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Seminars in Reproductive Medicine Mar 2022Hyperandrogenism-clinical features resulting from increased androgen production and/or action-is not uncommon in peripubertal girls. Hyperandrogenism affects 3 to 20% of...
Hyperandrogenism-clinical features resulting from increased androgen production and/or action-is not uncommon in peripubertal girls. Hyperandrogenism affects 3 to 20% of adolescent girls and often is associated with hyperandrogenemia. In prepubertal girls, the most common etiologies of androgen excess are premature adrenarche (60%) and congenital adrenal hyperplasia (CAH; 4%). In pubertal girls, polycystic ovary syndrome (PCOS; 20-40%) and CAH (14%) are the most common diagnoses related to androgen excess. Androgen-secreting ovarian or adrenal tumors are rare (0.2%). Early pubic hair, acne, and/or hirsutism are the most common clinical manifestations, but signs of overt virilization in adolescent girls-rapid progression of pubic hair or hirsutism, clitoromegaly, voice deepening, severe cystic acne, growth acceleration, increased muscle mass, and bone age advancement past height age-should prompt detailed evaluation. This article addresses the clinical manifestations of and management considerations for non-PCOS-related hyperandrogenism in adolescent girls. We propose an algorithm to aid diagnostic evaluation of androgen excess in this specific patient population.
Topics: Acne Vulgaris; Adolescent; Androgens; Female; Hirsutism; Humans; Hyperandrogenism; Polycystic Ovary Syndrome
PubMed: 35052005
DOI: 10.1055/s-0041-1742259 -
Journal of Cachexia, Sarcopenia and... Aug 2023Androgens are anabolic steroid hormones that exert their function by binding to the androgen receptor (AR). We have previously established that AR deficiency in limb...
BACKGROUND
Androgens are anabolic steroid hormones that exert their function by binding to the androgen receptor (AR). We have previously established that AR deficiency in limb muscles impairs sarcomere myofibrillar organization and decreases muscle strength in male mice. However, despite numerous studies performed in men and rodents, the signalling pathways controlled by androgens via their receptor in skeletal muscles remain poorly understood.
METHODS
Male AR (n = 7-12) and female AR mice (n = 9), in which AR is selectively ablated in myofibres of musculoskeletal tissue, and male AR , in which AR is selectively ablated in post-mitotic skeletal muscle myofibres (n = 6), were generated. Longitudinal monitoring of body weight, blood glucose, insulin, lipids and lipoproteins was performed, alongside metabolomic analyses. Glucose metabolism was evaluated in C2C12 cells treated with 5α-dihydrotestosterone (DHT) and the anti-androgen flutamide (n = 6). Histological analyses on macroscopic and ultrastructural levels of longitudinal and transversal muscle sections were conducted. The transcriptome of gastrocnemius muscles from control and AR mice was analysed at the age of 9 weeks (P < 0.05, 2138 differentially expressed genes) and validated by RT-qPCR analysis. The AR (4691 peaks with false discovery rate [FDR] < 0.1) and H3K4me2 (47 225 peaks with FDR < 0.05) cistromes in limb muscles were determined in 11-week-old wild-type mice.
RESULTS
We show that disrupting the androgen/AR axis impairs in vivo glycolytic activity and fastens the development of type 2 diabetes in male, but not in female mice. In agreement, treatment with DHT increases glycolysis in C2C12 myotubes by 30%, whereas flutamide has an opposite effect. Fatty acids are less efficiently metabolized in skeletal muscles of AR mice and accumulate in cytoplasm, despite increased transcript levels of genes encoding key enzymes of beta-oxidation and mitochondrial content. Impaired glucose and fatty acid metabolism in AR-deficient muscle fibres is associated with 30% increased lysine and branched-chain amino acid catabolism, decreased polyamine biosynthesis and disrupted glutamate transamination. This metabolic switch generates ammonia (2-fold increase) and oxidative stress (30% increased H O levels), which impacts mitochondrial functions and causes necrosis in <1% fibres. We unravel that AR directly activates the transcription of genes involved in glycolysis, oxidative metabolism and muscle contraction.
CONCLUSIONS
Our study provides important insights into diseases caused by impaired AR function in musculoskeletal system and delivers a deeper understanding of skeletal muscle pathophysiological dynamics that is instrumental to develop effective treatment for muscle disorders.
Topics: Animals; Female; Male; Mice; Androgens; Diabetes Mellitus, Type 2; Dihydrotestosterone; Flutamide; Muscle Contraction; Muscle, Skeletal; Receptors, Androgen
PubMed: 37208984
DOI: 10.1002/jcsm.13251 -
Molecular and Cellular Endocrinology Apr 2018Androgens play an important role in metabolic homeostasis and reproductive health in both men and women. Androgen signalling is dependent on androgen receptor... (Review)
Review
Androgens play an important role in metabolic homeostasis and reproductive health in both men and women. Androgen signalling is dependent on androgen receptor activation, mostly by testosterone and 5α-dihydrotestosterone. However, the intracellular or intracrine activation of C androgen precursors to active androgens in peripheral target tissues of androgen action is of equal importance. Intracrine androgen synthesis is often not reflected by circulating androgens but rather by androgen metabolites and conjugates. In this review we provide an overview of human C steroid biosynthesis including the production of 11-oxygenated androgens, their transport in circulation and uptake into peripheral tissues. We conceptualise the mechanisms of intracrinology and review the intracrine pathways of activation and inactivation in selected human tissues. The contribution of liver and kidney as organs driving androgen inactivation and renal excretion are also highlighted. Finally, the importance of quantifying androgen metabolites and conjugates to assess intracrine androgen production is discussed.
Topics: Androgens; Animals; Biosynthetic Pathways; Humans; Organ Specificity; Reproduction; Steroids
PubMed: 28865807
DOI: 10.1016/j.mce.2017.08.016 -
Clinical Breast Cancer Dec 2023Triple negative breast cancer (TNBC) is characterized by high rates of disease recurrence after definitive therapy, and median survival of less than 18 months in the... (Review)
Review
Triple negative breast cancer (TNBC) is characterized by high rates of disease recurrence after definitive therapy, and median survival of less than 18 months in the metastatic setting. Systemic therapy options for TNBC consist primarily of cytotoxic chemotherapy-containing regimens, and while recently FDA-approved chemo-immunotherapy combinations and antibody-drug conjugates such as Sacituzumab govitecan have improved clinical outcomes, there remains an unmet need for more effective and less toxic therapies. A subset of TNBC expresses the androgen receptor (AR), a nuclear hormone steroid receptor that activates an androgen-responsive transcriptional program, and gene expression profiling has revealed a TNBC molecular subtype with AR expression and luminal and androgen responsive features. Both preclinical and clinical data suggest biologic similarities between luminal AR (LAR) TNBC and ER+ luminal breast cancer, including lower proliferative activity, relative chemoresistance, and high rates of oncogenic activating mutations in the phosphatidylinositol-3-kinase (PI3K) pathway. Preclinical LAR-TNBC models are sensitive to androgen signaling inhibitors (ASIs), and particularly given the availability of FDA-approved ASIs with robust efficacy in prostate cancer, there has been great interest in targeting this pathway in AR+ TNBC. Here, we review the underlying biology and completed and ongoing androgen-targeted therapy studies in early stage and metastatic AR+ TNBC.
Topics: Humans; Triple Negative Breast Neoplasms; Receptors, Androgen; Androgens; Neoplasm Recurrence, Local; Signal Transduction
PubMed: 37419745
DOI: 10.1016/j.clbc.2023.06.009 -
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 -
Endocrine Practice : Official Journal... Mar 2018
Topics: Adrenal Cortex Neoplasms; Adrenocortical Carcinoma; Adrenocorticotropic Hormone; Clitoris; Dehydroepiandrosterone Sulfate; Female; Humans; Hypertrophy; Magnetic Resonance Imaging; Middle Aged; Testosterone; Tomography, X-Ray Computed; Virilism
PubMed: 29144800
DOI: 10.4158/EP-2017-0122 -
Sexual Medicine Reviews Jun 2024Androgens play important roles in regulating the growth and development of the male reproductive system and maintaining libido and erectile function. The specific... (Review)
Review
INTRODUCTION
Androgens play important roles in regulating the growth and development of the male reproductive system and maintaining libido and erectile function. The specific mechanisms by which androgen deficiency leads to erectile dysfunction (ED) are not yet fully understood.
OBJECTIVES
To understand the mechanisms and treatment of androgen deficiency-related ED.
METHODS
A literature search in the past 10 years was conducted in PubMed and Google Scholar to determine the effects of androgen deficiency on erectile function and the treatment of androgen deficiency.
RESULTS
Androgen deficiency can be caused by hypothalamic-pituitary lesions and injuries, testicular-related diseases and injuries, endocrine and metabolic disorders, the side effects of medication, and age. Androgen deficiency can lead to ED by inhibiting the NOS/NO/cGMP pathway (nitric oxide synthase/nitric oxide/cyclic guanosine monophosphate) and altering the expression of ion channel proteins, as well as by inducing oxidative stress, death, and fibrosis in penile corpus cavernosum cells. Testosterone replacement therapy is effective at improving the serum testosterone levels and erectile function in patients with androgen deficiency. For patients who need to maintain a low androgenic state, erectile function can be improved by lifestyle changes, treatment with phosphodiesterase type 5 inhibitors, low-intensity extracorporeal shock wave therapy, and stem cell therapy.
CONCLUSIONS
Androgen deficiency can affect the structure and function of the penile corpus cavernosum, leading to ED. Areas of further study include how androgen replacement therapy can improve erectile function and how to improve the maintenance of erectile function in patients with hypoandrogenic status.
Topics: Humans; Erectile Dysfunction; Male; Androgens; Hormone Replacement Therapy; Testosterone; Phosphodiesterase 5 Inhibitors
PubMed: 38719619
DOI: 10.1093/sxmrev/qeae030 -
Current Opinion in Endocrinology,... Jun 2018To summarize recent data on the adverse reproductive consequences of androgen abuse, focusing on the recovery of reproductive function following androgen discontinuation. (Review)
Review
PURPOSE OF REVIEW
To summarize recent data on the adverse reproductive consequences of androgen abuse, focusing on the recovery of reproductive function following androgen discontinuation.
RECENT FINDINGS
Evidence is mostly based on case reports and observational studies. Androgen abuse leads to a state of hypogonadotropic hypogonadism associated with impaired spermatogenesis, testicular atrophy, gynecomastia as well as menstrual irregularities, virilization and subfertility. Recovery of the hypothalamic-pituitary-gonadal axis following androgen withdrawal depends on the type and characteristics of androgen administration (dose, duration of use) as well as those of the user (age, previous reproductive function). Biochemical and clinical features of hypogonadism may be evident months or even years following androgen discontinuation. To prevent androgen-related adverse effects and accelerate recovery of gonadal function, users take androgens in a cyclical fashion and use drugs such as human chorionic gonadotropin, antiestrogens and aromatase inhibitors, even though there is limited evidence to support efficacy of these strategies. As few studies refer to female androgen users, there is a lack of data concerning recovery from androgen-related reproductive side effects in women.
SUMMARY
Androgen abuse has profound and commonly under-recognized effects on the reproductive system; recovery following androgen withdrawal may be prolonged and occasionally incomplete.
Topics: Androgens; Chorionic Gonadotropin; Female; Humans; Hypogonadism; Infertility, Female; Infertility, Male; Male; Menstruation Disturbances; Reproduction; Spermatogenesis; Substance-Related Disorders; Testis; Virilism
PubMed: 29389675
DOI: 10.1097/MED.0000000000000406 -
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 -
Sexual Medicine Reviews Oct 2022For several decades, testosterone and its synthetic derivatives have been used for anabolic and androgenic purposes. Initially restricted to professional bodybuilders,... (Review)
Review
INTRODUCTION
For several decades, testosterone and its synthetic derivatives have been used for anabolic and androgenic purposes. Initially restricted to professional bodybuilders, these substances gradually became more popular with recreational weightlifters. Considering its increasing prevalence, the consumption of anabolic androgenic steroids (AAS) has become a matter of great concern. Although most side effects are mild and reversible, some of them can cause permanent damage or can be potentially life threatening.
OBJECTIVES
To review and summarize medical literature regarding misuse and abuse of testosterone and other androgens, in order to provide evidence-based information on the main topics related to this subject, such as how to identify and how to deal with these patients, and to elucidate the multiple possible adverse effects secondary to this practice.
METHODS
Key studies were retrieved from PubMed (1989-2021) with reference searches from relevant articles. Search terms included "hypogonadism", "anabolic androgenic steroids", "androgens", "misuse AND testosterone", "abuse AND testosterone", and "side effects AND testosterone".
RESULTS
There is a significant lack of information in the peer-reviewed literature describing demographic data, implications for different organ systems and the management of current or former AAS users; however, androgen abuse has been already linked to a wide variety of cardiovascular diseases, metabolic, endocrine, neurological, psychiatric and liver disorders. Despite all this, most physicians still feel uncomfortable and hesitate to discuss the issue with patients.
CONCLUSIONS
The chronic use of high doses of AAS is associated with adverse effects in several organ systems; however, there are still many gaps in our knowledge about the long-term consequences of this practice and how to deal with these patients. Healthcare professionals have a crucial role in combating this public health problem, recognizing and preventing the spread of androgen abuse.
Topics: Humans; Anabolic Agents; Anabolic Androgenic Steroids; Androgens; Hypogonadism; Testosterone; Testosterone Congeners
PubMed: 37051948
DOI: 10.1016/j.sxmr.2021.10.002