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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 -
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 -
Experimental and Clinical Endocrinology... Jan 2024Hyperandrogenism is among the most common endocrine disorders in women. Clinically, it manifests as hirsutism, acne, and alopecia. A healthy lifestyle, including...
BACKGROUND
Hyperandrogenism is among the most common endocrine disorders in women. Clinically, it manifests as hirsutism, acne, and alopecia. A healthy lifestyle, including nutritious dietary patterns and physical activity, may influence the clinical manifestation of the disease. This study determined the effect of a low-glycemic index anti-inflammatory diet on testosterone levels and sex hormone-binding globulin (SHBG) and clinical symptoms in hyperandrogenic women at their reproductive age.
METHODS
The study included 44 overweight and obese women diagnosed with hyperandrogenism. The anthropometrics (weight, height, body mass index, waist circumference, hip circumference), physical activity, and dietary habits were assessed using valid questionnaires, scales, stadiometer, and tape meter. The significant p-value was <0.001. Serum testosterone and SHBG levels were measured using automated immunoassay instruments.
RESULTS
The intervention based on a low-glycemic index diet with anti-inflammatory elements and slight energy deficit decreased total testosterone levels (p<0.003), increased SHBG levels (p<0.001), and decreased the free androgen index (FAI; p<0.001). Post-intervention, overall well-being was much higher than in the pre-intervention period (p<0.001), and stress was diminished (p<0.001). Western nutritional patterns positively correlate with clinical hyperandrogenism progression, whereas several factors of the low-glycemic index diet with anti-inflammatory elements and slight energy deficit positively associate with reduced clinical hyperandrogenism symptoms.
CONCLUSIONS
In overweight and obese women, proper selection of diet, introduction of moderate physical activity, and reduction in weight, stress factors, and alcohol consumption translate into several positive effects, including reduced FAI and symptoms such as acne, hirsutism, menstrual disorders, and infertility.
Topics: Female; Humans; Hyperandrogenism; Hirsutism; Androgens; Polycystic Ovary Syndrome; Testosterone; Overweight; Obesity; Acne Vulgaris; Diet; Hypoglycemia; Anti-Inflammatory Agents; Sex Hormone-Binding Globulin; Body Mass Index
PubMed: 38237611
DOI: 10.1055/a-2201-8618 -
Epigenetics Dec 2023Research suggests that polycystic ovary syndrome (PCOS) traits (e.g., hyperandrogenism) may create a suboptimal intrauterine environment and induce epigenetic...
Research suggests that polycystic ovary syndrome (PCOS) traits (e.g., hyperandrogenism) may create a suboptimal intrauterine environment and induce epigenetic modifications. Therefore, we assessed the associations of PCOS traits with neonatal DNA methylation (DNAm) using two independent cohorts. DNAm was measured in both cohorts using the Infinium MethylationEPIC array. Multivariable robust linear regression was used to determine associations of maternal PCOS exposure or preconception testosterone with methylation β-values at each CpG probe and corrected for multiple testing by false-discovery rate (FDR). In the birth cohort, 12% (102/849) had a PCOS diagnosis (8.1% PCOS without hirsutism; 3.9% PCOS with hirsutism). Infants exposed to maternal PCOS with hirsutism compared to no PCOS had differential DNAm at cg02372539 [β(SE): -0.080 (0.010); FDR = 0.009], cg08471713 [β(SE):0.077 (0.014); FDR = 0.016] and cg17897916 [β(SE):0.050 (0.009); FDR = 0.009] with adjustment for maternal characteristics including pre-pregnancy BMI. PCOS with hirsutism was also associated with 8 differentially methylated regions (DMRs). PCOS without hirsutism was not associated with individual CpGs. In an independent preconception cohort, total testosterone concentrations were associated with 3 DMRs but not with individual CpGs, though the top quartile of testosterone compared to the lowest was marginally associated with increased DNAm at cg21472377 near an uncharacterized locus (FDR = 0.09). Examination of these probes and DMRs indicate they may be under foetal genetic control. Overall, we found several associations among newborns exposed to PCOS, specifically when hirsutism was reported, and among newborns of women with relatively higher testosterone around conception.
Topics: Pregnancy; Infant; Humans; Infant, Newborn; Female; Polycystic Ovary Syndrome; Hirsutism; DNA Methylation; Hyperandrogenism; Testosterone
PubMed: 37992405
DOI: 10.1080/15592294.2023.2282319 -
Clinical Endocrinology Jul 2023As part of the update of the International Evidence-Based Guidelines for the Assessment and Management of polycystic ovary syndrome (PCOS), a systematic review was...
OBJECTIVE
As part of the update of the International Evidence-Based Guidelines for the Assessment and Management of polycystic ovary syndrome (PCOS), a systematic review was performed to inform evidence-based recommendations.
DESIGN
Systematic review. Only randomised controlled trial were included.
PATIENTS
Women with PCOS; the use of combined oral contraceptive pills (COCP) was compared with no medical treatment.
MEASUREMENTS
Outcomes were designed in collaboration with clinical experts, researchers, and consumers. Critical outcomes included hirsutism, irregular cycles, quality of life, body mass index (BMI), and weight.
RESULTS
1660 publications were identified, but only four studies were included. No studies could be combined for meta-analysis. COCP treatment improved cycle regularity compared with no medical treatment (100% vs. 0%, with low certainty of evidence). COCP showed no difference in improvement of hirsutism or BMI compared with placebo or lifestyle; a lower weight after COCP compared with no treatment (mean difference [MD] -8.0 (95% confidence interval, CI -11.67); -4.33 kg); and improvement in quality of life (MD 1.2 [95% CI 0.96]; 1.44), but these results were all very low certainty of evidence.
CONCLUSION
Results show that COCP benefit cycle regulation, but other benefits or potential adverse effects were only identified with very low certainty of evidence. The COCP is frontline medical treatment in PCOS, but this is still based on established efficacy in the broader general population. Our results show that research in PCOS is seriously lacking and should be prioritised to capture core reproductive, metabolic and psychological outcomes important in PCOS.
Topics: Female; Humans; Contraceptives, Oral, Combined; Hirsutism; Polycystic Ovary Syndrome; Quality of Life
PubMed: 36939017
DOI: 10.1111/cen.14913 -
Medicine Sep 2023This study goaled to evaluate the ABO/Rh blood group distribution and its relationship with clinical and biochemical factors in polycystic ovary syndrome (PCOS)...
This study goaled to evaluate the ABO/Rh blood group distribution and its relationship with clinical and biochemical factors in polycystic ovary syndrome (PCOS) patients. ABO/Rh blood group distribution of the patients and the healthy individuals were compared. In addition, the features of clinical and biochemical factors were compared according to the ABO/Rh blood groups. Two hundred and sixty-five patients were involved in the study. At the time of diagnosis, hirsutism (86%) and oligomenorrhea (80.9%) were the most prevalent symptoms. There were 166 (62.6%) patients with baseline ultrasonography results consistent with PCOS. In 111 (41.9%) patients, insulin resistance was found. ABO blood group distributions in the patient (42.6% A, 17% B, 9.4% AB, 30.9% O) and control (42% A, 16% B, 8% AB, 34% O) groups were found to be similar (P = .9). There was no difference between oligomenorrhea, hirsutism, hair loss, acne, obesity, high androgen level, insulin resistance, and ultrasound characteristics according to ABO/Rh blood groups. In this study, ABO/Rh blood group distribution in individuals with PCOS was found to be similar to healthy individuals, and it was determined that ABO/Rh blood group was not a risk factor for PCOS. In addition, no correlation was found between the clinical and biochemical characteristics of the patients at the time of diagnosis and the ABO/Rh blood group.
Topics: Female; Humans; Polycystic Ovary Syndrome; Hirsutism; ABO Blood-Group System; Insulin Resistance; Oligomenorrhea; Risk Factors; Rh-Hr Blood-Group System
PubMed: 37682192
DOI: 10.1097/MD.0000000000034944 -
Medicine Dec 2023Disorders/differences of sex development (DSD) include a diverse group of congenital conditions in which the development of chromosomal, gonadal, or anatomical sex is... (Review)
Review
RATIONALE
Disorders/differences of sex development (DSD) include a diverse group of congenital conditions in which the development of chromosomal, gonadal, or anatomical sex is discordant. It involves several variant genes, and one of them is NR5A1. NR5A1 encodes a signal transduction regulator in the hypothalamic-pituitary-gonadal and hypothalamic-pituitary-adrenal pathway, and pathogenic mutation in this gene is a cause of 46,XY DSD.
PATIENT CONCERNS
A 12-year-old individual raised as a girl was admitted to the hospital due to hirsutism and a deep voice that began at 11 years old. The individual exhibited testicular hypoplasia, clitoral hypertrophy, and female external genitalia.
DIAGNOSES
The patient was diagnosed 46,XY partial gonadal dysgenesis. The cytogenetics revealed a 46,XY karyotype and DNA sequencing shown a variant in NR5A1. Pelvic magnetic resonance imaging showed absence of uterus and ovaries. The abdominopelvic ultrasound revealed bilateral testicle in bilateral groin. Pathology confirmed testes dysgenesis.
INTERVENTIONS
The patient underwent bilateral orchiectomy at age 12 years and was given a feminizing hormonal treatment of 0.5 mg/day of estradiol valerate tablets.
OUTCOMES
The patient recovered well after surgery and hormonal treatment and had a regression in hirsutism and clitoromegaly.
LESSONS
46,XY DSD is a rare disease that the development of chromosomal, gonadal, or anatomical sex is discordant, when diagnosed 46,XY DSD, the identification of an NR5A1 variant should be considered.
Topics: Male; Humans; Female; Child; Testis; Disorder of Sex Development, 46,XY; Hirsutism; Mutation; Gonadal Dysgenesis; Steroidogenic Factor 1; Gonadal Dysgenesis, 46,XY
PubMed: 38206718
DOI: 10.1097/MD.0000000000036725 -
European Review For Medical and... Sep 2023There is insufficient data on which cut-off value must be used to measure the increase in total testosterone (TT) compared to the upper limit of normal (CULN) in the...
OBJECTIVE
There is insufficient data on which cut-off value must be used to measure the increase in total testosterone (TT) compared to the upper limit of normal (CULN) in the diagnosis of androgen-secreting tumor (ASTM) in female individuals with premenopausal hirsutism (FIPH).
PATIENTS AND METHODS
A total of 413 FIPH over 18 years of age who were admitted to the endocrinology clinic between May 2013 and 30 April 2018 were eligible for the study. Hormone profiles of the participants in the follicular phase and other information were obtained from their files. The androgen suppression ratio (ASR) was analyzed after 48 hours of low-dose dexamethasone suppression test (LDDST) in those whose TT CULN (nmol/L) increased two-fold.
RESULTS
Idiopathic hirsutism was found in 193 participants (46.73%) and polycystic ovary syndrome (PCOS) in 200 (48.43%) and other sources of hirsutism; non-classical congenital adrenal hyperplasia (NCCAH) in 10 patients (2.42%), hyperprolactinemia in 6 patients (1.45%), ASTM of ovarian origin in 2 patients (0.48%), Cushing's disease in 1 patient (0.24%), and adrenal ASTM in 1 patient (0.24%). A cut-off value of two-fold CULN increase for TT sensitivity of 100% and a specificity of 99.5% in indicating an ASTM source, and ASR above 49% in LDDST sensitivity of 80% and a specificity of 100% in excluding an ASTM source, was used.
CONCLUSIONS
At the TT level, a two-fold increase CULN in FIPH indicates an ASTM source. In addition, ASR after LDDST is a useful parameter in the exclusion of ASTM sources in the same patient population.
Topics: Humans; Female; Adolescent; Adult; Testosterone; Androgens; Hirsutism; Testosterone Congeners; Neoplasms
PubMed: 37782181
DOI: 10.26355/eurrev_202309_33791 -
Pediatric Surgery International Mar 2024To present our surgical experience and outcomes in congenital adrenal hyperplasia (CAH) patients with severe virilization using a combined technique of total urogenital...
PURPOSE
To present our surgical experience and outcomes in congenital adrenal hyperplasia (CAH) patients with severe virilization using a combined technique of total urogenital mobilization (TUM) and a modified pull-through vaginoplasty to perform a safe and effective one-stage feminizing genital reconstruction for these children.
METHODS
Fourteen CAH patients with severe virilization, defined by a Prader IV and V rating of the external genitalia, underwent TUM followed by a limited vaginal pull-through procedure from June 2016 to December 2020. Postoperative anatomical and cosmetic outcomes, and urinary continence, were evaluated.
RESULTS
Out of the 14 cases in this study, 8 were classified as prader IV and 6 as Prader V. The median age at surgery was 11 months (range 6-36 months), and the mean urethral length was 1.4 cm (range 1.2-1.8 cm). The median follow-up period was 4 years. Our cosmetic outcomes were good in 11 (78.5%), satisfactory in 2, and poor in one case. All patients achieved age-appropriate toilet training without urinary incontinence.
CONCLUSION
Adopting our surgical approach of TUM with modified pull-through vaginoplasty has simplified feminizing surgical reconstruction in CAH cases with severe genital atypia and a very high vaginal confluence with short urethral length, yielding adequate introitus with good anatomical and cosmetic appearance and adequate urinary continence outcomes.
Topics: Child; Female; Humans; Infant; Child, Preschool; Adrenal Hyperplasia, Congenital; Virilism; Postoperative Period; Urethra; Vagina
PubMed: 38446278
DOI: 10.1007/s00383-024-05638-8