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Clinica Chimica Acta; International... Jun 2022Hirsutism is the excessive growth of terminal hair in a male pattern in a female. In most hirsute women, hirsutism is caused by increased androgens. However, not all... (Review)
Review
BACKGROUND
Hirsutism is the excessive growth of terminal hair in a male pattern in a female. In most hirsute women, hirsutism is caused by increased androgens. However, not all women with hirsutism actually show elevated levels of circulating androgens with standard laboratory tests, in which case we speak of idiopathic hirsutism (IH).
OBJECTIVES
The aim of this paper is to investigate whether there are biochemical markers that can be used to unravel the cause in IH.
METHODS
An electronic search through the PubMed database was conducted to find studies describing potential biomarkers for IH.
RESULTS
The majority of included studies claimed an increased 5α-reductase (5α-RD) activity in women with IH by means of increased DHT metabolite levels. Studies investigating abnormalities of the androgen receptor (AR) and serum levels of indirect markers showed no significant differences.
CONCLUSIONS
Our literature search showed that polymorphisms of the AR as well as indirect markers seem to be nonspecific, but that the dihydrotestosterone-reduced metabolite 5α-androstane-3α,17β-diol glucuronide is markedly enhanced in women with IH, suggesting an increased 5α-RD activity in these women. Further studies need to be performed to determine the clinical usefulness of 3α-diol G as a biomarker for IH.
Topics: Androgens; Androstane-3,17-diol; Dihydrotestosterone; Female; Hirsutism; Humans; Testosterone
PubMed: 35292252
DOI: 10.1016/j.cca.2022.03.011 -
The Journal of Clinical Endocrinology... Nov 2023Epidemiological and preclinical data support cardiovascular, mainly protective, effects of sex steroids in men, but the mechanisms underlying the cardiovascular actions...
CONTEXT
Epidemiological and preclinical data support cardiovascular, mainly protective, effects of sex steroids in men, but the mechanisms underlying the cardiovascular actions of sex steroids are poorly understood. Vascular calcification parallels the development of atherosclerosis, but is increasingly recognized as a diversified, highly regulated process, which itself may have pathophysiological importance for clinical cardiovascular events.
OBJECTIVE
To investigate the association between serum sex steroids and coronary artery calcification (CAC) in elderly men.
METHODS
We used gas chromatography tandem mass spectrometry to analyze a comprehensive sex steroid profile, including levels of dehydroepiandrosterone (DHEA), androstenedione, estrone, testosterone, estradiol, and dihydrotestosterone, in men from the population-based AGES-Reykjavik study (n = 1287, mean 76 years). Further, sex hormone-binding globulin (SHBG) was assayed and bioavailable hormone levels calculated. CAC score was determined by computed tomography. The main outcome measures were cross-sectional associations between dehydroepiandrosterone, androstenedione, estrone, testosterone, dihydrotestosterone, and estradiol and quintiles of CAC.
RESULTS
Serum levels of DHEA, androstenedione, testosterone, dihydrotestosterone, and bioavailable testosterone showed significant inverse associations with CAC, while estrone, estradiol, bioavailable estradiol, and SHBG did not. DHEA, testosterone, and bioavailable testosterone remained associated with CAC after adjustment for traditional cardiovascular risk factors. In addition, our results support partially independent associations between adrenal-derived DHEA and testes-derived testosterone and CAC.
CONCLUSION
Serum levels of DHEA and testosterone are inversely associated with CAC in elderly men, partially independently from each other. These results raise the question whether androgens from both the adrenals and the testes may contribute to male cardiovascular health.
Topics: Aged; Humans; Male; Androstenedione; Coronary Artery Disease; Dehydroepiandrosterone; Dihydrotestosterone; Estradiol; Estrone; Sex Hormone-Binding Globulin; Testosterone; Vascular Calcification
PubMed: 37391895
DOI: 10.1210/clinem/dgad351 -
Frontiers in Endocrinology 2023Recent evidence support that androgens play an important role in the etiology of endometrial cancer (EC). Adrenal-derived 11-oxygenated androgens are highly potent...
CONTEXT
Recent evidence support that androgens play an important role in the etiology of endometrial cancer (EC). Adrenal-derived 11-oxygenated androgens are highly potent agonists of the androgen receptor (AR), comparable to testosterone (T) and dihydrotestosterone (DHT) that have not been studied in the context of EC.
METHODOLOGY
We studied a cohort of 272 newly diagnosed postmenopausal EC cases undergoing surgical treatment. Circulating concentrations of seven 11-oxygenated androgens including precursors, potent androgens and their metabolites were established in serum samples collected before and 1 month after surgery using a validated liquid chromatography tandem mass spectrometry method (LC-MS/MS). Free (unconjugated) and total (free + sulfate and glucuronide conjugates following enzymatic hydrolysis) were analyzed in relation to clinicopathological features, recurrence and disease-free survival (DFS).
RESULTS
Levels of 11-oxygenated androgens were weakly correlated to those of canonical androgens such as testosterone (T) and dihydrotestosterone (DHT), with no evidence of their association with clinicopathological features. Levels of 11-oxygenated androgens declined after surgery but remained higher in overweight and obese compared to normal weight cases. Higher levels of preoperative free 11-ketoandrosterone (11KAST) were associated with an increased risk of recurrence (Hazard ratio (HR) of 2.99 (95%CI=1.09-8.18); =0.03). Postoperative free 11β-hydroxyandrosterone (11OHAST) levels were adversely associated with recurrence and DFS (HR = 3.23 (1.11-9.40); =0.03 and 3.27 (1.34-8.00); =0.009, respectively).
CONCLUSION
11-oxygenated androgen metabolites emerge as potential prognostic markers of EC.
Topics: Humans; Female; Androgens; Dihydrotestosterone; Chromatography, Liquid; Tandem Mass Spectrometry; Testosterone; Endometrial Neoplasms
PubMed: 37288302
DOI: 10.3389/fendo.2023.1156680 -
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 -
Cell Biology International Apr 2022The predominance of cardiovascular diseases among men compared to premenopausal women has been attributed to testosterone, which is implicated in vascular remodeling....
The predominance of cardiovascular diseases among men compared to premenopausal women has been attributed to testosterone, which is implicated in vascular remodeling. Molecular mechanisms underlying its role have not been clarified but oxidative stress-induced inflammation may be important. We therefore investigated in vitro the effects of testosterone and dihydrotestosterone, (a nonaromatized androgen), on redox homeostasis in absence (basal conditions) and after corticotropin-releasing hormone-induced pro-oxidant action in macroendothelial cells. More specifically, we explored their role on well-established antioxidant enzymes activity, namely endothelial nitric oxide synthase, superoxide dismutase, catalase, and glutathione. We observed that both androgens significantly increased the intracellular reactive oxygen species levels, endothelial nitric oxide synthase activity, nitric oxide concentration as well as superoxide dismutase activity and decreased catalase activity. These effects of Testosterone and DHT were reversed in the presence of the androgen receptor antagonist, flutamide. Moreover, testosterone and dihydrotestosterone similarly enhanced the stimulatory effect of corticotropin-releasing hormone on intracellular reactive oxygen species levels and superoxide dismutase activity but did not influence the inhibitory effect on endothelial nitric oxide synthase activity, nitric oxide release and catalase activity. Finally, androgens did not have a detectable effect on glutathione levels or the glutathione/glutathione plus glutathione disulfide ratio. Our results reveal that testosterone and DHT rise the intracellular redox threshold of the endothelial cell and increases NO synthesis. These findings suggest that the action of testosterone is affected by the redox status of the endothelium and help to explain its controversial effects on the cardiovascular system.
Topics: Dihydrotestosterone; Endothelium; Endothelium, Vascular; Female; Homeostasis; Humans; Male; Nitric Oxide; Oxidation-Reduction; Testosterone
PubMed: 35066972
DOI: 10.1002/cbin.11768 -
European Urology Open Science Jun 2023Finasteride competitively inhibits 5α-reductase (5-AR) isoenzymes, which blocks dihydrotestosterone (DHT) production, thereby reducing DHT. Finasteride is used in the...
UNLABELLED
Finasteride competitively inhibits 5α-reductase (5-AR) isoenzymes, which blocks dihydrotestosterone (DHT) production, thereby reducing DHT. Finasteride is used in the management of benign prostatic hyperplasia (BPH) and androgenic alopecia. Amid patient reports of suicidal ideation (SI), the Post Finasteride Syndrome advocacy group has petitioned for either a stop to selling of the drug or advertisement of stronger warnings. The US Food and Drug Administration recently added SI to the adverse effects listed for finasteride. Here we provide a brief but comprehensive review of the literature on the psychological side effects of 5-AR inhibitors (5-ARIs) to provide an opinion to help in guiding treating urologists. Most of the current evidence, obtained from the literature on dermatology, suggests that 5-ARI users experience a higher rate of depressive symptoms. However, given the lack of comprehensive randomised studies, the causal link between finasteride and SI remains unclear. Urologists prescribing 5-ARIs should be aware of the recent addition of suicide and SI risk to the list of side effects. A mental health screen should be performed and appropriate resources provided to patients commencing treatment. Furthermore, a review should be arranged with the general practitioner to assess new-onset mental health or SI symptoms.
PATIENT SUMMARY
We provide recommendations for urologists who prescribe finasteride for the treatment of benign prostate enlargement. Urologists should be aware of the recent addition of suicidal ideation to the list of side effects for this drug. Finasteride prescription should be continued; however, we recommend a detailed medical history to screen for prior mental health and personality disorders, with discontinuation of the medication in patients with new onset of depression or suicidal symptoms. Close liaison with the patient's general practitioner is vital for management of depressive or suicidal symptoms.
PubMed: 37182121
DOI: 10.1016/j.euros.2023.04.009 -
Cell Communication and Signaling : CCS Mar 2024Prostatitis is a highly prevalent condition that seriously affects men's physical and mental health. Although epidemiological investigations have provided evidence of a...
PURPOSE
Prostatitis is a highly prevalent condition that seriously affects men's physical and mental health. Although epidemiological investigations have provided evidence of a correlation between insufficient sleep and prostatitis, the pathogenesis of prostatitis remains unclear. We sought to identify the underlying mechanism involved and identify a promising therapeutic target.
METHODS
Sleep deprivation (SD) was utilized to establish a mouse model of insufficient sleep in a special device. Prostatitis was observed at different time points post-SD. The degree of prostatitis was evaluated by pathological section and behavioural tests. Using immunofluorescence, western blot, and proteomic analyses, the underlying mechanism of SD-related prostatitis was investigated, and the development and therapeutic target of prostatitis were elucidated.
RESULTS
SD, as an initial pathological trigger, resulted in a reduction in dihydrotestosterone and melatonin levels. Proteomic analysis revealed that the cGAS-STING pathway may play a significant role in inducing prostatitis. The subsequent results illustrated that the dual reduction in dihydrotestosterone and melatonin led to an accumulation of reactive oxygen species and the release of mitochondrial DNA (mt-DNA). The accumulation of mt-DNA activated the cGAS-STING pathway, which recruited inflammatory cells into the prostatic stroma through the secretion of interferon-β. Consequently, an inflammatory microenvironment was formed, ultimately promoting the development of prostatitis. Notably, mice with SD-induced prostatitis gradually recovered to a normal state within 7 days of recovery sleep. However, after being subjected to SD again, these mice tended to have a more pronounced manifestation of prostatitis within a shorter timeframe, which suggested that prostatitis is prone to relapse.
CONCLUSIONS
The cGAS-STING pathway activated by dual deficiency of dihydrotestosterone and melatonin plays a comprehensive inflammatory role in SD-related prostatitis. This research provides valuable insights into the pathogenesis, therapeutic targets, and prevention strategies of prostatitis.
Topics: Humans; Male; Animals; Mice; Sleep Deprivation; Dihydrotestosterone; Melatonin; Prostatitis; Proteomics; Sleep; DNA, Mitochondrial; Nucleotidyltransferases
PubMed: 38491517
DOI: 10.1186/s12964-024-01554-5 -
International Journal of Sports... Nov 2021To establish if training volume was associated with androgen baselines and androgen responsiveness to acute exercise.
PURPOSE
To establish if training volume was associated with androgen baselines and androgen responsiveness to acute exercise.
METHODS
During a "high-volume" training phase, 28 cyclists (14 men and 14 women) undertook oxygen-uptake and maximal-work-capacity testing. Two days later, they completed a repeat-sprint protocol, which was repeated 3 weeks later during a "low-volume" phase. Blood and saliva samples were collected before and after (+5 and +60 min) the repeat-sprint protocol. Blood was assayed for total testosterone (TT), free testosterone (FT), and dihydrotestosterone (DHT) and saliva, for testosterone and DHT.
RESULTS
Pretrial TT, FT, and DHT concentration was greater for males (P < .001, large effect size differences), and in both genders TT, DHT, and saliva for DHT was higher during high-volume loading (moderate to large effect size). Area-under-the-curve analysis revealed larger TT, FT, and DHT responses to the repeat-sprint protocol among females, and high-volume training was linked to larger TT, DHT, and saliva for DHT responses (moderate to large effect size). Baseline TT and FT correlated with oxygen uptake and work capacity in both genders (P < .05).
CONCLUSION
DHT showed no acute performance correlation but was responsive to volume of training, particularly in females. This work informs on timelines and relationships of androgenic biomarkers in males and females across different training loads, adding to the complexity that should be considered in interpretation thereof. The authors speculate that testosterone may impact acute performance via behavioral mechanisms of motivation and attention; DHT, via training volume-induced androgenic promotion, may facilitate long-term adaptive changes, especially for females.
Topics: Athletes; Dihydrotestosterone; Exercise; Female; Humans; Male; Testosterone
PubMed: 33952710
DOI: 10.1123/ijspp.2020-0910 -
Reproductive Sciences (Thousand Oaks,... Apr 2020Paracrine interactions between ovarian theca-interstitial cells (TICs) and granulosa cells (GCs) play an important role in the regulation of follicular steroidogenesis....
Paracrine interactions between ovarian theca-interstitial cells (TICs) and granulosa cells (GCs) play an important role in the regulation of follicular steroidogenesis. Androgens serve as substrates for aromatization as well as affect GC function. This study evaluated the effects of co-culture of GC with TICs and the role of testosterone (T) and 5-alpha-dihydrotestosterone (DHT), and estradiol (E2) in modulation of GC expression of genes involved in the production of progesterone: 3β-hydroxysteroid dehydrogenase/Δ isomerase (Hsd3b) and cholesterol side-chain cleavage (Cyp11). GCs obtained from immature Sprague-Dawley rats and were cultured in chemically defined media without or with TICs, DHT, or T. Hsd3b and Cyp11 transcripts were analyzed by qt-PCR. Co-culture of GCs with TICs stimulated Hsd3b and CYP11 expression in GCs. DHT and T induced a concentration-dependent upregulation of Hsd3b and CYP11 expression, as well as increased progesterone concentrations in spent media. E2 also increased expression of Hsd3b, and Cyp11. Effects of androgens were abrogated in the presence of an anti-androgen bicalutamide and the antiestrogen ICI 182780 (ICI). In conclusion, present findings demonstrate that androgens upregulate production of progesterone in GCs; these effects are likely due to a combination of direct action on androgen receptors and effects mediated by estrogen receptors.
Topics: Androgens; Animals; Cells, Cultured; Dihydrotestosterone; Estradiol; Female; Granulosa Cells; RNA, Messenger; Rats, Sprague-Dawley; Testosterone; Theca Cells
PubMed: 31916094
DOI: 10.1007/s43032-019-00099-0 -
Drug Testing and Analysis Apr 2022The ready detectability of synthetic androgens by mass spectrometry (MS)-based antidoping tests has reoriented androgen doping to using testosterone (T), which must be...
The ready detectability of synthetic androgens by mass spectrometry (MS)-based antidoping tests has reoriented androgen doping to using testosterone (T), which must be distinguished from its endogenous counterpart making detection of exogenous T harder. We investigated urine and serum steroid and hematological profiling individually and combined to determine the optimal detection model for T administration in women. Twelve healthy females provided six paired blood and urine samples over 2 weeks prior to treatment consisting of 12.5-mg T in a topical transdermal gel applied daily for 7 days. Paired blood and urine samples were then obtained at the end of treatment and Days 1, 2, 4, 7, and 14 days later. Compliance with treatment and sampling was high, and no adverse effects were reported. T treatment significantly increased serum and urine T, serum dihydrotestosterone (DHT), urine 5α-androstane-3α,17β-diol (5α-diol) epitestosterone (E), and urine T/E ratio with a brief window of detection (2-4 days) as well as total and immature (medium and high fluorescence) reticulocytes that remained elevated over the full 14 posttreatment days. Carbon isotope ratio MS and the OFF score and Abnormal Blood Profile score (ABPS) were not discriminatory. The optimal multivariate model to identify T exposure combined serum T, urine T/E ratio with three hematological variables (% high fluorescence reticulocytes, mean corpuscular hemoglobin, and volume) with the five variables providing 93% correct classification (4% false positive, 10% false negatives). Hence, combining select serum and urine steroid MS variables with reticulocyte measures can achieve a high but imperfect detection of T administration to healthy females.
Topics: Androgens; Dihydrotestosterone; Doping in Sports; Epitestosterone; Female; Humans; Steroids; Testosterone
PubMed: 34811948
DOI: 10.1002/dta.3202