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Indian Journal of Pediatrics Oct 2023Hyperandrogenism is a common condition encountered by pediatric and adolescent physicians. Most girls with hyperandrogenism represent physiological pubertal variation;... (Review)
Review
Hyperandrogenism is a common condition encountered by pediatric and adolescent physicians. Most girls with hyperandrogenism represent physiological pubertal variation; pathology may be present in a substantial minority. Systematic evaluation is essential to avoid unnecessary work-up in physiological causes while not missing pathological causes. Polycystic ovarian syndrome (PCOS), unexplained, persistent hyperandrogenism of ovarian origin, is the most common form in adolescent girls. The high prevalence of physiological peripubertal hirsutism, anovulation, and polycystic ovarian morphology results in mislabeling many girls as having the polycystic ovarian syndrome, a disorder with lifelong implications. The use of strict criteria of age-specific anovulation, hyperandrogenism, and duration is essential to reduce their stigmatization. The exclusion of secondary causes by screening tests (cortisol, thyroid profile, prolactin, and 17OHP) is essential before undertaking treatment for PCOS. Lifestyle measures, estrogen-progesterone preparations, antiandrogens, and metformin are the cornerstone of managing the disorder.
Topics: Female; Adolescent; Humans; Child; Hyperandrogenism; Polycystic Ovary Syndrome; Anovulation; Hirsutism
PubMed: 37402107
DOI: 10.1007/s12098-023-04678-7 -
Expert Review of Endocrinology &... Mar 2024Hirsutism is a prevalent condition among women and represents a primary clinical feature of polycystic ovary syndrome (PCOS). (Review)
Review
INTRODUCTION
Hirsutism is a prevalent condition among women and represents a primary clinical feature of polycystic ovary syndrome (PCOS).
AREAS COVERED
Our study aims to address the principal challenges associated with this hyperandrogenic manifestation in PCOS women. Our narrative review based on the available indexed literature explored the complexities of establishing mFG cutoff values for various ethnic groups, investigated hirsutism during peri- and postmenopausal stages, and examined the role of oxyandrogens.
EXPERT OPINION
Hirsutism may have a negative impact on the quality of life and on the mental health, being associated with anxiety and depression. Future perspectives for its diagnosis include the use of artificial intelligence and the consideration of the distress caused by excessive hair growth.
Topics: Female; Humans; Hirsutism; Polycystic Ovary Syndrome; Quality of Life; Artificial Intelligence
PubMed: 38305206
DOI: 10.1080/17446651.2024.2310558 -
Clinical Chemistry Dec 2023Androgens are synthesized from cholesterol through sequential conversions by enzymes in the adrenal glands and gonads. Serum levels of androgens change during the... (Review)
Review
BACKGROUND
Androgens are synthesized from cholesterol through sequential conversions by enzymes in the adrenal glands and gonads. Serum levels of androgens change during the different phases of life and regulate important developmental and maturational processes. Androgen excess or deficiency can therefore present at various ages in various ways.
CONTENT
The diagnostic approach for atypical genitalia, premature pubarche, delayed pubertal onset or progression, and hirsutism or virilization, including measurement of androgens (testosterone, androstenedione, 17-OHprogesterone, dehydroepiandrosterone, and dihydrotestosterone) is discussed in the current review. Androgens can be measured in serum, saliva, urine, or dried blood spots. Techniques to measure androgens, including immunoassays and LC-MS, have their own advantages and pitfalls. In addition, pre- and postanalytical issues are important when measuring androgens.
SUMMARY
During clinical interpretation of androgen measurements, it is important to take preanalytical circumstances, such as time of blood withdrawal, into account. As immunoassays have major drawbacks, especially in samples from women and neonates, concentrations measured using these assays should be interpreted with care. Reference intervals can only be used in relation to the measurement technique and the standardization of the assay. In the near future, new androgens will probably be added to the current repertoire to further improve the diagnosis and follow-up of androgen excess or deficiency.
Topics: Infant, Newborn; Female; Humans; Androgens; Testosterone; Androstenedione; Virilism; Hirsutism; Dehydroepiandrosterone
PubMed: 37794651
DOI: 10.1093/clinchem/hvad146 -
International Journal of Molecular... Jul 2023Endometrial receptivity is a state of the endometrium defined by its readiness for embryo implantation. When the receptivity of the endometrium is impaired due to... (Review)
Review
Endometrial receptivity is a state of the endometrium defined by its readiness for embryo implantation. When the receptivity of the endometrium is impaired due to hyperandrogenism or androgen excess, this condition can lead to pregnancy loss or infertility. Hyperandrogenism encompasses a wide range of clinical manifestations, including polycystic ovary syndrome (PCOS), idiopathic hirsutism, hirsutism and hyperandrogaenemia, non-classical congenital adrenal hyperplasia, hyperandrogenism, insulin resistance, acanthosis nigricans (HAIR-AN), ovarian or adrenal androgen-secreting neoplasms, Cushing's syndrome, and hyperprolactinaemia. Recurrent miscarriages have been shown to be closely related to elevated testosterone levels, which alter the endometrial milieu so that it is less favourable for embryo implantation. There are mechanisms for endometrial receptivity that are affected by excess androgen. The HOXA gene, aVβ3 integrin, CDK signalling pathway, MECA-79, and MAGEA-11 were the genes and proteins affect endometrial receptivity in the presence of a hyperandrogenic state. In this review, we would like to explore the other manifestations of androgen excess focusing on causes other than PCOS and learn possible mechanisms of endometrial receptivity behind androgen excess leading to pregnancy loss or infertility.
Topics: Female; Pregnancy; Humans; Hyperandrogenism; Polycystic Ovary Syndrome; Hirsutism; Androgens; Endometrium; Infertility
PubMed: 37569402
DOI: 10.3390/ijms241512026 -
Frontiers in Endocrinology 2023Due to its high heterogenicity and unclear etiology, there is currently no specific treatment for polycystic ovary syndrome (PCOS). Metformin, as an insulin sensitizer,... (Meta-Analysis)
Meta-Analysis
AIMS
Due to its high heterogenicity and unclear etiology, there is currently no specific treatment for polycystic ovary syndrome (PCOS). Metformin, as an insulin sensitizer, combined with spironolactone, an antiandrogen medication, may exert complementary effects on PCOS. We therefore performed a meta-analysis of trials in which metformin combined with spironolactone was applied to treat PCOS to evaluate the efficacy and safety of the combination therapy.
METHODS
We retrieved the PubMed, Embase, Scopus, Cochrane Library, CNKI, CBM, Wangfang, and VIP databases for literatures published from their inception to December 16, 2022 on the effects of metformin combined with spironolactone in the treatment of PCOS. Inclusion criteria according to P.I.C.O.S criteria were: PCOS patients, metformin combined with spironolactone interventions, metformin alone control group, and randomized controlled trials with the following outcome data: body mass index (BMI), hirsutism score, luteinizing hormone (LH), follicle-stimulating hormone (FSH), total testosterone (TT), fasting blood glucose (FBG), Homeostatic Model Assessment for Insulin Resistance (HOMA-IR), and side effects including nausea, vomiting, diarrhea and drug withdrawal.
RESULTS
Our results revealed that metformin combined with spironolactone significantly reduced BMI and TT, but that it exerted no significant effects on hirsutism score, or on FSH or LH concentrations. Combined treatment also resulted in a significant diminution in FBG and insulin resistance using the HOMA-IR when the interventional time was greater than 6 months. In addition, the combination did not have a higher occurrence of adverse reactions than metformin alone.
CONCLUSION
Compared with metformin alone, metformin combined with spironolactone therapy may be more effective in reducing BMI and serum androgen levels, but the combination showed no significant effect on the hirsutism score or gonadotropin hormone levels, and was not associated with an elevation in side-effects. Moreover, when the treatment course was greater than 6 months, combination therapy reduced FBG and improved insulin resistance more effectively than metformin alone. However, more research is needed to determine the most effective course of treatment.
SYSTEMATIC REVIEW REGISTRATION
https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42022355515.
Topics: Female; Humans; Hirsutism; Insulin Resistance; Polycystic Ovary Syndrome; Spironolactone; Drug-Related Side Effects and Adverse Reactions; Follicle Stimulating Hormone, Human; Luteinizing Hormone
PubMed: 37635987
DOI: 10.3389/fendo.2023.1223768 -
Journal of Obstetrics and Gynaecology... Dec 2023This guideline reviews the etiology, diagnosis, evaluation, and treatment of hirsutism.
OBJECTIVE
This guideline reviews the etiology, diagnosis, evaluation, and treatment of hirsutism.
TARGET POPULATION
Women with hirsutism.
OPTIONS
Three approaches to management include: 1) mechanical hair removal; 2) suppression of androgen production; and 3) androgen receptor blockade.
OUTCOMES
The main limitations of the management options include the adverse effects, costs, and duration of treatment.
BENEFITS, HARMS, AND COSTS
Implementation of the recommendations in this guideline may improve the management of hirsutism in women with this condition. Adverse effects and a potential long duration of treatment are the main drawbacks to initiating treatment, as is the possibility of significant financial costs for certain treatments.
EVIDENCE
A comprehensive literature review was updated to April 2022, following the same methods as for the prior Society of Obstetricians and Gynaecologists of Canada (SOGC) Hirsutism guidelines. Results were restricted to systematic reviews, randomized controlled trials, controlled clinical trials, and observational studies. There were no date limits, but results were limited to English- or French-language materials.
VALIDATION METHODS
The authors rated the quality of evidence and strength of recommendations using the modified Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach, along with the option of designating a recommendation as a "good practice point." See online Appendix A (Tables A1 for definitions and A2 for interpretations of strong and conditional [weak] recommendations).
INTENDED AUDIENCE
Primary care providers, family medicine physicians, obstetricians and gynaecologists, reproductive endocrinologists and others who manage the care of patients with hirsutism.
TWEETABLE ABSTRACT
Management of hirsutism involves a 3-pronged approach of mechanical hair removal, suppression of androgen production, and androgen receptor blockade.
SUMMARY STATEMENTS
RECOMMENDATIONS.
Topics: Female; Humans; Androgens; Canada; Hirsutism; Receptors, Androgen
PubMed: 38049282
DOI: 10.1016/j.jogc.2023.102272 -
European Journal of Endocrinology Jul 2023To compare between different combined oral contraceptive pills (COCPs) as part of the update of the International Evidence-Based Guidelines on the Assessment and... (Meta-Analysis)
Meta-Analysis
OBJECTIVE
To compare between different combined oral contraceptive pills (COCPs) as part of the update of the International Evidence-Based Guidelines on the Assessment and Management of polycystic ovary syndrome (PCOS).
DESIGN
A systematic review and meta-analysis was performed, Prospero CRD42022345640.
METHODS
MEDLINE, EMBASE, All EBM, CINAHL, and PsycINFO was searched on July, 8, 2022, for studies including women with PCOS, comparing 2 different COCPs in randomized controlled trials.
RESULTS
A total of 1660 studies were identified, and 19 randomized controlled trials (RCTs) were included.Fourth-generation COCP resulted in lower body mass index (BMI) (mean difference [MD] 1.17 kg/m2 [95% confidence interval {CI} 0.33; 2.02]) and testosterone (MD 0.60 nmol/L [95% CI 0.13; 1.07]) compared with third-generation agents, but no difference was seen in hirsutism.Ethinyl estradiol (EE)/cyproterone acetate (CPA) was better in reducing hirsutism as well as biochemical hyperandrogenism (testosterone [MD 0.38 nmol/L {95% CI 0.33-0.43}]) and BMI (MD 0.62 kg/m2 [95% CI 0.05-1.20]) compared with conventional COCPs.There was no difference in hirsutism between high and low EE doses. No evidence regarding natural estrogens in COCP was identified.
CONCLUSION
With current evidence, combined regimens containing an antiandrogen (EE/CPA) may be better compared with conventional COCPs in reducing hyperandrogenism, but EE/CPA will not be recommended as a first-line COCP treatment by the pending PCOS guideline update, due to higher venous thrombotic events (VTE) risk in the general population. Later-generation progestins offer theoretical benefits, but better evidence on clinical outcomes is needed in women with PCOS.
TRIAL REGISTRATION
The protocol for the systematic review was registered prospectively in Prospero, CRD42022345640.
Topics: Female; Humans; Polycystic Ovary Syndrome; Hirsutism; Hyperandrogenism; Contraceptives, Oral, Combined; Ethinyl Estradiol; Cyproterone Acetate; Testosterone
PubMed: 37440702
DOI: 10.1093/ejendo/lvad082 -
Reproductive Sciences (Thousand Oaks,... Nov 2023While polycystic ovarian syndrome (PCOS) is one of the most common hormonal endocrine disorders among women of reproductive age, the psychosocial impact of PCOS has not... (Review)
Review
While polycystic ovarian syndrome (PCOS) is one of the most common hormonal endocrine disorders among women of reproductive age, the psychosocial impact of PCOS has not been evaluated across different quality of life (QoL) indicators. We rigorously analyzed available evidence pertaining to the psychosocial burden of PCOS in women of reproductive age and compared validated QoL scores of women with and without PCOS before and after treatment. We searched and considered publications from PubMed, PsychINFO, Embase, and Cochrane Library that evaluated the association between diagnosed PCOS and QoL by standardized and validated questionnaires at baseline and after treatment. Reviewers assessed the risk of bias using established Cochrane and Newcastle-Ottawa Scale guidelines. A total of 33 studies were included in the review: 14 randomized controlled trials and 19 observational studies. The 36-Item Short Form Survey and World Health Organization Quality of Life - BREF questionnaire both revealed that the diagnosis and life experience of PCOS had a disability score that was similar to or surpassed that of heart disease, diabetes mellitus, or breast cancer. QoL scores, associated with mental health issues, infertility, sexual dysfunction, obesity, menstrual disorder, and hirsutism, were lower at the baseline than after treatment in the majority of instruments measuring these variables in women with PCOS. PCOS is associated with significant psychosocial stress and reduced QoL across baseline measures and in comparison, to other diseases. Evidence suggests that treatment with therapy, medications, and lifestyle management decreased psychosocial burdens and alleviated QoL experienced by women with PCOS.
Topics: Female; Humans; Polycystic Ovary Syndrome; Quality of Life; Hirsutism; Infertility; Life Style
PubMed: 37341924
DOI: 10.1007/s43032-023-01285-x -
The Cochrane Database of Systematic... Jul 2023Statins are lipid-lowering agents with pleiotropic actions. Experts have proposed that in addition to improving the dyslipidaemia associated with polycystic ovary... (Review)
Review
BACKGROUND
Statins are lipid-lowering agents with pleiotropic actions. Experts have proposed that in addition to improving the dyslipidaemia associated with polycystic ovary syndrome (PCOS), statins may also exert other beneficial metabolic and endocrine effects, such as reducing testosterone levels. This is an update of a Cochrane Review first published in 2011.
OBJECTIVES
To assess the efficacy and safety of statin therapy in women with PCOS who are not actively trying to conceive.
SEARCH METHODS
We searched the Cochrane Gynaecology and Fertility Group specialised register, CENTRAL, MEDLINE, Embase, PsycINFO, CINAHLs, and four ongoing trials registers on 7 November 2022. We also handsearched relevant conference proceedings and the reference lists of relevant trials for any additional studies, and we contacted experts in the field for any further ongoing studies.
SELECTION CRITERIA
We included randomised controlled trials (RCTs) that evaluated the effects of statin therapy in women with PCOS not actively trying to conceive. Eligible comparisons were statin versus placebo or no treatment, statin plus another agent versus the other agent alone, and statin versus another agent. We performed statistical analysis using Review Manager 5, and we assessed the certainty of the evidence using GRADE methods.
DATA COLLECTION AND ANALYSIS
We used standard Cochrane methodology. Our primary outcomes were resumption of menstrual regularity and resumption of spontaneous ovulation. Our secondary outcomes were clinical and physiological measures including hirsutism, acne severity, testosterone levels, and adverse events.
MAIN RESULTS
Six RCTs fulfilled the criteria for inclusion. They included 396 women with PCOS who received six weeks, three months, or six months of treatment; 374 women completed the studies. Three studies evaluated the effects of simvastatin and three studies evaluated the effects of atorvastatin. We summarised the results of the studies under the following comparisons. Statins versus placebo (3 RCTs) One trial measured resumption of menstrual regularity as menstrual cycle length in days. We are uncertain if statins compared with placebo shorten the mean length of the menstrual cycle (mean difference (MD) -2.00 days, 95% confidence interval (CI) -24.86 to 20.86; 37 participants; very low-certainty evidence). No studies reported resumption of spontaneous ovulation, improvement in hirsutism, or improvement in acne. We are uncertain if statins compared with placebo reduce testosterone levels after six weeks (MD 0.06, 95% CI -0.72 to 0.84; 1 RCT, 20 participants; very low-certainty evidence), after 3 months (MD -0.53, 95% CI -1.61 to 0.54; 2 RCTs, 64 participants; very low-certainty evidence), or after 6 months (MD 0.10, 95% CI -0.43 to 0.63; 1 RCT, 28 participants; very low-certainty evidence) Two studies recorded adverse events, and neither reported significant differences between the groups. Statins plus metformin versus metformin alone (1 RCT) The single RCT included in this comparison measured resumption of menstrual regularity as the number of spontaneous menses per six months. We are uncertain if statins plus metformin compared with metformin improves resumption of menstrual regularity (MD 0.60 menses, 95% CI 0.08 to 1.12; 69 participants; very low-certainty evidence). The study did not report resumption of spontaneous ovulation. We are uncertain if statins plus metformin compared with metformin alone improves hirsutism measured using the Ferriman-Gallwey score (MD -0.16, 95% CI -0.91 to 0.59; 69 participants; very low-certainty evidence), acne severity measured on a scale of 0 to 3 (MD -0.31, 95% CI -0.67 to 0.05; 69 participants; very low-certainty evidence), or testosterone levels (MD -0.03, 95% CI -0.37 to 0.31; 69 participants; very low-certainty evidence). The study reported that no significant adverse events occurred. Statins plus oral contraceptive pill versus oral contraceptive pill alone (1 RCT) The single RCT included in this comparison did not report resumption of menstrual regularity or spontaneous ovulation. We are uncertain if statins plus the oral contraceptive pill (OCP) improves hirsutism compared with OCP alone (MD -0.12, 95% CI -0.41 to 0.17; 48 participants; very low-certainty evidence). The study did not report improvement in acne severity. We are also uncertain if statins plus OCP compared with OCP alone reduces testosterone levels, because the certainty of the evidence was very low (MD -0.82, 95% CI -1.38 to -0.26; 48 participants). The study reported that no participants experienced significant side effects. Statins versus metformin (2 RCTs) We are uncertain if statins improve menstrual regularity compared with metformin (number of spontaneous menses per six months) compared to metformin (MD 0.50 menses, 95% CI -0.05 to 1.05; 1 RCT, 61 participants, very low-certainty evidence). No studies reported resumption of spontaneous ovulation. We are uncertain if statins compared with metformin reduce hirsutism measured using the Ferriman-Gallwey score (MD -0.26, 95% CI -0.97 to 0.45; 1 RCT, 61 participants; very low-certainty evidence), acne severity measured on a scale of 0 to 3 (MD -0.18, 95% CI -0.53 to 0.17; 1 RCT, 61 participants; very low-certainty evidence), or testosterone levels (MD -0.24, 95% CI -0.58 to 0.10; 1 RCT, 61 participants; very low-certainty evidence). Both trials reported that no significant adverse events had occurred. Statins versus oral contraceptive pill plus flutamide (1 RCT) According to the study report, no participants experienced any significant side effects. There were no available data for any other main outcomes.
AUTHORS' CONCLUSIONS
The evidence for all main outcomes of this review was of very low certainty. Due to the limited evidence, we are uncertain if statins compared with placebo, or statins plus metformin compared with metformin alone, improve resumption of menstrual regularity. The trial evaluating statin plus OCP versus OCP alone reported neither of our primary outcomes. No other studies reported resumption of spontaneous ovulation. We are uncertain if statins improve hirsutism, acne severity, or testosterone. All trials that measured adverse events reported no significant differences between the groups.
Topics: Female; Humans; Polycystic Ovary Syndrome; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hirsutism; Metformin; Acne Vulgaris; Contraceptives, Oral; Testosterone
PubMed: 37462232
DOI: 10.1002/14651858.CD008565.pub3 -
European Journal of Pharmaceutical... Nov 2023Oral contraceptives (OCs), insulin sensitizers, and antiandrogens (AAs), alone or in combination, are commonly used for treating non-fertility indications in polycystic... (Meta-Analysis)
Meta-Analysis
Oral contraceptives (OCs), insulin sensitizers, and antiandrogens (AAs), alone or in combination, are commonly used for treating non-fertility indications in polycystic ovary syndrome (PCOS). However, unclear risk-benefit profiles jeopardize their appropriate clinical applications. This study aimed to quantitatively evaluate the effects of the aforementioned medications and to compare their risk-benefit profiles. Randomized controlled trials published until 14th March 2022 were searched in PubMed and Embase. A model-based meta-analysis was developed to examine the time-effect profiles of each medication. The maximal percentage change of the effect (E) and time to achieve half of E (T) were estimated. Primary outcomes included menstruation, hirsutism score, free androgen index (FAI), body mass index (BMI), insulin sensitivity, and lipid profiles. Overall, 200 studies (9,685 patients and 385 arms) were identified for modeling. OCs performed exceptionally well in improving menstruation (E: 149%; T: 7.44 weeks), hirsutism score (E: 66.2%; T: 26.2 weeks), and FAI (E: 75.7%; T: 0.51 weeks). However, OCs elevated the triglyceride (TG) level (E: 12.6%; T:1.19 weeks). After 12-week OC treatment, the TG level of approximately 30% of patients, whose baselines were normal, exceeded the reference limit. This suggested that OC-induced dyslipidemia should be routinely monitored. The maximal BMI-lowering effect of metformin was similar to that of placebo (E: 3.80%); however, metformin had a shorter T (6.67 weeks versus 12.9 weeks). Further, active lifestyle intervention plus placebo significantly decreased BMI (E: 8.78%). Adding metformin to active lifestyle intervention accelerated the BMI-lowering effect within 24 weeks, whereas with the extension of this addition beyond 24 weeks, BMI did not reduce further, which indicated that benefits were limited from this prolonged addition. AAs were less potent in reducing hirsutism score (E: 40.2% versus 66.2%) and FAI (E: 34.5% versus 75.7%) compared to OCs. OC plus metformin combined OC-derived androgen-suppressing effects and metformin-derived insulin-sensitizing effects, and partially relieved the OC-induced TG increase (E: 9.76%). Baseline dependency was found in most clinical responses, implying that pharmacotherapies tailored based on baselines achieved more clinical improvements. This study presents new quantitative evidence on pharmacotherapies for PCOS. Currently, long-term risk-benefit profiles and emerging therapies are inadequately reported and require more further research.
Topics: Humans; Female; Polycystic Ovary Syndrome; Contraceptives, Oral; Androgen Antagonists; Insulin; Hirsutism; Androgens; Metformin; Hypoglycemic Agents
PubMed: 37666459
DOI: 10.1016/j.ejps.2023.106577