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The Journal of Clinical Endocrinology... Aug 2023The most common form of congenital adrenal hyperplasia is 21-hydroxylase deficiency (21OHD), which in the classic (severe) form occurs in roughly 1:16 000 newborns... (Review)
Review
The most common form of congenital adrenal hyperplasia is 21-hydroxylase deficiency (21OHD), which in the classic (severe) form occurs in roughly 1:16 000 newborns worldwide. Lifelong treatment consists of replacing cortisol and aldosterone deficiencies, and supraphysiological dosing schedules are typically employed to simultaneously attenuate production of adrenal-derived androgens. Glucocorticoid titration in 21OHD is challenging as it must balance the consequences of androgen excess vs those from chronic high glucocorticoid exposure, which are further complicated by interindividual variability in cortisol kinetics and glucocorticoid sensitivity. Clinical assessment and biochemical parameters are both used to guide therapy, but the specific purpose and goals of each biomarker vary with age and clinical context. Here we review the approach to medication titration for children and adults with classic 21OHD, with an emphasis on how to interpret adrenal biomarker values in guiding this process. In parallel, we illustrate how an understanding of the pathophysiologic and pharmacologic principles can be used to avoid and to correct complications of this disease and consequences of its management using existing treatment options.
Topics: Child; Adult; Humans; Infant, Newborn; Adrenal Hyperplasia, Congenital; Glucocorticoids; Hydrocortisone; Steroids; Biomarkers; Disease Management; Steroid 21-Hydroxylase
PubMed: 36950738
DOI: 10.1210/clinem/dgad134 -
The Journal of Obstetrics and... May 2024Polycystic ovary syndrome (PCOS) is a common endocrine disorder characterized by menstrual irregularities, androgen excess, and polycystic ovarian morphology, but its... (Review)
Review
AIM
Polycystic ovary syndrome (PCOS) is a common endocrine disorder characterized by menstrual irregularities, androgen excess, and polycystic ovarian morphology, but its pathogenesis remains largely unknown. This review focuses on how androgen excess influences the molecular basis of energy metabolism, mitochondrial function, and mitophagy in granulosa cells and oocytes, summarizes our current understanding of the pathogenesis of PCOS, and discuss perspectives on future research directions.
METHODS
A search of PubMed and Google Scholar databases were used to identify relevant studies for this narrative literature review.
RESULTS
Female offspring born of pregnant animals exposed to androgens recapitulates the PCOS phenotype. Abnormal mitochondrial morphology, altered expression of genes related to glycolysis, mitochondrial biogenesis, fission/fusion dynamics, and mitophagy have been identified in PCOS patients and androgenic animal models. Androgen excess causes uncoupling of the electron transport chain and depletion of the cellular adenosine 5'-triphosphate pool, indicating further impairment of mitochondrial function. A shift toward mitochondrial fission restores mitochondrial quality control mechanisms. However, prolonged mitochondrial fission disrupts autophagy/mitophagy induction due to loss of compensatory reserve for mitochondrial biogenesis. Disruption of compensatory mechanisms that mediate the quality control switch from mitophagy to apoptosis may cause a disease phenotype. Furthermore, genetic predisposition, altered expression of genes related to glycolysis and oxidative phosphorylation, or a combination of these factors may also contribute to the development of PCOS.
CONCLUSION
In conclusion, fetuses exposed to a hyperandrogenemic intrauterine environment may cause the PCOS phenotype possibly through disruption of the compensatory regulation of the mitophagy-apoptosis axis.
Topics: Polycystic Ovary Syndrome; Female; Humans; Mitophagy; Apoptosis; Animals; Mitochondria
PubMed: 38417972
DOI: 10.1111/jog.15916 -
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 -
ELife Jul 2023Variations in B cell numbers are associated with polycystic ovary syndrome (PCOS) through unknown mechanisms. Here, we demonstrate that B cells are not central mediators...
Variations in B cell numbers are associated with polycystic ovary syndrome (PCOS) through unknown mechanisms. Here, we demonstrate that B cells are not central mediators of PCOS pathology and that their frequencies are altered as a direct effect of androgen receptor activation. Hyperandrogenic women with PCOS have increased frequencies of age-associated double-negative B memory cells and increased levels of circulating immunoglobulin M (IgM). However, the transfer of serum IgG from women into wild-type female mice induces only an increase in body weight. Furthermore, RAG1 knockout mice, which lack mature T- and B cells, fail to develop any PCOS-like phenotype. In wild-type mice, co-treatment with flutamide, an androgen receptor antagonist, prevents not only the development of a PCOS-like phenotype but also alterations of B cell frequencies induced by dihydrotestosterone (DHT). Finally, B cell-deficient mice, when exposed to DHT, are not protected from developing a PCOS-like phenotype. These results urge further studies on B cell functions and their effects on autoimmune comorbidities highly prevalent among women with PCOS.
Topics: Humans; Female; Mice; Animals; Polycystic Ovary Syndrome; Androgens; Body Weight; Phenotype
PubMed: 37401759
DOI: 10.7554/eLife.86454 -
The Prostate Nov 2023The discovery of androgen receptor (AR) having transrepression effects completes the circle of its functionalities as a typical transcription factor, which intrinsically...
BACKGROUND
The discovery of androgen receptor (AR) having transrepression effects completes the circle of its functionalities as a typical transcription factor, which intrinsically bears dual functions of activation and repression linked to co-factor competition and redistribution. Indeed, AR dual functions are exemplified by locus-wide regulation of the oncogenic 8q24-MYC region.
METHODS
RT-qPCR assay and public RNA-profiling datasets were used to assess MYC transcription in androgen-sensitive cell lines. Public ChIP-seq and RNA-Seq datasets were computed to evaluate AR-MYC direct and indirect signatures. Gene sets in typical MYC and AR pathways were monitored to validate their cross-talks. Bio-informatics and chromosome conformation capture (3C) assay were performed in the AR gene locus to examine androgen-elicited distal regulation. Finally, co-factor re-distribution were globally tracked between AR and MYC binding sites.
RESULTS
In this report, we found MYC responded negatively to androgen with hypersensitivity, rivaling AR natural functions as an innate androgen effector. Furthermore, both direct and indirect AR and MYC transcriptional programs were actively in equilibration. With established androgen-mediated versus MYC-mediated gene subsets, we validated AR and MYC pathways were both bidirectional and extensively entangled. In addition, we determined that the AR gene locus resembled the MYC gene region and both loci were androgen-repressed via epigenetics and chromatin architectural alterations. Significantly, transcriptional factor profiling along the prostate cancer (PCa) genome exposed that PCa transcriptomes were dynamically equilibrated between AR-binding site and MYC-binding site.
CONCLUSION
Together, our findings stratified AR-MYC interactions that are extensively wired and intricately organized to compensate for essential PCa transcriptional programs and neutralize excessive signaling.
Topics: Male; Humans; Receptors, Androgen; Androgens; Transcriptome; Cell Line, Tumor; Prostatic Neoplasms; Transcription Factors; Gene Expression Regulation, Neoplastic
PubMed: 37565264
DOI: 10.1002/pros.24603 -
Cureus Dec 2023Menopause, when menstrual cycles stop, is brought on by a decline in the level of the hormones progesterone and oestrogen synthesised by the ovaries. Menopause is an... (Review)
Review
Menopause, when menstrual cycles stop, is brought on by a decline in the level of the hormones progesterone and oestrogen synthesised by the ovaries. Menopause is an unavoidable stage of a female's lifecycle, but because experiences differ for every woman, several women require health care aid to manage their health problems. The physiological variations that take place at various periods of the reproducing age, along with the kind and timing of menopause, are components that are frequently associated with a greater threat of cardiometabolic illness. The most researched associations between menopause and cardiometabolic health are reduced levels of ovarian estrogen synthesis and excessive amounts of androgen during the onset of menopause. Although testosterone and oestrogens have differing effects on adipocyte physiology, it is debatable how important oestrogens are for the emergence of metabolic disorders following menopause. The control of adipocyte differentiation by the brain as well as potential roles of oestrogen and endocrine disruptors chemicals are reviewed in this systematic review of the subject. In general, women had a greater frequency of metabolic syndrome compared to men. Female metabolism was significantly impacted by overt hyperthyroidism and subclinical hypothyroidism. Osteoporosis is another medical condition that menopausal women may experience. Estrogen deprivation is the main contributor to osteoporosis in menopausal women. The regular cycle of bone turnover is disrupted by the decrease in estrogen secretion, which boosts osteoclastic resorption activity while decreasing osteoblastic activity. The entire article assesses and provides information on all the changes in a woman's life after menopause.
PubMed: 38288203
DOI: 10.7759/cureus.51287 -
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 -
American Journal of Physiology. Heart... Aug 2023We tested the hypothesis that hyperandrogenemia in androgen excess polycystic ovary syndrome (AE-PCOS) is a primary driver in blood pressure (BP) dysregulation via...
We tested the hypothesis that hyperandrogenemia in androgen excess polycystic ovary syndrome (AE-PCOS) is a primary driver in blood pressure (BP) dysregulation via altered sympathetic nervous system activity (SNSA), reduced integrated baroreflex gain and increased renin-angiotensin system (RAS) activation. We measured resting SNSA (microneurography), integrated baroreflex gain, and RAS with lower body negative pressure in obese insulin-resistant (IR) women with AE-PCOS [ = 8, 23 ± 4 yr; body mass index (BMI) = 36.3 ± 6.4 kg/m] and obese IR controls ( = 7, control, 29 ± 7 yr; BMI = 34.9 ± 6.8 kg/m), at baseline (BSL), after 4 days of gonadotropin-releasing hormone antagonist (ANT, 250 μg/day) and 4 days of ANT + testosterone (ANT + T, 5 mg/day) administration. Resting BP was similar between groups for systolic blood pressure (SBP; 137 ± 14 vs. 135 ± 14 mmHg, AE-PCOS, control) and diastolic BP (89 ± 21 vs. 76 ± 10 mmHg, AE-PCOS, control). BSL integrated baroreflex gain was similar between groups [1.4 ± 0.9 vs. 1.0 ± 1.3 forearm vascular resistance (FVR) U/mmHg], but AE-PCOS had lower SNSA (10.3 ± 2.0 vs. 14.4 ± 4.4 burst/100 heartbeats, = 0.04). In AE-PCOS, T suppression increased integrated baroreflex gain, which was restored to BSL with ANT + T (4.3 ± 6.5 vs. 1.5 ± 0.8 FVR U/mmHg, ANT, and ANT + T, = 0.04), with no effect in control. ANT increased SNSA in AE-PCOS (11.2 ± 2.4, = 0.04). Serum aldosterone was greater in AE-PCOS versus control (136.5 ± 60.2 vs. 75.7 ± 41.4 pg/mL, AE-PCOS, control, = 0.04) at BSL but was unaffected by intervention. Serum angiotensin-converting enzyme was greater in AE-PCOS versus control (101.9 ± 93.4 vs. 38.2 ± 14.7 pg/mL, = 0.04) and reduced by ANT in AE-PCOS (77.7 ± 76.5 vs. 43.4 ± 27.3 µg/L, ANT, and ANT + T, = 0.04) with no impact on control. Obese, IR women with AE-PCOS showed decreased integrated baroreflex gain and increased RAS activation compared with control. Here we present evidence for an important role of testosterone in baroreflex control of blood pressure and renal responses to baroreceptor unloading in women with a common, high-risk androgen excess polycystic ovary syndrome (AE-PCOS) phenotype. These data indicate a direct effect of testosterone on the vascular system of women with AE-PCOS independent of body mass index (BMI) and insulin-resistant (IR). Our study indicates that hyperandrogenemia is a central underlining mechanism of heightened cardiovascular risk in women with PCOS.
Topics: Female; Humans; Androgens; Blood Pressure; Body Mass Index; Insulin; Insulin Resistance; Obesity; Polycystic Ovary Syndrome; Testosterone
PubMed: 37327000
DOI: 10.1152/ajpheart.00164.2023 -
Medicina (Kaunas, Lithuania) Jan 2024Polycystic ovary syndrome (PCOS) manifests a multifactorial pathology characterized by polycystic ovaries, menstrual cycle disorders, varying degrees of... (Review)
Review
Polycystic ovary syndrome (PCOS) manifests a multifactorial pathology characterized by polycystic ovaries, menstrual cycle disorders, varying degrees of hyperandrogenism, and an ad-verse metabolic risk profile. The position of hyperandrogenism in this syndrome has been extensively studied. A multitude of mechanisms place it in the position of cause but also of consequence; therefore, ongoing research efforts are focused on identifying medications that can effectively reduce levels of androgens in women with PCOS. Moreover, lipid abnormalities are common in this population, with up to 70% of patients having dyslipidemia. Statins may have potential therapeutic benefits for women with PCOS, as they have been shown to improve insulin resistance and reduce the risk of cardiovascular disease. In addition, their role in accelerated steroidogenesis by limiting one source of cholesterol, influencing enzymatic activity, and providing several other beneficial mechanisms is widely investigated. This review aimed to provide a comprehensive overview of the pathogenesis of androgen excess and dyslipidemia in PCOS, as well as the therapeutic potential of statins.
Topics: Humans; Female; Polycystic Ovary Syndrome; Hyperandrogenism; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Insulin Resistance; Dyslipidemias
PubMed: 38399531
DOI: 10.3390/medicina60020244 -
EBioMedicine Nov 2023Polycystic ovary syndrome (PCOS) is the most common endocrine disorder leading to anovulatory infertility. Abnormalities in the central neuroendocrine system governed by...
BACKGROUND
Polycystic ovary syndrome (PCOS) is the most common endocrine disorder leading to anovulatory infertility. Abnormalities in the central neuroendocrine system governed by gonadotropin-releasing hormone (GnRH) neurons might be related to ovarian dysfunction in PCOS, although the link in this disordered brain-to-ovary communication remains unclear. Here, we manipulated GnRH neurons using chemogenetics in adult female mice to unveil whether chronic overaction of these neurons would trigger PCOS-like hormonal and reproductive impairments.
METHODS
We used adult Gnrh1 female mice to selectively target and express the designer receptors exclusively activated by designer drugs (DREADD)-based chemogenetic tool hM3D(Gq) in hypophysiotropic GnRH neurons. Chronic chemogenetic activation protocol was carried out with clozapine N-oxide (CNO) i.p. injections every 48 h over a month. We evaluated the reproductive and hormonal profile before, during, and two months after chemogenetic manipulations.
FINDINGS
We discovered that the overactivation of GnRH neurons was sufficient to disrupt reproductive cycles, promote hyperandrogenism, and induce ovarian dysfunction. These PCOS features were detected with a long-lasting neuroendocrine dysfunction through abnormally high luteinizing hormone (LH) pulse secretion. Additionally, the GnRH-R blockade prevented the establishment of long-term neuroendocrine dysfunction and androgen excess in these animals.
INTERPRETATION
Taken together, our results show that hyperactivity of hypothalamic GnRH neurons is a major driver of reproductive and hormonal impairments in PCOS and suggest that antagonizing the aberrant GnRH signaling could be an efficient therapeutic venue for the treatment of PCOS.
FUNDING
European Research Council (ERC) under the European Union's Horizon 2020 research and innovation program (grant agreement n◦ 725149).
Topics: Humans; Female; Mice; Animals; Polycystic Ovary Syndrome; Luteinizing Hormone; Gonadotropin-Releasing Hormone; Neurons
PubMed: 37898094
DOI: 10.1016/j.ebiom.2023.104850