-
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 -
The Journal of Steroid Biochemistry and... Jun 1995Male sexual differentiation and development proceed under direct control of androgens. Androgen action is mediated by the intracellular androgen receptor, which belongs... (Review)
Review
Male sexual differentiation and development proceed under direct control of androgens. Androgen action is mediated by the intracellular androgen receptor, which belongs to the superfamily of ligand-dependent transcription factors. At least three pathological situations are associated with abnormal androgen receptor structure and function: androgen insensitivity syndrome (AIS), spinal and bulbar muscular atrophy (SBMA) and prostate cancer. In the X-linked androgen insensitivity syndrome, defects in the androgen receptor gene have prevented the normal development of both internal and external male structures in 46,XY individuals. Complete or gross deletions of the androgen receptor gene have not been found frequently in persons with complete androgen insensitivity syndrome. Point mutations at several different sites in exons 2-8 encoding the DNA- and androgen-binding domain, have been reported for partial and complete forms of androgen insensitivity. A relatively high number of mutations were reported in two different clusters in exon 5 and in exon 7. The number of mutations in exon 1 is extremely low and no mutations have been reported in the hinge region, located between the DNA-binding domain and the ligand-binding domain and which is encoded by the first half of exon 4. Androgen receptor gene mutations in prostate cancer are very rare and are reported only in exons 4-8. The X-linked spinal and bulbar muscle atrophy (SBMA; Kennedy's disease) is associated with an expanded length (> 40 residues) of one of the polyglutamine stretches in the N-terminal domain of the androgen receptor.
Topics: Amino Acid Sequence; Androgens; Binding Sites; DNA-Binding Proteins; Humans; Male; Molecular Sequence Data; Motor Neuron Disease; Point Mutation; Prostatic Neoplasms; Receptors, Androgen; Syndrome
PubMed: 7626493
DOI: 10.1016/0960-0760(95)00090-m -
Archives of Dermatological Research Sep 2012Androgen and androgen receptor (AR) may play important roles in several skin-related diseases, such as androgenetic alopecia and acne vulgaris. Current treatments for... (Review)
Review
Androgen and androgen receptor (AR) may play important roles in several skin-related diseases, such as androgenetic alopecia and acne vulgaris. Current treatments for these androgen/AR-involved diseases, which target the synthesis of androgens or prevent its binding to AR, can cause significant adverse side effects. Based on the recent studies using AR knockout mice, it has been suggested that AR and androgens play distinct roles in the skin pathogenesis, and AR seems to be a better target than androgens for the treatment of these skin diseases. Here, we review recent studies of androgen/AR roles in several skin-related disorders, including acne vulgaris, androgenetic alopecia and hirsutism, as well as cutaneous wound healing.
Topics: Acne Vulgaris; Alopecia; Androgen Antagonists; Androgens; Animals; Hirsutism; Humans; Mice; Mice, Knockout; Molecular Targeted Therapy; Receptors, Androgen; Wound Healing
PubMed: 22829074
DOI: 10.1007/s00403-012-1265-x -
Human Reproduction Update 2010Hirsutism is the presence of excess body or facial terminal (coarse) hair growth in females in a male-like pattern, affects 5-15% of women, and is an important sign of... (Review)
Review
BACKGROUND
Hirsutism is the presence of excess body or facial terminal (coarse) hair growth in females in a male-like pattern, affects 5-15% of women, and is an important sign of underlying androgen excess. Different methods are available for the assessment of hair growth in women.
METHODS
We conducted a literature search and analyzed the published studies that reported methods for the assessment of hair growth. We review the basic physiology of hair growth, the development of methods for visually quantifying hair growth, the comparison of these methods with objective measurements of hair growth, how hirsutism may be defined using a visual scoring method, the influence of race and ethnicity on hirsutism, and the impact of hirsutism in diagnosing androgen excess and polycystic ovary syndrome.
RESULTS
Objective methods for the assessment of hair growth including photographic evaluations and microscopic measurements are available but these techniques have limitations for clinical use, including a significant degree of complexity and a high cost. Alternatively, methods for visually scoring or quantifying the amount of terminal body and facial hair growth have been in use since the early 1920s; these methods are semi-quantitative at best and subject to significant inter-observer variability. The most common visual method of scoring the extent of body and facial terminal hair growth in use today is based on a modification of the method originally described by Ferriman and Gallwey in 1961 (i.e. the mFG method).
CONCLUSION
Overall, the mFG scoring method is a useful visual instrument for assessing excess terminal hair growth, and the presence of hirsutism, in women.
Topics: Androgens; Female; Hair; Hirsutism; Humans; Polycystic Ovary Syndrome
PubMed: 19567450
DOI: 10.1093/humupd/dmp024 -
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 -
Postgraduate Medical Journal Apr 1975Hirsutism is usually caused either by an increase in androgen production by the ovary or adrenal or it may be due to increased sensitivity of the hair follicle to normal...
Hirsutism is usually caused either by an increase in androgen production by the ovary or adrenal or it may be due to increased sensitivity of the hair follicle to normal amounts of circulating androgens. The diagnostic possibilities can be resolved on clinical grounds by laparoscopy and by hormone measurements. The commonest causes of this symptom are ‘idiopathic hirsutism’ and the polycystic ovary syndrome. Treatment is of the underlying condition or, when that is not possible, by local removal of hair or by the administration of oral contraceptives or glucocorticoids.
Topics: Adrenal Glands; Androgens; Female; Hirsutism; Humans; Ovary
PubMed: 1197153
DOI: 10.1136/pgmj.51.594.236 -
Physiological Research Sep 2020The adrenal glands produce significant amounts of steroid hormones and their metabolites, with various levels of androgenic activities. Until recently, the androgenic... (Review)
Review
The adrenal glands produce significant amounts of steroid hormones and their metabolites, with various levels of androgenic activities. Until recently, the androgenic potency of these adrenal-derived compounds were not well known, but some recent studies have shown that the production of 11-oxo- and 11beta-hydroxy-derived testosterone and dihydrotestosterone evidently have high androgenic activity. This fact has clinical importance, for instance, in various types of congenital adrenal hyperplasia with androgenization or polycystic ovarian syndrome, and laboratory determinations of these substances could help to better evaluate the total androgen pressure in patients with these disorders. Another area of concern is the treatment of prostate cancer with androgen deprivation, which loses effectiveness after a certain time. The concurrent blocking of the secretion of adrenal C(19)-steroids, whether using corticoids or adrenostatics, could increase the effectiveness of androgen-deprivation therapy.
Topics: Adrenal Hyperplasia, Congenital; Androgen Antagonists; Androgens; Animals; Humans; Male; Molecular Targeted Therapy; Prostatic Neoplasms; Testosterone
PubMed: 33094617
DOI: 10.33549/physiolres.934516 -
Journal of Endocrinological... Aug 2022Selective androgen and estrogen receptor modulators, ostarine (OST) and raloxifen (RAL), reportedly improve muscle tissue and offer therapeutic approaches to muscle...
PURPOSE
Selective androgen and estrogen receptor modulators, ostarine (OST) and raloxifen (RAL), reportedly improve muscle tissue and offer therapeutic approaches to muscle maintenance in the elderly. The present study evaluated the effects of OST and RAL and their combination on musculoskeletal tissue in orchiectomized rats.
METHODS
Eight-month-old Sprague Dawley rats were analyzed. Experiment I: (1) Untreated non-orchiectomized rats (Non-ORX), (2) untreated orchiectomized rats (ORX), (3) ORX rats treated with OST during weeks 0-18 (OST-P), (4) ORX rats treated with OST during weeks 12-18 (OST-T). Experiment II: 1) Non-ORX, (2) ORX, 3) OST-P, (4) ORX rats treated with RAL, during weeks 0-18 (RAL-P), 5) ORX rats treated with OST + RAL, weeks 0-18 (OST + RAL-P). The average daily doses of OST and RAL were 0.4 and 7 mg/kg body weight (BW). Weight, fiber size, and capillarization of muscles, gene expression, serum markers and the lumbar vertebral body were analyzed.
RESULTS
OST-P exerted favorable effects on muscle weight, expression of myostatin and insulin growth factor-1, but increased prostate weight. OST-T partially improved muscle parameters, showing less effect on the prostate. RAL-P did not show anabolic effects on muscles but improved body constitution by reducing abdominal area, food intake, and BW. OST + RAL-P had an anabolic impact on muscle, reduced androgenic effect on the prostate, and normalized food intake. OST and RAL improved osteoporotic bone.
CONCLUSIONS
The OST + RAL treatment appeared to be a promising option in the treatment of androgen-deficient conditions and showed fewer side effects than the respective single treatments.
Topics: Androgens; Animals; Bone Density; Estrogen Receptor Modulators; Male; Orchiectomy; Rats; Rats, Sprague-Dawley; Selective Estrogen Receptor Modulators
PubMed: 35429299
DOI: 10.1007/s40618-022-01794-7 -
Neuroscience Jun 2013Neurotrophic factors and steroid hormones interact to regulate a variety of neuronal processes such as neurite outgrowth, differentiation, and neuroprotection. The... (Review)
Review
Neurotrophic factors and steroid hormones interact to regulate a variety of neuronal processes such as neurite outgrowth, differentiation, and neuroprotection. The coexpression of steroid hormone and neurotrophin receptor mRNAs and proteins, as well as their reciprocal regulation provides the necessary substrates for such interactions to occur. This review will focus on androgen brain-derived neurotrophic factor (BDNF) interactions in the spinal cord, describing androgen regulation of BDNF in neuromuscular systems following castration, androgen manipulation, and injury. Androgens interact with BDNF during development to regulate normally-occurring motoneuron death, and in adulthood, androgen-BDNF interactions are involved in the maintenance of several features of neuromuscular systems. Androgens regulate BDNF and trkB expression in spinal motoneurons. Androgens also regulate BDNF levels in the target musculature, and androgenic action at the muscle regulates BDNF levels in motoneurons. These interactions have important implications for the maintenance of motoneuron morphology. Finally, androgens interact with BDNF after injury, influencing soma size, dendritic morphology, and axon regeneration. Together, these findings provide further insight into the development and maintenance of neuromuscular systems and have implications for the neurotherapeutic/neuroprotective roles of androgens and trophic factors in the treatment of motoneuron disease and recovery from injury.
Topics: Androgens; Animals; Brain-Derived Neurotrophic Factor; Humans; Male; Motor Neurons; Muscle, Skeletal; Neurons; Spinal Cord
PubMed: 23103213
DOI: 10.1016/j.neuroscience.2012.10.028 -
Frontiers in Endocrinology 2020The prevalence of cardiovascular mortality is higher in men than in age-matched premenopausal women. Gender differences are linked to circulating sex-related steroid... (Review)
Review
The prevalence of cardiovascular mortality is higher in men than in age-matched premenopausal women. Gender differences are linked to circulating sex-related steroid hormone levels and their cardio-specific actions, which are critical factors involved in the prevalence and features of age-associated cardiovascular disease. In women, estrogens have been described as cardioprotective agents, while in men, testosterone is the main sex steroid hormone. The effects of testosterone as a metabolic regulator and cardioprotective agent in aging men are poorly understood. With advancing age, testosterone levels gradually decrease in men, an effect associated with increasing fat mass, decrease in lean body mass, dyslipidemia, insulin resistance and adjustment in energy substrate metabolism. Aging is associated with a decline in metabolism, characterized by modifications in cardiac function, excitation-contraction coupling, and lower efficacy to generate energy. Testosterone deficiency -as found in elderly men- rapidly becomes an epidemic condition, associated with prominent cardiometabolic disorders. Therefore, it is highly probable that senior men showing low testosterone levels will display symptoms of androgen deficiency, presenting an unfavorable metabolic profile and increased cardiovascular risk. Moreover, recent reports establish that testosterone replacement improves cardiomyocyte bioenergetics, increases glucose metabolism and reduces insulin resistance in elderly men. Thus, testosterone-related metabolic signaling and gene expression may constitute relevant therapeutic target for preventing, or treating, age- and gender-related cardiometabolic diseases in men. Here, we will discuss the impact of current evidence showing how cardiac metabolism is regulated by androgen levels in aging men.
Topics: Aged; Aging; Androgens; Cardiovascular Diseases; Humans; Male
PubMed: 32499759
DOI: 10.3389/fendo.2020.00316