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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 -
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 -
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 -
Adrenal androgens and androgen precursors-definition, synthesis, regulation and physiologic actions.Comprehensive Physiology Oct 2014The human adrenal produces more 19 carbon (C19) steroids, by mass, than either glucocorticoids or mineralocorticoids. However, the mechanisms regulating adrenal C19... (Review)
Review
The human adrenal produces more 19 carbon (C19) steroids, by mass, than either glucocorticoids or mineralocorticoids. However, the mechanisms regulating adrenal C19 steroid biosynthesis continue to represent one of the most intriguing mysteries of endocrine physiology. This review will discuss the C19 steroids synthesized by the human adrenal and the features within the adrenal that allow production of these steroids. Finally, we consider the effects of these steroids in normal physiology and disorders of adrenal C19 steroid excess.
Topics: Adrenal Glands; Androgens; Androstanes; Animals; Humans
PubMed: 25428847
DOI: 10.1002/cphy.c140006 -
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 -
Integrative and Comparative Biology Nov 2012In the environment, there are aquatic pollutants that disrupt androgen signaling in fish. Laboratory and field-based experiments have utilized omics technologies to... (Review)
Review
In the environment, there are aquatic pollutants that disrupt androgen signaling in fish. Laboratory and field-based experiments have utilized omics technologies to characterize the molecular mechanisms underlying androgen-receptor agonism/antagonism. Transcriptomics and proteomics studies with 17β-trenbolone, a growth-promoting pharmaceutical found in water systems surrounding cattle feed lots, and androgens such as 17α-methyltestosterone and 17α-methyldihydrotestosterone, have been conducted in ovary and liver of fish that include the fathead minnow (FHM) (Pimephales promelas), common carp (Cyprinus carpio), Qurt medaka (Oryzias latipes), and zebrafish (Danio rerio). In this mini-review, we survey recent omics studies in fish and reveal that, despite the diversity of species and tissues examined, there are common cellular responses that are observed with waterborne androgenic treatments. Recurring themes in gene ontology include apoptosis, transport and oxidation of lipids, synthesis and transport of hormones, immune response, protein metabolism, and cell proliferation. However, we also discuss other mechanisms other than androgen receptor (AR) activation, such as responses to toxicant stress, estrogen receptor agonism, aromatization of androgens into estrogens, and inhibitory feedback mechanisms by high levels of androgens that may also explain molecular responses in fish. To further explore androgen-responsive protein networks, a sub-network enrichment analysis was performed on protein data collected from the livers of female FHMs exposed to 17β-trenbolone. We construct a putative AR-regulated protein/cell process network in the liver that includes B-lymphocyte differentiation, xenobiotic clearance, low-density lipoprotein oxidation, proliferation of smooth muscle cells, and permeability of blood vessels. We demonstrate that construction of protein networks can offer insight into cell processes that are potentially regulated by androgens.
Topics: Androgens; Animal Fins; Animals; Ecotoxicology; Environmental Monitoring; Fish Proteins; Fishes; Gene Expression Profiling; Liver; Proteomics; Receptors, Androgen; Sexual Development; Signal Transduction; Water Pollutants, Chemical
PubMed: 22596056
DOI: 10.1093/icb/ics072 -
Frontiers in Neuroendocrinology May 2008Previous work in the endocrine and neuroendocrine fields has viewed the androgen receptor (AR) as a transcription factor activated by testosterone or one of its many... (Review)
Review
Previous work in the endocrine and neuroendocrine fields has viewed the androgen receptor (AR) as a transcription factor activated by testosterone or one of its many metabolites. The bound AR acts as transcription regulatory element by binding to specific DNA response elements in target gene promoters, causing activation or repression of transcription and subsequently protein synthesis. Over the past two decades evidence at the cellular and organismal level has accumulated to implicate rapid responses to androgens, dependent or independent of the AR. Androgen's rapid time course of action; its effects in the absence or inhibition of the cellular machinery necessary for transcription/translation; and in the absence of translocation to the nucleus suggest a method of androgen action not initially dependent on genomic mechanisms (i.e. non-genomic in nature). In the present paper, the non-genomic effects of androgens are reviewed, along with a discussion of the possible role non-genomic androgen actions have on animal physiology and behavior.
Topics: Androgens; Animals; Calcium Signaling; Cell Membrane; Dihydrotestosterone; Genome; Gonadotropin-Releasing Hormone; Membrane Fluidity; Receptors, Androgen; Second Messenger Systems; Sexual Behavior, Animal; Testosterone; Time Factors
PubMed: 18093638
DOI: 10.1016/j.yfrne.2007.10.005 -
Hormone and Metabolic Research =... Dec 2022By the end of December 2019 new corona virus began to spread from Wuhan, China and caused a worldwide pandemic. COVID-19 deaths and prevalence represented sex discrepant... (Review)
Review
By the end of December 2019 new corona virus began to spread from Wuhan, China and caused a worldwide pandemic. COVID-19 deaths and prevalence represented sex discrepant patterns with higher rate of deaths and infection in males than females which could be justified by androgen-mediated mechanisms. This review aimed to assess the role of androgens in COVID-19 severity and mortality. Androgens increase expressions of Type II transmembrane Serine Protease (TMPRSS2) and Angiotensin Converting Enzyme 2 (ACE2), which both facilitate new corona virus entry into host cell and their expression is higher in young males than females. According to observational studies, prevalence of COVID-19 infections and deaths was more in androgenic alopecic patients than patients without androgenic alopecia. The COVID-19 mortality rates in aged men (>60 years) were substantially higher than aged females and even young males caused by high inflammatory activities such as cytokine storm due to hypogonadism in this population. Use of anti-androgen and TMPRSS2 inhibitor drugs considerably modified COVID-19 symptoms. Androgen deprivation therapy also improved COVID-19 symptoms in prostate cancer: overall the role of androgens in severity of COVID-19 and its associated mortality seemed to be very important. So, more studies in variety of populations are required to define the absolute role of androgens.
Topics: Humans; Male; Aged; Androgens; COVID-19; Androgen Antagonists; Prostatic Neoplasms; China
PubMed: 36195265
DOI: 10.1055/a-1954-5605 -
Revista Da Associacao Medica Brasileira... 2010The evidence suggest that androgen deficiency in women induces sexual dysfunction as its main clinical manifestation, in particular reduced libido. However, other... (Review)
Review
The evidence suggest that androgen deficiency in women induces sexual dysfunction as its main clinical manifestation, in particular reduced libido. However, other factors may be involved in the genesis of this disease, such as interpersonal relationships, social stressors, physical inactivity and the partner. The prevalence of sexual problems among women ranges from 9 to 43% and, recently, many studies have reported that androgens are beneficial not only for women's sexual function, but also for mood disorders and vasomotor symptoms. This is why physicians should include androgen deficiency syndrome in their differential diagnosis, even in women with adequate estrogen levels. Our objective was to present the practical aspects of this disease, emphasizing diagnosis and focusing on treatment. This review searched PUBMED for publications from the last 51 years, up to May 2010, including consensus statements and expert opinions and identified 105 articles. We concluded that the androgen deficiency syndrome in women is overlooked in clinical practice. There is no consensus in the literature regarding diagnosis or treatment, including choice of drug, route of administration and time of application.
Topics: Androgens; Dehydroepiandrosterone; Dehydroepiandrosterone Sulfate; Female; Hormone Replacement Therapy; Humans; Menopause; Sexual Dysfunction, Physiological
PubMed: 21152832
DOI: 10.1590/s0104-42302010000500021 -
Asian Journal of Andrology 2014
Topics: Androgens; Humans; Male; Syndrome
PubMed: 24480923
DOI: 10.4103/1008-682X.122587