Follicle Stimulating Hormone; Granulosa Cells; Humans; Insulin; Luteinizing Hormone; Ovarian Follicle; Ovulation; Polycystic Ovary Syndrome
PubMed: 22874072
DOI: 10.1016/j.mce.2012.07.011 -
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 -
Endocrinology and Metabolism Clinics of... Mar 2021Evidence of clinical and/or biochemical androgen excess poses a unique differential in postmenopausal women. Some signs and symptoms of postmenopausal hyperandrogenism... (Review)
Review
Evidence of clinical and/or biochemical androgen excess poses a unique differential in postmenopausal women. Some signs and symptoms of postmenopausal hyperandrogenism can be normal and attributed to the natural aging process. However, the causes of androgen excess in this group include both nontumorous and tumorous causes. Treatment of androgen excess may improve both quality of life and long-term metabolic outcomes.
Topics: Female; Humans; Hyperandrogenism; Postmenopause; Quality of Life; Testosterone
PubMed: 33518189
DOI: 10.1016/j.ecl.2020.12.002 -
American Family Physician Feb 2012Hirsutism is excess terminal hair that commonly appears in a male pattern in women. Although hirsutism is generally associated with hyperandrogenemia, one-half of women... (Review)
Review
Hirsutism is excess terminal hair that commonly appears in a male pattern in women. Although hirsutism is generally associated with hyperandrogenemia, one-half of women with mild symptoms have normal androgen levels. The most common cause of hirsutism is polycystic ovary syndrome, accounting for three out of every four cases. Many medications can also cause hirsutism. In patients whose hirsutism is not related to medication use, evaluation is focused on testing for endocrinopathies and neoplasms, such as polycystic ovary syndrome, adrenal hyperplasia, thyroid dysfunction, Cushing syndrome, and androgen-secreting tumors. Symptoms and findings suggestive of neoplasm include rapid onset of symptoms, signs of virilization, and a palpable abdominal or pelvic mass. Patients without these findings who have mild symptoms and normal menses can be treated empirically. For patients with moderate or severe symptoms, an early morning total testosterone level should be obtained, and if moderately elevated, it should be followed by a plasma free testosterone level. A total testosterone level greater than 200 ng per dL (6.94 nmol per L) should prompt evaluation for an androgen-secreting tumor. Further workup is guided by history and physical examination, and may include thyroid function tests, prolactin level, 17-hydroxyprogesterone level, and corticotropin stimulation test. Treatment includes hair removal and pharmacologic measures. Shaving is effective but needs to be repeated often. Evidence for the effectiveness of electrolysis and laser therapy is limited. In patients who are not planning a pregnancy, first-line pharmacologic treatment should include oral contraceptives. Topical agents, such as eflornithine, may also be used. Treatment response should be monitored for at least six months before making adjustments.
Topics: Adrenal Hyperplasia, Congenital; Androgen Antagonists; Endocrine Gland Neoplasms; Female; Hair Removal; Hirsutism; Humans; Hyperandrogenism; Polycystic Ovary Syndrome
PubMed: 22335316
DOI: No ID Found -
Journal of Endocrinological... Mar 2024Maternal hyperandrogenism during pregnancy is associated with adverse gestational outcomes and chronic non-communicable diseases in offspring. However, few studies are...
PURPOSE
Maternal hyperandrogenism during pregnancy is associated with adverse gestational outcomes and chronic non-communicable diseases in offspring. However, few studies are reported to demonstrate the association between maternal androgen excess and cardiac health in offspring. This study aimed to explore the relation between androgen exposure in utero and cardiac health of offspring in fetal and adult period. Its underlying mechanism is also illustrated in this research.
METHODS
Pregnant mice were injected with dihydrotestosterone (DHT) from gestational day (GD) 16.5 to GD18.5. On GD18.5, fetal heart tissue was collected for metabolite and morphological analysis. The hearts from adult offspring were also collected for morphological and qPCR analysis. H9c2 cells were treated with 75 μM androsterone. Immunofluorescence, flow cytometry, qPCR, and western blot were performed to observe cell proliferation and explore the underlying mechanism.
RESULTS
Intrauterine exposure to excessive androgen led to thinner ventricular wall, decreased number of cardiomyocytes in fetal offspring and caused cardiac hypertrophy, compromised cardiac function in adult offspring. The analysis of steroid hormone metabolites in fetal heart tissue by ultra performance liquid chromatography and tandem mass spectrometry showed that the content of androgen metabolite androsterone was significantly increased. Mechanistically, H9c2 cells treated with androsterone led to a significant decrease in phosphorylated retinoblastoma protein (pRB) and cell cycle-related protein including cyclin-dependent kinase 2 (CDK2), cyclin-dependent kinase 4 (CDK4), and cyclin D1 (CCND1) in cardiomyocytes. This resulted in cell cycle arrest at G1-S phase, which in turn inhibited cardiomyocyte proliferation.
CONCLUSION
Taken together, our results indicate that in utero exposure to DHT, its metabolite androsterone could directly decrease cardiomyocytes proliferation through cell cycle arrest, which has a life-long-lasting effect on cardiac health. Our study highlights the importance of monitoring sex hormones in women during pregnancy and the follow-up of cardiac function in offspring with high risk of intrauterine androgen exposure.
Topics: Humans; Adult; Pregnancy; Female; Animals; Mice; Androgens; Myocytes, Cardiac; Androsterone; Cell Cycle Checkpoints; Cell Proliferation; Cell Cycle Proteins; Dihydrotestosterone; Cardiomegaly
PubMed: 37642904
DOI: 10.1007/s40618-023-02178-1 -
The Journal of Steroid Biochemistry and... Apr 2021Women with polycystic ovary syndrome (PCOS) are at higher risk for metabolic disorders compared to healthy women, and about 51 % of women with PCOS suffer from...
OBJECTIVE
Women with polycystic ovary syndrome (PCOS) are at higher risk for metabolic disorders compared to healthy women, and about 51 % of women with PCOS suffer from non-alcoholic fatty liver disease (NAFLD). Investigation into the pathological mechanism behind this association will provide insights for the prevention and treatment of this complication.
METHODS
Dihydrotestosterone (DHT), a nonaromatic androgen, was used to mimic the pathological conditions of hyperandrogenism and insulin resistance. Hematoxylin and eosin staining, Oil Red O staining, immunofluorescent staining, Western blots, and qRT-PCR were used to verify the hepatic steatosis and inflammation, and the latter two methods were also used for energy and mitochondrion-related assays. ELISA was used to measure the level of reactive oxygen species.
RESULTS
Twelve weeks of DHT exposure led to obesity and insulin resistance as well as hepatic steatosis, lipid deposition, and different degrees of inflammation. The expression of molecules involved in respiratory chain and aerobic respiration processes, such as electron transfer complex II, pyruvate dehydrogenase, and succinate dehydrogenase complex subunit A, was inhibited. In addition, molecules associated with apoptosis and autophagy were also abnormally expressed, such as increased Bak mRNA, an increased activated caspase-3 to caspase-3 ratio, and increased Atg12 protein expression. All of these changes are associated with the mitochondria and lead to lipid deposition and inflammation in the liver.
CONCLUSIONS
Long-term androgen excess contributes to insulin resistance and hepatic steatosis by affecting mitochondrial function and causing an imbalance in apoptosis and autophagy, thus suggesting the pathogenesis of NAFLD in women with PCOS.
Topics: Androgens; Animals; Apoptosis; Autophagy-Related Protein 12; Dihydrotestosterone; Disease Models, Animal; Female; Humans; Insulin Resistance; Lipid Metabolism; Non-alcoholic Fatty Liver Disease; Obesity; Polycystic Ovary Syndrome; Reactive Oxygen Species; Risk Factors; bcl-2 Homologous Antagonist-Killer Protein
PubMed: 33513383
DOI: 10.1016/j.jsbmb.2021.105829 -
Journal of Applied Physiology... Apr 2023Polycystic ovary syndrome (PCOS) is associated with endothelial dysfunction; whether this is attributable to comorbid hyperandrogenism and/or obesity remains to be...
Polycystic ovary syndrome (PCOS) is associated with endothelial dysfunction; whether this is attributable to comorbid hyperandrogenism and/or obesity remains to be established. Therefore, we ) compared endothelial function between lean and overweight/obese (OW/OB) women with and without androgen excess (AE)-PCOS and ) examined androgens as potential modulators of endothelial function in these women. The flow-mediated dilation (FMD) test was applied in 14 women with AE-PCOS (lean: = 7; OW/OB: = 7) and 14 controls (CTRL; lean: = 7, OW/OB: = 7) at baseline (BSL) and following 7 days of ethinyl estradiol supplementation (EE; 30 µg/day) to assess the effect of a vasodilatory therapeutic on endothelial function; at each time point we assessed peak increases in diameter during reactive hyperemia (%FMD), shear rate, and low flow-mediated constriction (%LFMC). BSL %FMD was attenuated in lean AE-PCOS versus both lean CTRL (5.2 ± 1.5 vs. 10.3 ± 2.6%, < 0.01) and OW/OB AE-PCOS (5.2 ± 1.5 vs. 6.6 ± 0.9%, = 0.048). A negative correlation between BSL %FMD and free testosterone was observed in lean AE-PCOS only ( = 0.68, = 0.02). EE increased %FMD in both OW/OB groups (CTRL: 7.6 ± 0.6 vs. 10.4 ± 2.5%, AE-PCOS: 6.6 ± 0.9 vs. 9.6 ± 1.7%, < 0.01), had no impact on %FMD in lean AE-PCOS (5.17 ± 1.5 vs. 5.17 ± 1.1%, = 0.99), and reduced %FMD in lean CTRL (10.3 ± 2.6 vs. 7.6 ± 1.2%, = 0.03). Collectively, these data indicate that lean women with AE-PCOS exhibit more severe endothelial dysfunction than their OW/OB counterparts. Furthermore, endothelial dysfunction appears to be mediated by circulating androgens in lean but not in OW/OB AE-PCOS, suggesting a difference in the endothelial pathophysiology of AE-PCOS between these phenotypes. We present evidence for marked endothelial dysfunction in lean women with androgen excess polycystic ovary syndrome (AE-PCOS) that is ) associated with free testosterone levels, ) impaired relative to overweight/obese women with AE-PCOS, and ) unchanged following short-term ethinyl estradiol supplementation. These data indicate an important direct effect of androgens on the vascular system in women with AE-PCOS. Our data also suggest that the relationship between androgens and vascular health differs between phenotypes of AE-PCOS.
Topics: Humans; Female; Polycystic Ovary Syndrome; Androgens; Overweight; Body Mass Index; Obesity; Ethinyl Estradiol; Testosterone
PubMed: 36861670
DOI: 10.1152/japplphysiol.00583.2022 -
Pediatric Research Jun 2022Premature adrenarche is a condition of childhood adrenal androgen excess (AAE) in the absence of gonadotropin-dependent puberty, and has been linked to insulin...
BACKGROUND
Premature adrenarche is a condition of childhood adrenal androgen excess (AAE) in the absence of gonadotropin-dependent puberty, and has been linked to insulin resistance and progression to metabolic syndrome. Microbial dysbiosis is associated with progression of inflammatory states and chronic diseases. Here, we aimed to examine the salivary microbiomes of children with AAE and assess the relationship with adrenal androgens and metabolic parameters.
METHODS
In a prospective cross-sectional study of children with AAE and healthy controls, adrenal and metabolic parameters were characterized and salivary microbiome was profiled using V3-V4 16S rDNA gene amplicon sequencing.
RESULTS
There was increased α-diversity in AAE (5 M, 15 F) compared to controls (3 M, 8 F), with positive correlation of 11OHA4, 11KA4, testosterone, androstenedione, DHEA, and DHEAS. Subanalyses showed increased α-diversity in both overweight/obese AAE and normal weight AAE compared to normal weight controls. Genus Peptostreptococcus, Veillonella, and Streptococcus salivarius were increased in normal weight AAE. Genus Prevotella, Abiotrophia, and Neisseria were increased in overweight/obese AAE.
CONCLUSION
These pilot data demonstrate differences in salivary microbiome profiles of children with and without AAE. Further studies are needed to assess the causal relationships between adrenal androgens, metabolic dysfunction, and salivary microbiome composition.
IMPACT
This study is the first to report the salivary microbiome of prepubertal children with adrenal androgen excess (AAE). α-Diversity is increased in the salivary microbiome of children with AAE independent of weight status, and in this study cohort several serum androgens are positively associated with α-diversity. Several taxa that have been associated with periodontal disease and inflammation are found to be significantly increased in AAE.
Topics: Androgens; Child; Cross-Sectional Studies; Dehydroepiandrosterone; Humans; Microbiota; Obesity; Overweight; Prospective Studies
PubMed: 34341500
DOI: 10.1038/s41390-021-01661-w -
Human Reproduction Update 2010Hirsutism is the presence of excess body or facial terminal (coarse) hair growth in females in a male-like pattern, affects 5-15% of women, and is an important sign of... (Review)
Review
BACKGROUND
Hirsutism is the presence of excess body or facial terminal (coarse) hair growth in females in a male-like pattern, affects 5-15% of women, and is an important sign of underlying androgen excess. Different methods are available for the assessment of hair growth in women.
METHODS
We conducted a literature search and analyzed the published studies that reported methods for the assessment of hair growth. We review the basic physiology of hair growth, the development of methods for visually quantifying hair growth, the comparison of these methods with objective measurements of hair growth, how hirsutism may be defined using a visual scoring method, the influence of race and ethnicity on hirsutism, and the impact of hirsutism in diagnosing androgen excess and polycystic ovary syndrome.
RESULTS
Objective methods for the assessment of hair growth including photographic evaluations and microscopic measurements are available but these techniques have limitations for clinical use, including a significant degree of complexity and a high cost. Alternatively, methods for visually scoring or quantifying the amount of terminal body and facial hair growth have been in use since the early 1920s; these methods are semi-quantitative at best and subject to significant inter-observer variability. The most common visual method of scoring the extent of body and facial terminal hair growth in use today is based on a modification of the method originally described by Ferriman and Gallwey in 1961 (i.e. the mFG method).
CONCLUSION
Overall, the mFG scoring method is a useful visual instrument for assessing excess terminal hair growth, and the presence of hirsutism, in women.
Topics: Androgens; Female; Hair; Hirsutism; Humans; Polycystic Ovary Syndrome
PubMed: 19567450
DOI: 10.1093/humupd/dmp024 -
The Journal of Clinical Endocrinology... Mar 2018Androgen excess in women is predominantly due to underlying polycystic ovary syndrome (PCOS). However, there is a lack of clarity regarding patterns and severity of...
CONTEXT
Androgen excess in women is predominantly due to underlying polycystic ovary syndrome (PCOS). However, there is a lack of clarity regarding patterns and severity of androgen excess that should be considered predictive of non-PCOS pathology.
OBJECTIVE
We examined the diagnostic utility of simultaneous measurement of serum dehydroepiandrosterone sulfate (DHEAS), androstenedione (A4), and testosterone (T) to delineate biochemical signatures and cutoffs predictive of non-PCOS disorders in women with androgen excess.
DESIGN
Retrospective review of all women undergoing serum androgen measurement at a large tertiary referral center between 2012 and 2016. Serum A4 and T were measured by tandem mass spectrometry and DHEAS by immunoassay. Patients with at least one increased serum androgen underwent phenotyping by clinical notes review.
RESULTS
In 1205 women, DHEAS, A4, and T were measured simultaneously. PCOS was the most common diagnosis in premenopausal (89%) and postmenopausal women (29%). A4 was increased in all adrenocortical carcinoma (ACC) cases (n = 15) and T in all ovarian hyperthecosis (OHT) cases (n = 7); all but one case of congenital adrenal hyperplasia (CAH; n = 18) were identified by increased levels of A4 and/or T. In premenopausal women, CAH was a prevalent cause of severe A4 (59%) and T (43%) excess; severe DHEAS excess was predominantly due to PCOS (80%). In postmenopausal women, all cases of severe DHEAS and A4 excess were caused by ACC and severe T excess equally by ACC and OHT.
CONCLUSIONS
Pattern and severity of androgen excess are important predictors of non-PCOS pathology and may be used to guide further investigations as appropriate.
Topics: Adrenal Cortex Neoplasms; Adrenal Hyperplasia, Congenital; Adrenocortical Carcinoma; Adult; Androgens; Androstenedione; Dehydroepiandrosterone Sulfate; Female; Humans; Hyperandrogenism; Middle Aged; Ovarian Diseases; Polycystic Ovary Syndrome; Postmenopause; Predictive Value of Tests; Premenopause; Reference Values; Retrospective Studies; Severity of Illness Index; Testosterone
PubMed: 29342266
DOI: 10.1210/jc.2017-02426