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Molecular Metabolism May 2020Polycystic ovary syndrome (PCOS) is the most common endocrinopathy among reproductive age women. Although its cardinal manifestations include hyperandrogenism,...
BACKGROUND
Polycystic ovary syndrome (PCOS) is the most common endocrinopathy among reproductive age women. Although its cardinal manifestations include hyperandrogenism, oligo/anovulation, and/or polycystic ovarian morphology, PCOS women often display also notable metabolic comorbidities. An array of pathogenic mechanisms have been implicated in the etiology of this heterogeneous endocrine disorder; hyperandrogenism at various developmental periods is proposed as a major driver of the metabolic and reproductive perturbations associated with PCOS. However, the current understanding of the pathophysiology of PCOS-associated metabolic disease is incomplete, and therapeutic strategies used to manage this syndrome's metabolic complications remain limited.
SCOPE OF REVIEW
This study is a systematic review of the potential etiopathogenic mechanisms of metabolic dysfunction frequently associated with PCOS, with special emphasis on the metabolic impact of androgen excess on different metabolic tissues and the brain. We also briefly summarize the therapeutic approaches currently available to manage metabolic perturbations linked to PCOS, highlighting current weaknesses and future directions.
MAJOR CONCLUSIONS
Androgen excess plays a prominent role in the development of metabolic disturbances associated with PCOS, with a discernible impact on key peripheral metabolic tissues, including the adipose, liver, pancreas, and muscle, and very prominently the brain, contributing to the constellation of metabolic complications of PCOS, from obesity to insulin resistance. However, the current understanding of the pathogenic roles of hyperandrogenism in metabolic dysfunction of PCOS and the underlying mechanisms remain largely incomplete. In addition, the development of more efficient, even personalized therapeutic strategies for the metabolic management of PCOS patients persists as an unmet need that will certainly benefit from a better comprehension of the molecular basis of this heterogeneous syndrome.
Topics: Adipose Tissue; Androgens; Animals; Bariatric Surgery; Female; Humans; Hyperandrogenism; Insulin Resistance; Metabolic Syndrome; Mice; Obesity; Polycystic Ovary Syndrome
PubMed: 32244180
DOI: 10.1016/j.molmet.2020.01.001 -
Clinica Chimica Acta; International... Mar 2020Polycystic ovary syndrome (PCOS) is a complex and heterogeneous endocrine disease characterized by clinical or laboratorial hyperandrogenism, oligo-anovulation and... (Review)
Review
Polycystic ovary syndrome (PCOS) is a complex and heterogeneous endocrine disease characterized by clinical or laboratorial hyperandrogenism, oligo-anovulation and metabolic abnormalities, including insulin resistance, excessive weight or obesity, type II diabetes, dyslipidemia and an increased risk of cardiovascular disease. The most significant clinical manifestation of PCOS is hyperandrogenism. Excess androgen profoundly affects granulosa cell function and follicular development via complex mechanisms that lead to obesity and insulin resistance. Most PCOS patients with hyperandrogenism have steroid secretion defects that result in abnormal folliculogenesis and failed dominant follicle selection. Hyperandrogenism induces obesity, hairy, acne, and androgenetic alopecia. These symptoms can bring great psychological stress to women. Drugs such as combined oral contraceptive pills, metformin, pioglitazone and low-dose spironolactone help improve pregnancy rates by decreasing androgen levels in vivo. Notably, PCOS is heterogeneous, and hyperandrogenism is not the only pathogenic factor. Obesity and insulin resistance aggravate the symptoms of hyperandrogenism, forming a vicious cycle that promotes PCOS development. Although numerous studies have been conducted, the definitive pathogenic mechanisms of PCOS remain uncertain. This review summarizes and discusses previous and recent findings regarding the relationship between hyperandrogenism, insulin resistance, obesity and PCOS.
Topics: Androgens; Female; Humans; Hyperandrogenism; Hypoglycemic Agents; Insulin Resistance; Metformin; Obesity; Pioglitazone; Polycystic Ovary Syndrome; Spironolactone
PubMed: 31733195
DOI: 10.1016/j.cca.2019.11.003 -
Frontiers in Endocrinology 2022Polycystic ovary syndrome (PCOS) is a common reproductive endocrine disease in women of reproductive age. Ovarian dysfunction including abnormal steroid hormone...
Polycystic ovary syndrome (PCOS) is a common reproductive endocrine disease in women of reproductive age. Ovarian dysfunction including abnormal steroid hormone synthesis and follicular arrest play a vital role in PCOS pathogenesis. Hyperandrogenemia is one of the important characteristics of PCOS. However, the mechanism of regulation and interaction between hyperandrogenism and ovulation abnormalities are not clear. To investigate androgen-related metabolic state in granulosa cells of PCOS patients, we identified the transcriptome characteristics of PCOS granulosa cells by RNA-seq. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis of differentially expressed genes (DEGs) revealed that genes enriched in lipid metabolism pathway, fatty acid biosynthetic process and ovarian steroidogenesis pathway were abnormally expressed in PCOS granulosa cells in comparison with that in control. There are close interactions among these three pathways as identified by analysis of the protein-protein interaction (PPI) network of DEGs. Furthermore, mouse follicle culture system was established to explore the effect of high androgen and its related metabolic dysfunction on follicular growth and ovulation. RT-qPCR results showed that follicles cultured with dehydroepiandrosterone (DHEA) exhibited decreased expression levels of cumulus expansion-related genes (, , and ) and oocyte maturation-related genes ( and ), which may be caused by impaired steroid hormone synthesis and lipid metabolism, thus inhibited follicular development and ovulation. Furthermore, the inhibition effect of DHEA on follicle development and ovulation was ameliorated by flutamide, an androgen receptor (AR) antagonist, suggesting the involvement of AR signaling. In summary, our study offers new insights into understanding the role of androgen excess induced granulosa cell metabolic disorder in ovarian dysfunction of PCOS patients.
Topics: Androgens; Animals; Dehydroepiandrosterone; Female; Granulosa Cells; Humans; Mice; Polycystic Ovary Syndrome; Steroids
PubMed: 35237237
DOI: 10.3389/fendo.2022.815968 -
Science (New York, N.Y.) Jun 2024Polycystic ovary syndrome (PCOS), a prevalent reproductive disorder in women of reproductive age, features androgen excess, ovulatory dysfunction, and polycystic...
Polycystic ovary syndrome (PCOS), a prevalent reproductive disorder in women of reproductive age, features androgen excess, ovulatory dysfunction, and polycystic ovaries. Despite its high prevalence, specific pharmacologic intervention for PCOS is challenging. In this study, we identified artemisinins as anti-PCOS agents. Our finding demonstrated the efficacy of artemisinin derivatives in alleviating PCOS symptoms in both rodent models and human patients, curbing hyperandrogenemia through suppression of ovarian androgen synthesis. Artemisinins promoted cytochrome P450 family 11 subfamily A member 1 (CYP11A1) protein degradation to block androgen overproduction. Mechanistically, artemisinins directly targeted lon peptidase 1 (LONP1), enhanced LONP1-CYP11A1 interaction, and facilitated LONP1-catalyzed CYP11A1 degradation. Overexpression of LONP1 replicated the androgen-lowering effect of artemisinins. Our data suggest that artemisinin application is a promising approach for treating PCOS and highlight the crucial role of the LONP1-CYP11A1 interaction in controlling hyperandrogenism and PCOS occurrence.
Topics: Animals; Female; Humans; Mice; Rats; Androgens; Artemisinins; Cholesterol Side-Chain Cleavage Enzyme; Disease Models, Animal; Hyperandrogenism; Mitochondrial Proteins; Ovary; Polycystic Ovary Syndrome; Proteolysis; Mice, Inbred C57BL; Young Adult; Adult; Rats, Sprague-Dawley; ATP-Dependent Proteases
PubMed: 38870290
DOI: 10.1126/science.adk5382 -
Clinical and Experimental Dermatology Dec 2020Spironolactone is a synthetic aldosterone receptor antagonist, with a role off-label in various dermatological conditions. Its antiandrogenic properties make it suitable... (Review)
Review
Spironolactone is a synthetic aldosterone receptor antagonist, with a role off-label in various dermatological conditions. Its antiandrogenic properties make it suitable for diseases in which excess androgen production results in unwanted and psychologically distressing manifestations in susceptible females. Treatment with spironolactone aims to attenuate androgen-mediated conditions including acne, hidradenitis suppurativa, female pattern hair loss and hirsutism. We discuss the emerging utility of spironolactone in dermatology, its potential adverse effects and considerations for monitoring.
Topics: Acne Vulgaris; Adult; Alopecia; Dermatology; Drug Monitoring; Female; Hidradenitis Suppurativa; Hirsutism; Humans; Hyperkalemia; Hypotension; Middle Aged; Mineralocorticoid Receptor Antagonists; Retrospective Studies; Spironolactone; Treatment Outcome
PubMed: 32844462
DOI: 10.1111/ced.14340 -
Frontiers in Endocrinology 2023Polycystic ovary syndrome (PCOS) is the most common endocrine disorder among women of reproductive age. Although promising strides have been made in the field of PCOS... (Review)
Review
Polycystic ovary syndrome (PCOS) is the most common endocrine disorder among women of reproductive age. Although promising strides have been made in the field of PCOS over the past decades, the distinct etiologies of this syndrome are not fully elucidated. Prenatal factors, genetic variation, epigenetic mechanisms, unhealthy lifestyles, and environmental toxins all contribute to the development of this intricate and highly heterogeneous metabolic, endocrine, reproductive, and psychological disorder. Moreover, interactions between androgen excess, insulin resistance, disruption to the hypothalamic-pituitary-ovary (HPO) axis, and obesity only make for a more complex picture. In this review, we investigate and summarize the related molecular mechanisms underlying PCOS pathogenesis from the perspective of the level of signaling pathways, including PI3K/Akt, TGF-β/Smads, Wnt/β-catenin, and Hippo/YAP. Additionally, this review provides an overview of prospective therapies, such as exosome therapy, gene therapy, and drugs based on traditional Chinese medicine (TCM) and natural compounds. By targeting these aberrant pathways, these interventions primarily alleviate inflammation, insulin resistance, androgen excess, and ovarian fibrosis, which are typical symptoms of PCOS. Overall, we hope that this paper will pave the way for better understanding and management of PCOS in the future.
Topics: Pregnancy; Female; Humans; Polycystic Ovary Syndrome; Insulin Resistance; Hyperandrogenism; Androgens; Phosphatidylinositol 3-Kinases; Signal Transduction
PubMed: 37929034
DOI: 10.3389/fendo.2023.1191759 -
Current Pharmaceutical Design 2016Hirsutism is defined as the presence of terminal hair with male distribution in women, and polycystic ovary syndrome (PCOS) is the most common etiology of hirsutism. (Review)
Review
BACKGROUND
Hirsutism is defined as the presence of terminal hair with male distribution in women, and polycystic ovary syndrome (PCOS) is the most common etiology of hirsutism.
METHODS
The aim of this study is to review aspects of hair growth that are relevant for the understanding of hirsutism in PCOS, along with current treatment alternatives.
RESULTS
The prevalence of hirsutism in PCOS ranges from 70 to 80%, vs. 4% to 11% in women in the general population. Hirsutism in PCOS is associated with both ovarianderived androgen excess and individual sensitivity of the pilosebaceous unit to androgens. Interventions to decrease hirsutism in PCOS include the suppression of androgen excess by combined oral contraceptives (OCPs). If OCPs are contraindicated, mainly in the presence of insulin-resistance related comorbidities, a second-line option for reducing androgen secretion may be metformin associated with lifestyle changes. Other interventions should be guided by hirsutism severity, determined by the modified Ferriman-Gallwey score, and by the amount of distress hirsutism causes to the patient, and should be maintained for at least 6-12 months. Mild hirsutism is usually treated with a combination of non-pharmacological methods and OCPs, whereas moderate and severe hirsutism may require a combination of antiandrogens and OCPs, or, if OCPs cannot be used, antiandrogens plus a safe contraceptive method. In all cases, strong clinical support is crucial to ensure treatment adherence and success.
CONCLUSION
The understanding of the pathophysiology of hirsutism in PCOS, as well as classifying its severity and the distress it causes to each patient is essential to choose the proper treatment. The presence of metabolic comorbidities and menstrual disturbances will also guide the individualized management of hirsutism in women with PCOS.
Topics: Androgen Antagonists; Animals; Contraceptive Agents; Female; Hirsutism; Humans; Polycystic Ovary Syndrome
PubMed: 27510481
DOI: 10.2174/1381612822666160720151243 -
European Journal of Endocrinology Nov 2021Patients with 21-hydroxylase deficiency congenital adrenal hyperplasia (21OHD-CAH) have poor health outcomes with increased mortality, short stature, impaired fertility,... (Review)
Review
BACKGROUND
Patients with 21-hydroxylase deficiency congenital adrenal hyperplasia (21OHD-CAH) have poor health outcomes with increased mortality, short stature, impaired fertility, and increased cardiovascular risk factors such as obesity. To address this, there are therapies in development that target the clinical goal of treatment, which is to control excess androgens with an adrenal replacement dose of glucocorticoid.
METHODS
Narrative review of publications on recent clinical developments in the pharmacotherapy of congenital adrenal hyperplasia.
SUMMARY
Therapies in clinical development target different levels of the hypothalamo-pituitary-adrenal axis. Two corticotrophin-releasing factor type 1 (CRF1) receptor antagonists, Crinecerfont and Tildacerfont, have been trialled in poorly controlled 21OHD-CAH patients, and both reduced ACTH and androgen biomarkers while patients were on stable glucocorticoid replacement. Improvements in glucocorticoid replacement include replacing the circadian rhythm of cortisol that has been trialled with continuous s.c. infusion of hydrocortisone and Chronocort, a delayed-release hydrocortisone formulation. Chronocort optimally controlled 21OHD-CAH in 80% of patients on an adrenal replacement dose of hydrocortisone, which was associated with patient-reported benefits including restoration of menses and pregnancies. Adrenal-targeted therapies include the steroidogenesis-blocking drug Abiraterone acetate, which reduced adrenal androgen biomarkers in poorly controlled patients.
CONCLUSIONS
CRF1 receptor antagonists hold promise to avoid excess glucocorticoid replacement in patients not controlled on standard or circadian glucocorticoid replacement such as Chronocort. Gene and cell therapies are the only therapeutic approaches that could potentially correct both cortisol deficiency and androgen excess.
Topics: Adrenal Hyperplasia, Congenital; Androgens; Circadian Rhythm; Endocrinology; Glucocorticoids; Hormone Replacement Therapy; Humans; Hydrocortisone; Hypothalamo-Hypophyseal System
PubMed: 34735372
DOI: 10.1530/EJE-21-0794 -
Endocrinology and Metabolism Clinics of... Mar 2021Congenital adrenal hyperplasia encompasses a group of autosomal recessive defects in cortisol biosynthesis, and 21-hydroxylase deficiency accounts for 95% of such cases.... (Review)
Review
Congenital adrenal hyperplasia encompasses a group of autosomal recessive defects in cortisol biosynthesis, and 21-hydroxylase deficiency accounts for 95% of such cases. Non-classic 21-hydroxylase deficiency is due to partial enzymatic defects, which present with normal cortisol synthesis, but excessive production of adrenal androgens, including 11-oxygenated androgens. Non-classic 21-hydroxylase deficiency is relatively common, and its phenotype resembles closely that of polycystic ovary syndrome. This review focuses primarily on non-classic 21-hydroxylase deficiency, its clinical features, diagnosis, and management.
Topics: Adrenal Hyperplasia, Congenital; Androgens; Endocrinologists; Female; Humans; Polycystic Ovary Syndrome
PubMed: 33518183
DOI: 10.1016/j.ecl.2020.10.008 -
Nature Reviews. Endocrinology Jun 2022Treatment for congenital adrenal hyperplasia (CAH) was introduced in the 1950s following the discovery of the structure and function of adrenocortical hormones. Although... (Review)
Review
Treatment for congenital adrenal hyperplasia (CAH) was introduced in the 1950s following the discovery of the structure and function of adrenocortical hormones. Although major advances in molecular biology have delineated steroidogenic mechanisms and the genetics of CAH, management and treatment of this condition continue to present challenges. Management is complicated by a combination of comorbidities that arise from disease-related hormonal derangements and treatment-related adverse effects. The clinical outcomes of CAH can include life-threatening adrenal crises, altered growth and early puberty, and adverse effects on metabolic, cardiovascular, bone and reproductive health. Standard-of-care glucocorticoid formulations fall short of replicating the circadian rhythm of cortisol and controlling efficient adrenocorticotrophic hormone-driven adrenal androgen production. Adrenal-derived 11-oxygenated androgens have emerged as potential new biomarkers for CAH, as traditional biomarkers are subject to variability and are not adrenal-specific, contributing to management challenges. Multiple alternative treatment approaches are being developed with the aim of tailoring therapy for improved patient outcomes. This Review focuses on challenges and advances in the management and treatment of CAH due to 21-hydroxylase deficiency, the most common type of CAH. Furthermore, we examine new therapeutic developments, including treatments designed to replace cortisol in a physiological manner and adjunct agents intended to control excess androgens and thereby enable reductions in glucocorticoid doses.
Topics: Adrenal Hyperplasia, Congenital; Androgens; Biomarkers; Glucocorticoids; Humans; Hydrocortisone
PubMed: 35411073
DOI: 10.1038/s41574-022-00655-w