Acetate ameliorates ovarian mitochondrial dysfunction in letrozole-induced polycystic ovarian syndrome rat model by improving mitofusin-2.

Androgen excess and metabolic abnormality largely contribute to the pathogenesis of polycystic ovarian syndrome (PCOS), which primarily precipitates ovarian dysfunction and infertility in reproductive-age women. Impaired mitochondrial function and epigenetic alteration have been linked to the development of PCOS. However, it is unknown whether acetate would exert a therapeutic effect on ovarian mitochondrial dysfunction in PCOS. Herein, the study hypothesized that acetate reverses ovarian mitochondrial dysfunction in experimental PCOS rat model, possibly through modulation of mitofusin-2 (MFn2). Eight-week-old female Wistar rats were randomized into four groups (n = 5). Induction of PCOS was performed by 1 mg/kg letrozole (p.o.), administered for 21 days. Thereafter, the rats were treated with acetate (200 mg/kg; p.o.) for 6 weeks. The PCOS rats demonstrated androgen excess, multiple ovarian cysts, elevated anti-mullerian hormone and leptin and decreased SHBG, adiponectin and 17-ß estradiol with corresponding increase in ovarian transforming growth factor-ß1. Additionally, inflammation (tumor growth factor and nuclear factor-kB), elevated caspase-6, decreased hypoxia-inducible factor-1α and elevated histone deacetylase-2 (HDAC2) were observed in the ovaries of PCOS rats, while mitochondrial abnormality with evidence of decreased adenosine triphosphate synthase and MFn2 was observed in rats with PCOS. Treatment with acetate reversed the alterations. The present results collectively suggest that acetate ameliorates ovarian mitochondrial abnormality, a beneficial effect that is accompanied by MFn2 with consequent normalization of reproductive-endocrine profile and ovarian function. Perhaps, the present data provide hope for PCOS individuals that suffer infertility.

Extensive androgen exposure and meningioma risk - A matched cohort study.

INTRODUCTION: Meningiomas frequently occur within the field of neuro-oncology, but it is unclear whether exogenous or imbalanced endogenous hormones are involved in the pathophysiology. A previous case-control study found an almost 20-fold increase in the risk of developing meningioma among users of androgenic anabolic steroids. We, therefore, investigated this hypothesis. METHODS: We compared the incidence rate of meningioma in a cohort of males sanctioned for the use of androgenic anabolic steroids with age- and sex-matched controls with an identical enrollment date. RESULTS: We followed 1189 males sanctioned for using androgenic anabolic steroids for a total of 13,305 person-years and found 0 cases of meningioma. The control cohort of 59,450 males was followed for a total of 654,938 person-years, and 16 were diagnosed with meningioma. Thus, the incidence rate ratio was 0 (95% CI: 0-12.8). CONCLUSION: We did not find any evidence supporting the hypothesis of an increased risk of meningioma development with the use of androgenic anabolic steroids. Due to the limited sample size, we cannot exclude androgenic anabolic steroids as a potential risk factor for meningioma development, despite the lack of apparent evidence in this study.

Mortality Among Users of Anabolic Steroids.

This cohort study investigates mortality and cause of death among a large cohort of androgenic anabolic steroid users, compared with a control group, in Denmark from January 3, 2006, to March 1, 2018.

Liver abnormalities are frequent and persistent in patients with Fanconi anemia.

ABSTRACT: Liver disease has not been well described in patients with Fanconi anemia (FA). Improvements in outcomes of transplant mean that more individuals with FA are reaching adulthood and new features of the FA phenotype are being discovered. We performed a retrospective review of liver function in a cohort of 97 patients with FA followed-up for at least 10 years at a single center. We identified a high frequency of transaminitis (n = 31, 32%) without elevation of bilirubin and with no evidence of structural hepatic abnormality in patients with FA. Transaminitis was persistent in many cases, sometimes lasting more than a decade without clinical manifestation, although 2 patients with prolonged transaminitis are deceased from liver failure, indicating important long-term clinical consequences. Transaminitis was found in patients who had and had not received transplant but was more frequent in recipients of transplant. Exposure to total body irradiation increased risk (odds ratio, 15.5 [95% confidence interval, 2.44-304.54]; P = .01), whereas treatment with androgens did not. Review of limited numbers of liver biopsies and autopsy material showed a cholestatic pattern of liver injury, with progressive fibrosis, in the majority of patients. Occurrence in cases without transplant as well as cases with transplant argues against a potential diagnosis of atypical liver graft-versus-host disease. Limited data regarding therapy suggest no benefit from treatment with steroids or other immune suppressive medications or ursodeoxycholic acid. Our data show that liver disease is common in patients with FA, and because most children with FA now reach adulthood, end-stage liver disease in young adulthood means systematic testing of potential therapies is urgently needed.

Impact of anabolic androgenic steroids on COVID-19.

In the wake of the Novel Coronavirus arrival, the world witnessed the fragility of healthcare systems and the resilience of healthcare workers who stood on the front lines. SARS-CoV-2, also known as COVID-19 or severe acute respiratory syndrome, first appeared in China in December 2019. The infection quickly spread across the nation and the world. All countries severely restricted social interaction to stop the virus's transmission, impacting all sporting, social, and recreational activities. Anabolic androgenic steroids (AASs) are frequently used illegally to enhance strength and physical attractiveness. However, they could hurt immune system health. Much research hasn't been done yet on the connection between Covid-19 and AASs. Synthetic testosterone analogs known as anabolic androgenic steroids (AASs) can have an immune-system-altering effect. Sportspeople and bodybuilders are vulnerable to AAS abuse. Governmental reactions to the coronavirus infection issue over the last year have drawn much attention and discussion regarding public services, the experience and lessons learned from different limitations, and strategies for dealing with potential future pandemics. Using AAS has the potential to cause a variety of adverse reactions, including cardiovascular issues (including high blood pressure, heart disease, and blood clots), liver damage, renal failure, mood swings, aggressiveness, and psychiatric disorders. Individuals already suffering from severe respiratory conditions like COVID-19 may have these risks increased. This review mainly highlights the anabolic androgen steroids use and its unseen effects on coronavirus patients and gymnastics.

Elevated circulating adiponectin levels do not prevent anxiety-like behavior in a PCOS-like mouse model.

Polycystic ovary syndrome (PCOS) is associated with symptoms of moderate to severe anxiety and depression. Hyperandrogenism is a key feature together with lower levels of the adipocyte hormone adiponectin. Androgen exposure leads to anxiety-like behavior in female offspring while adiponectin is reported to be anxiolytic. Here we test the hypothesis that elevated adiponectin levels protect against the development of androgen-induced anxiety-like behavior. Pregnant mice overexpressing adiponectin (APNtg) and wildtypes were injected with vehicle or dihydrotestosterone to induce prenatal androgenization (PNA) in the offspring. Metabolic profiling and behavioral tests were performed in 4-month-old female offspring. PNA offspring spent more time in the closed arms of the elevated plus maze, indicating anxiety-like behavior. Intriguingly, neither maternal nor offspring adiponectin overexpression prevented an anxiety-like behavior in PNA-exposed offspring. However, adiponectin overexpression in dams had metabolic imprinting effects, shown as lower fat mass and glucose levels in their offspring. While serum adiponectin levels were elevated in APNtg mice, cerebrospinal fluid levels were similar between genotypes. Adiponectin overexpression improved metabolic functions but did not elicit anxiolytic effects in PNA-exposed offspring. These observations might be attributed to increased circulating but unchanged cerebrospinal fluid adiponectin levels in APNtg mice. Thus, increased adiponectin levels in the brain are likely needed to stimulate anxiolytic effects.

Maternal androgen excess inhibits fetal cardiomyocytes proliferation through RB-mediated cell cycle arrest and induces cardiac hypertrophy in adulthood.

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.

An expert panel's review on patients with hereditary angioedema switching from attenuated androgens to oral prophylactic therapy.

Background: Hereditary angioedema (HAE) is a rare condition marked by swelling episodes in various body parts, including the extremities, upper airway, face, intestinal tract, and genitals. Long-term prophylaxis (LTP), prescribed to control recurring HAE attacks, is integral to its management. Previously, attenuated androgens (AAs) were the only oral LTP options. However, in 2020, berotralstat, an oral plasma kallikrein inhibitor, was approved in the United States. A 2018 survey of adults with HAE type I or type II showed that almost all the patients who used prophylactic HAE medication preferred oral treatment (98%) and felt that it fit their lifestyle better than injectable treatment (96%). Still, guidelines lack consensus on transitioning patients from AAs to alternative oral prophylactic therapy. Objective: This paper aims to share expert insights and patient feedback on transitioning from AAs to berotralstat, an alternative oral prophylactic therapy, from the perspective of clinicians with extensive experience in treating patients with HAE. Methods: A panel of five HAE specialists convened for a virtual half-day roundtable discussion in April 2023. Results: Discussions about transitioning from AAs to berotralstat were prompted by routine consultations, patient inquiries based on independent research, ineffective current treatment, or worsening AA-related adverse effects. For patients who switched from AAs, the physicians reported that the decision was influenced by the alternative therapy's ability to prevent HAE attacks, its safety, and the once-daily administration schedule. All expert panel members identified fewer AA-related adverse effects; better quality of life; and less severe, shorter, and less frequent HAE attacks as clinical or patient goals they hoped to achieve through the treatment switch. Conclusion: The emergence of new, highly specific LTP drugs for HAE calls for the development of comprehensive recommendations and guidelines for transitioning from AAs to alternative oral prophylactic therapy. The expert panel highlighted key factors to consider during the development of such guidelines.

Characteristics of the Online Market for Anabolic-Androgenic Steroids in Central Asia: A Netnographic Analysis.

Background: With the online proliferation of illegal substances, the Internet offers a wide variety of information on the acquisition and intake of anabolic-androgenic steroids (AAS) and other performance and image enhancing drugs. This study focuses on investigating the characteristics of the online AAS market in Central Asia. OBJECTIVES: The primary objectives of this study were to investigate the accessibility and features of the online market for AAS in Central Asia. To achieve this, we employed a netnographic approach for a systematic exploration of websites advertising and selling AAS. The study aimed to conduct a comprehensive analysis of several key aspects, including the variety of AAS products offered, the quality of health advice provided the level of product availability, the procedures involved in making purchases, and the pricing structures within this market. RESULTS: Twenty-one websites supplying AAS in Central Asia met our inclusion criteria. Using content analysis, data were gathered on AAS offerings, quality of health advice provided, availability, purchase process, and prices. Data were synthesized using descriptive statistics. Results indicate that AAS are easily accessible for purchase without valid medical prescription in the Central Asia online market. Most websites advertised the aesthetic and ergogenic benefits of AAS use without indicating the potential complications and adverse effects. CONCLUSIONS: Public health efforts to mitigate AAS use in Central Asia should consider both the online accessibility of AAS and the lack of accompanying information on potential complications as well as adverse effects associated with their use. Efforts must be intensified to curtail the proliferation of AAS and related misleading information on the Central Asian online market.

Factors predicting normalization of reproductive hormones after cessation of anabolic-androgenic steroids in men: a single center retrospective study.

OBJECTIVE: Symptomatic hypogonadism discourages men from stopping anabolic-androgenic steroids (AAS). Some men illicitly take drugs temporarily stimulating endogenous testosterone following AAS cessation (post-cycle therapy; PCT) to lessen hypogonadal symptoms. We investigated whether prior PCT use was associated with the normalization of reproductive hormones following AAS cessation. METHODS: Retrospective analysis of 641 men attending a clinic between 2015-2022 for a single, nonfasting, random blood test <36 months following AAS cessation, with or without PCT. Normalized reproductive hormones (ie, a combination of reference range serum luteinizing hormone, follicle-stimulating hormone, and total testosterone levels) were the surrogate marker of biochemical recovery. RESULTS: Normalization of reproductive hormones was achieved in 48.2% of men. PCT use was associated with faster biochemical recovery (13.0 (IQR8.0-19.0) weeks, PCT; 26.0 (IQR10.5-52) weeks, no-PCT; P < .001). Odds of biochemical recovery during multivariable analysis were: (1) higher with PCT (OR3.80) vs no-PCT (P = .001), in men stopping AAS ≤3 months previously; (2) reduced when 2 (OR0.55), 3 (OR0.46), or 4 (OR0.25) AAS were administered vs 1 drug (P = .009); (3) lower with AAS >6 vs ≤3 months previously (OR0.34, P = .01); (4) higher with last reported AAS >3 months (OR 5.68) vs ≤3 months (P = .001). PCT use was not associated with biochemical recovery in men stopping AAS >3 months previously. CONCLUSION: Without evidence-based withdrawal protocols, men commonly try avoiding post-AAS hypogonadism with PCT, which is illicit, ill-defined, and not recommended. Only half of men had complete biochemical testicular recovery after stopping AAS. The surprising association of self-reported PCT use with short-term biochemical recovery from AAS-induced hypogonadism warrants further investigation.

No effects of the antiandrogens cyproterone acetate (CPA), flutamide and p,p'-DDE on early sexual differentiation but CPA-induced retardation of embryonic development in the domestic fowl (Gallus gallus domesticus).

Because a wide range of environmental contaminants are known to cause endocrine disorders in humans and animals, in vivo tests are needed to identify such endocrine disrupting chemicals (EDCs) and to assess their biological effects. Despite the lack of a standardized guideline, the avian embryo has been shown to be a promising model system which responds sensitively to EDCs. After previous studies on the effects of estrogenic, antiestrogenic and androgenic substances, the present work focuses on the effects of in ovo exposure to p,p'-DDE, flutamide and cyproterone acetate (CPA) as antiandrogenic model compounds regarding gonadal sex differentiation and embryonic development of the domestic fowl (Gallus gallus domesticus). The substances were injected into the yolk of fertilized eggs on embryonic day one. On embryonic day 19 sex genotype and phenotype were determined, followed by gross morphological and histological examination of the gonads. Treatment with flutamide (0.5, 5, 50 µg/g egg), p,p'-DDE (0.5, 5, 50 µg/g egg) or CPA (0.2, 2, 20 µg/g egg) did not affect male or female gonad development, assessed by gonad surface area and cortex thickness in both sexes and by the percentage of seminiferous tubules in males as endpoints. This leads to the conclusion that antiandrogens do not affect sexual differentiation during embryonic development of G. gallus domesticus, reflecting that gonads are not target organs for androgens in birds. In ovo exposure to 2 and 20 µg CPA/g egg, however, resulted in significantly smaller embryos as displayed by shortened lengths of skull, ulna and tarsometatarsus. Although gonadal endpoints were not affected by antiandrogens, the embryo of G. gallus domesticus is shown to be a suitable test system for the identification of substance-related mortality and developmental delays.

A review of recent evidence on androgen abuse from interviews with users.

PURPOSE OF REVIEW: Androgens (also known as anabolic-androgenic steroids; AAS) are increasingly being abused worldwide to enhance body physique or athletic performance. Qualitative studies including interviews provide a wider understanding of androgen abuse and focus specific support needs to this group. This narrative review summarizes recent studies (2021-2023) using interviews with individuals abusing androgens. RECENT FINDINGS: Motivations for androgen abuse in men include desires to achieve certain physicality, enhance self-confidence and improve libido. The risks of androgen abuse are justified to achieve these outcomes and men may use other illicit substances as postcycle-therapy to lessen the risks. Some adverse effects may be more pronounced with certain substances. The therapeutic relationship with healthcare professionals is often described negatively by androgen abusers due to stigma and a perceived lack of knowledge. Both healthcare professionals and androgen abusers agree that development of guidelines are needed. Androgen abuse in women is rare however body dissatisfaction and desires for improve appearance and strength are motivators. SUMMARY: Recent qualitative studies have helped further our understanding of men and women who abuse androgens, however the small number of recently published studies confirms there is still a paucity of evidence in the literature. Further research is needed to develop specific harm minimization strategies in those abusing androgens.

Anogenital distance, a biomarker of fetal androgen exposure and the risk of prostate cancer: A case-control study.

OBJECTIVE: Evaluate the association between AGD and the risk of PCa. METHODS: Incident case-control study, conducted on 153 patients. All patients underwent prostate biopsy for abnormal digital rectal exam and/or prostate antigen elevation. Two variants of AGD [anus to scrotum base (AGDas) and anus to dorsal insertion of penis (AGDap) were measured. Student's t-test was used to analyze continuous variables and chi-square for discrete variables. Differences in AGD (raw and adjusted) measures between cases and controls were assessed using the ANCOVA test. RESULTS: There is significant association between the diagnose of PCa and both AGD, patients diagnosed with PCa had both AGD measures shortened, in the crude and the full adjusted models. CONCLUSIONS: This research suggests that the same gestational environmental exposures, could represent a weak androgen signaling and may also have an increased risk of prostate cancer.

The Influences of Perinatal Androgenic Exposure on Cardiovascular and Metabolic Disease of Offspring of PCOS.

Hyperandrogenism is an endocrine disorder affecting a large population of reproductive-aged women, thus proportionally high number of fetuses are subjected to prenatal androgenic exposure (PNA). The short-term stimulations at critical ontogenetic stages can wield lasting influences on the health. The most commonly diagnosed conditions in reproductive age women is polycystic ovary syndrome (PCOS). PNA may affect the growth and development of many systems in the whole body and disrupts the normal metabolic trajectory in the offspring of PCOS, contributing to the prevalence of cardiovascular and metabolic diseases (CVMD), including myocardial hypertrophy, hypertension, hyperinsulinemia, insulin resistance, hyperglycemia, obesity, and dyslipidemia, which are the leading causes of hospitalizations in young PCOS offspring. In this review, we focus on the effects of prenatal androgenic exposure on the cardiovascular and metabolic diseases in offspring, discuss the possible pathogenesis respectively, and summarize potential management strategies to improve metabolic health of PCOS offspring. It is expected that the incidence of CVMD and the medical burden will be reduced in the future.