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International Journal of Molecular... Dec 2022Androgens such as testosterone and dihydrotestosterone (DHT) are essential for male sexual development, masculinisation, and fertility. Testosterone is produced via the... (Review)
Review
Androgens such as testosterone and dihydrotestosterone (DHT) are essential for male sexual development, masculinisation, and fertility. Testosterone is produced via the canonical androgen production pathway and is essential for normal masculinisation and testis function. Disruption to androgen production can result in disorders of sexual development (DSD). In the canonical pathway, 17β-hydroxysteroid dehydrogenase type 3 (HSD17B3) is viewed as a critical enzyme in the production of testosterone, performing the final conversion required. HSD17B3 deficiency in humans is associated with DSD due to low testosterone concentration during development. Individuals with mutations have poorly masculinised external genitalia that can appear as ambiguous or female, whilst having internal Wolffian structures and testes. Recent studies in mice deficient in HSD17B3 have made the surprising finding that testosterone production is maintained, male mice are masculinised and remain fertile, suggesting differences between mice and human testosterone production exist. We discuss the phenotypic differences observed and the possible other pathways and enzymes that could be contributing to testosterone production and male development. The identification of alternative testosterone synthesising enzymes could inform the development of novel therapies to endogenously regulate testosterone production in individuals with testosterone deficiency.
Topics: Humans; Male; Female; Mice; Animals; Testosterone; Androgens; Virilism; Mutation; Dihydrotestosterone; 17-Hydroxysteroid Dehydrogenases
PubMed: 36555196
DOI: 10.3390/ijms232415555 -
Journal of Drugs in Dermatology : JDD Mar 2020The effects of androgens on human skin include growth and differentiation of sebaceous glands, terminal hair growth, epidermal barrier function, wound healing, and... (Review)
Review
The effects of androgens on human skin include growth and differentiation of sebaceous glands, terminal hair growth, epidermal barrier function, wound healing, and modification of the cutaneous microbiome. Androgens exert their activities via ligand formation with intracytoplasmic androgen receptors which can then translocate to the nucleus and interact with genetic androgen response elements to influence signaling cascades. Differences in tissue distribution and activities of enzymes that modify androgen synthesis and catabolism, variations related to gender and ethnicity/race, and genetic polymorphisms that affect androgen receptor functionality directly impact androgen physiology and the pathophysiology associated with a variety of disease states. This manuscript reviews the fundamentals of androgen physiology, androgen synthesis and catabolism in local skin tissue, androgen receptor activity, as well as the impact of genetic polymorphisms and gender. Emphasis is placed on the roles of androgenic activity in sebaceous gland development, sebum production, and the pathophysiology of acne vulgaris. J Drugs Dermatol. 2020;19(3 Suppl 1):s30-35.
Topics: Acne Vulgaris; Androgens; Humans; Receptors, Androgen; Skin; Skin Physiological Phenomena
PubMed: 32550699
DOI: No ID Found -
Neuroscience and Biobehavioral Reviews May 2019Supraphysiologic-dose anabolic-androgenic steroid (AAS) use is associated with physiologic, cognitive, and brain abnormalities similar to those found in people at risk... (Review)
Review
Supraphysiologic-dose anabolic-androgenic steroid (AAS) use is associated with physiologic, cognitive, and brain abnormalities similar to those found in people at risk for developing Alzheimer's Disease and its related dementias (AD/ADRD), which are associated with high brain β-amyloid (Aβ) and hyperphosphorylated tau (tau-P) protein levels. Supraphysiologic-dose AAS induces androgen abnormalities and excess oxidative stress, which have been linked to increased and decreased expression or activity of proteins that synthesize and eliminate, respectively, Aβ and tau-P. Aβ and tau-P accumulation may begin soon after initiating supraphysiologic-dose AAS use, which typically occurs in the early 20s, and their accumulation may be accelerated by other psychoactive substance use, which is common among non-medical AAS users. Accordingly, the widespread use of supraphysiologic-dose AAS may increase the numbers of people who develop dementia. Early diagnosis and correction of sex-steroid level abnormalities and excess oxidative stress could attenuate risk for developing AD/ADRD in supraphysiologic-dose AAS users, in people with other substance use disorders, and in people with low sex-steroid levels or excess oxidative stress associated with aging.
Topics: Alzheimer Disease; Amyloid beta-Peptides; Androgens; Animals; Brain; Dementia; Humans; Hypogonadism; Oxidative Stress; Phosphorylation; Risk Factors; Testosterone Congeners; tau Proteins
PubMed: 30817935
DOI: 10.1016/j.neubiorev.2019.02.014 -
Cells Jan 2023Steroid hormones and growth factors control neuritogenesis through their cognate receptors under physiological and pathological conditions. We have already shown that...
Steroid hormones and growth factors control neuritogenesis through their cognate receptors under physiological and pathological conditions. We have already shown that nerve growth factor and androgens induce neurite outgrowth of PC12 cells through a reciprocal crosstalk between the NGF receptor, TrkA and the androgen receptor. Here, we report that androgens or NGF induce neuritogenesis in PC12 cells through inactivation of RhoA. Ectopic expression of the dominant negative RhoA N19 promotes, indeed, the neurite-elongation of unchallenged and androgen- or NGF-challenged PC12 cells and the increase in the expression levels of βIII tubulin, a specific neuronal marker. Pharmacological inhibition of the Ser/Thr kinase ROCK, an RhoA effector, induces neuritogenesis in unchallenged PC12 cells, and potentiates the effect of androgens and NGF, confirming the role of RhoA/ROCK axis in the neuritogenesis induced by androgen and NGF, through the phosphorylation of Akt. These findings suggest that therapies based on new selective androgen receptor modulators and/or RhoA/ROCK inhibitors might exert beneficial effects in the treatment of neuro-disorders, neurological diseases and ageing-related processes.
Topics: Animals; Rats; Androgens; Nerve Growth Factor; Neurites; Neuronal Outgrowth; PC12 Cells; Receptors, Androgen
PubMed: 36766714
DOI: 10.3390/cells12030373 -
Clinics in Dermatology 2017Acne is a common, worldwide problem that is usually multifactorial in etiology, but androgens may play a pivotal role in the development and severity of acne....
Acne is a common, worldwide problem that is usually multifactorial in etiology, but androgens may play a pivotal role in the development and severity of acne. Endocrinopathies, such as polycystic ovarian syndrome, ovarian tumors, or adrenal hyperplasia or tumors, may be detected in some patients with acne, especially if acne is sudden in onset, associated with hirsutism or menstrual irregularities, or associated with cushingoid facies, acanthosis nigricans, patterned hair loss, or deepened voice. In these instances, serum-free and total testosterone, dehydroepiandrosterone, luteinizing hormone, and follicle stimulating hormone should be tested. Appropriate referral and long-term follow-up is warranted in patients diagnosed with an endocrinopathy. Hormonal therapies for acne include systemic medications with various mechanisms: androgen receptor blockers, adrenal androgen production blockers, or ovarian androgen production blockers. Androgen receptor blockers include spironolactone, cyproterone acetate, chlormadinone, and flutamide; adrenal androgen production blockers include glucocorticoids; and ovarian production blockers include gonadotropin-releasing agonists and oral contraceptives. Practical guidelines are shared for the practicing physician treating hormonally related acne.
Topics: Acne Vulgaris; Alopecia; Androgen Antagonists; Androgens; Contraceptives, Oral; Female; Gonadotropin-Releasing Hormone; Hirsutism; Humans; Polycystic Ovary Syndrome
PubMed: 28274354
DOI: 10.1016/j.clindermatol.2016.10.009 -
Journal of Ethnopharmacology Feb 2016Historically, aphrodisiacs have had a reputation for making sex more achievable and satisfying. It has been long believed that Tribulus terrestris L. (TT), an annual... (Review)
Review
ETHNO-PHARMACOLOGICAL RELEVANCE
Historically, aphrodisiacs have had a reputation for making sex more achievable and satisfying. It has been long believed that Tribulus terrestris L. (TT), an annual plant of the family Zygophyllaceae, possesses aphrodisiac properties purportedly attributed to its ability to influence levels or mimic function of sex hormones. Due to this appealing beliefs, the popularity of medicinal products from TT is expanding at a remarkable pace among consumers who are attempting to enhance their sexual health. However, reliable scientific evidence supporting these purported bioactivities are scant and far from conclusive.
AIM OF THE REVIEW
To critically analyze and updated the evidence supporting a role for TT as an aphrodisiac and to reappraise the widely believed view of TT as an androgen enhancing botanical supplement.
MATERIAL AND METHOD
An extensive review of the literature was carried out based on systematic search of major scientific databases (PubMed, Elsevier, Springer Link, Google Scholar, Medline Plus, and Web of Science) for studies of phytochemical, pharmacological and traditional uses of TT published between 1968 and 2015. In addition, the reference lists of the available articles were reviewed and relevant studies including material in journals which are not indexed internationally were reviewed.
RESULTS
Analysis of phytochemical and pharmacological studies in humans and animals revealed an important role for TT in treating erectile dysfunction and sexual desire problems; however, empirical evidence to support the hypothesis that this desirable effects are due to androgen enhancing properties of TT is, at best, inconclusive, and analysis of empirical evidence from a comprehensive review of available literature proved this hypothesis wrong. While the mechanisms underlying TT aphrodisiac activity remain largely unknown, there is emerging compelling evidence from experimental studies in animals for possible endothelium and nitric oxide-dependent mechanisms underlying TT aphrodisiac and pro-erectile activities.
CONCLUSION
It is becoming increasingly clear that the deep-seated traditional view of TT bioactivity focused exclusively on its androgen enhancing properties is outdated and incapable for accommodating the emerging evidence from recent clinical and experimental studies pointing toward new and, perhaps, more plausible modes of action. Novel paradigms guiding the development of new testable hypotheses for TT aphrodisiac properties are needed to stimulate further investigations into potential biological mechanisms in which many apparently conflicting observations can be reconciled.
Topics: Androgens; Animals; Aphrodisiacs; Erectile Dysfunction; Humans; Libido; Male; Penile Erection; Sexual Behavior; Sexual Behavior, Animal; Tribulus
PubMed: 26727646
DOI: 10.1016/j.jep.2015.12.055 -
The Oncologist Jun 2023Inhibition of androgen receptor (AR) signaling has been the mainstay of treatment of advanced prostate cancer (PCa) for the past 80 years. Combination and sequential... (Review)
Review
Inhibition of androgen receptor (AR) signaling has been the mainstay of treatment of advanced prostate cancer (PCa) for the past 80 years. Combination and sequential AR-inhibiting therapies are highly effective palliative therapy, but they are not curative. All patients eventually develop resistance to primary castrating therapy [ie, castration-resistant PCa (CRPC)]. At this point, they are treated with subsequent lines of secondary AR inhibitory therapies. However, resistance to these agents also develops and patients progress to a state we have termed complete androgen inhibition-resistant PCa. This phase of the disease is associated with poor prognosis. At this point, treatment shifts to non-hormonal cytotoxic therapies (eg, chemotherapy and radiopharmaceuticals). However, the majority of PCas remain addicted to signaling through AR throughout the course of the disease. Resistant PCa cells adaptively upregulate AR activity, despite castration and AR inhibitors, via mechanisms such as AR overexpression, gene amplification, mutation, and expression of ligand-independent variants to permit sustained liganded and non-liganded AR signaling. Studies dating back nearly 30 years indicate that high expression of AR induced by prolonged castration becomes a vulnerability of CRPC cells in vitro and in mouse xenografts to supraphysiologic androgen (SPA), which induces cell death and growth arrest in this context. Based on these studies, we developed a counterintuitive treatment called bipolar androgen therapy (BAT) for patients with CRPC, in which SPA is administered intermittently to result in cycling of serum testosterone from the polar extremes of supraphysiologic to near-castrate levels. This rapid cycling is intended to disrupt the adaptive of AR regulation associated with chronic exposure to high or low levels of testosterone, while simultaneously targeting the spectrum of AR expression present in heterogeneous CRPC tumors. We have now tested BAT in >250 patients with CRPC. Here we present a review of these clinical studies, which have demonstrated collectively that BAT can be safely given to men with CRPC, improves quality of life, and produces therapeutic responses in ~30% of patients. As expected, resistance to BAT is associated with adaptive downregulation of AR expression. Intriguingly, this downregulation is associated with restoration of sensitivity to subsequent AR inhibitor therapies.
Topics: Male; Humans; Animals; Mice; Androgens; Receptors, Androgen; Prostatic Neoplasms, Castration-Resistant; Quality of Life; Testosterone; Cell Line, Tumor
PubMed: 37027449
DOI: 10.1093/oncolo/oyad055 -
Journal of the American Academy of... Jun 2019Androgen-mediated cutaneous disorders (AMCDs) in women, including acne, hirsutism, and female pattern hair loss, can be treated with hormone-modulating therapies. In the... (Review)
Review
Androgen-mediated cutaneous disorders (AMCDs) in women, including acne, hirsutism, and female pattern hair loss, can be treated with hormone-modulating therapies. In the second article in this Continuing Medical Education series, we discuss the hormone-modulating therapies available to dermatologists for the treatment of AMCDs, including combined oral contraceptives, spironolactone, finasteride, dutasteride, and flutamide. Available hormone-modulating treatments used for each AMCDs are reviewed, along with mechanisms of androgen modulation, safety profile, contraindications, monitoring parameters, and evidence of efficacy. Medications discussed include those that are approved by the US Food and Drug Administration for certain AMCDs and some that are used off-label. Despite the ubiquity of hormone-modulating therapies used for AMCDs, this review highlights the need for more rigorous studies to evaluate these therapies for acne, hirsutism, and female pattern hair loss.
Topics: 5-alpha Reductase Inhibitors; Acne Vulgaris; Adrenal Hyperplasia, Congenital; Alopecia; Androgen Antagonists; Androgens; Contraceptives, Oral, Combined; Dutasteride; Female; Finasteride; Flutamide; Hirsutism; Humans; Polycystic Ovary Syndrome; Receptors, Androgen; Spironolactone
PubMed: 30312645
DOI: 10.1016/j.jaad.2018.08.061 -
Journal of Ovarian Research Apr 2023Polycystic ovarian syndrome (PCOS) is a complex multi-factorial syndrome associated with androgen excess and anovulatory infertility. In the current study, we...
Polycystic ovarian syndrome (PCOS) is a complex multi-factorial syndrome associated with androgen excess and anovulatory infertility. In the current study, we investigated the role of dihydrotestosterone-induced exosomal miR-379-5p release in determining the destiny of the developing follicles. Our hypothesis was that androgen regulates granulosa cell miR-379-5p content by facilitating its exosomal release in a follicular-stage dependent manner, a process which determines granulosa cell fate. Compared to human non-PCOS subjects, individuals with PCOS exhibit higher follicular fluid free testosterone levels, lower exosomal miR-379-5p content and granulosa cell proliferation. Androgenized rats exhibited lower granulosa cell miR-379-5p but higher phosphoinositide-dependent kinase-1 (PDK1; a miR-379-5p target) content and proliferation. Androgen reduced granulosa cell miR-379-5p content by increasing its exosomal release in preantral follicles, but not in antral follicles in vitro. Studies with an exosomal release inhibitor confirmed that androgen-induced exosomal miR-379-5p release decreased granulosa cell miR-379-5p content and proliferation. Ovarian overexpression of miR-379-5p suppressed granulosa cell proliferation, and basal and androgen-induced preantral follicle growth in vivo. These findings suggest that increased exosomal miR-379-5p release in granulosa cells is a proliferative response to androgenic stimulation specific for the preantral stage of follicle development and that dysregulation of this response at the antral stage is associated with follicular growth arrest, as observed in human PCOS.
Topics: Female; Humans; Rats; Animals; Androgens; Polycystic Ovary Syndrome; Granulosa Cells; MicroRNAs
PubMed: 37046285
DOI: 10.1186/s13048-023-01141-1 -
Pharmacological Research Sep 2021Androgens in women, as well as in men, are intrinsic to maintenance of (i) reproductive competency, (ii) cardiac health, (iii) appropriate bone remodeling and mass... (Review)
Review
Androgens in women, as well as in men, are intrinsic to maintenance of (i) reproductive competency, (ii) cardiac health, (iii) appropriate bone remodeling and mass retention, (iii) muscle tone and mass, and (iv) brain function, in part, through their mitigation of neurodegenerative disease effects. In recognition of the pluripotency of endogenous androgens, exogenous androgens, and selected congeners, have been prescribed off-label for several decades to treat low libido and sexual dysfunction in menopausal women, as well as, to improve physical performance. However, long-term safety and efficacy of androgen administration has yet to be fully elucidated. Side effects often observed include (i) hirsutism, (ii) acne, (iii) deepening of the voice, and (iv) weight gain but are associated most frequently with supra-physiological doses. By contrast, short-term clinical trials suggest that the use of low-dose testosterone therapy in women appears to be effective, safe and economical. There are, however, few clinical studies, which have focused on effects of androgen therapy on pre- and post-menopausal women; moreover, androgen mechanisms of action have not yet been thoroughly explained in these subjects. This review considers clinical effects of androgens on women's health in order to prevent chronic diseases and reduce cancer risk in gynecological tissues.
Topics: Androgens; Animals; Bone and Bones; Breast Neoplasms; Cardiovascular Diseases; Female; Genitalia, Female; Humans; Muscles; Neurodegenerative Diseases; Receptors, Androgen; Sexual Behavior; Women's Health
PubMed: 34242799
DOI: 10.1016/j.phrs.2021.105758