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Endocrine-related Cancer Aug 2014Prostate cancer is the second leading cause of death in adult males in the USA. Recent advances have revealed that the fatal form of this cancer, known as... (Review)
Review
Prostate cancer is the second leading cause of death in adult males in the USA. Recent advances have revealed that the fatal form of this cancer, known as castration-resistant prostate cancer (CRPC), remains hormonally driven despite castrate levels of circulating androgens. CRPC arises as the tumor undergoes adaptation to low levels of androgens by either synthesizing its own androgens (intratumoral androgens) or altering the androgen receptor (AR). This article reviews the major routes to testosterone and dihydrotestosterone synthesis in CRPC cells and examines the enzyme targets and progress in the development of isoform-specific inhibitors that could block intratumoral androgen biosynthesis. Because redundancy exists in these pathways, it is likely that inhibition of a single pathway will lead to upregulation of another so that drug resistance would be anticipated. Drugs that target multiple pathways or bifunctional agents that block intratumoral androgen biosynthesis and antagonize the AR offer the most promise. Optimal use of enzyme inhibitors or AR antagonists to ensure maximal benefits to CRPC patients will also require application of precision molecular medicine to determine whether a tumor in a particular patient will be responsive to these treatments either alone or in combination.
Topics: Dihydrotestosterone; Enzyme Inhibitors; Humans; Male; Prostatic Neoplasms, Castration-Resistant; Testosterone
PubMed: 24829267
DOI: 10.1530/ERC-14-0109 -
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 -
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 -
Journal of Endocrinological... Mar 2023The aim of this review is to discuss the role of androgens in the progression of endometrial carcinoma (EC) with particular focus on the different kinds of androgenic... (Review)
Review
PURPOSE
The aim of this review is to discuss the role of androgens in the progression of endometrial carcinoma (EC) with particular focus on the different kinds of androgenic hormones, androgen receptor (AR) and intracrine androgen metabolism.
METHODS
A comprehensive literature search within PubMed was performed. Selected publications related to androgens and EC were reviewed.
RESULTS
There are different kinds of androgenic hormones, and different kinds of androgens may have different effects. Elevated androgens (especially testosterone) have been associated with an increased EC risk in postmenopausal women. 5α-reductases (5α-Reds) and 17β-hydroxysteroid dehydrogenase type 2 (17βHSD2) pathway may inhibit the progression of EC mediated by dihydrotestosterone (DHT), but aromatases stimulate further progression of EC. The most of studies accessing the prognostic value of AR have found that AR expression may be a favorable prognostic indicator.
CONCLUSION
Androgens may have both oncogenic and tumor suppressive roles. Androgen-specific biases in metabolism and the expression of AR may contribute to the different prognosis of patients with EC.
Topics: Humans; Female; Androgens; Dihydrotestosterone; Endometrial Neoplasms; Receptors, Androgen; Testosterone
PubMed: 36583833
DOI: 10.1007/s40618-022-01916-1 -
The New Phytologist Oct 2023Progestogens and androgens have been found in many plants, but little is known about their biosynthesis and the evolution of steroidogenesis in these organisms. Here, we...
Progestogens and androgens have been found in many plants, but little is known about their biosynthesis and the evolution of steroidogenesis in these organisms. Here, we show that the occurrence and biosynthesis of progestogens and androgens are conserved across the viridiplantae lineage. An UHPLC-ESI-MS/MS method allowed high-throughput analysis of the occurrence and chemical conversion of progestogens and androgens in 41 species across the green plant lineage. Dehydroepiandrosterone, testosterone, and 5α-dihydrotestosterone are plants' most abundant mammalian-like steroids. Progestogens are converted into 17α-hydroxyprogesterone and 5α-pregnane-3,20-dione. Androgens are converted into testosterone and 5α-dihydrotestosterone. 17,20-Lyases, essential for converting progestogens to androgens, seem to be most effective in monocot species. Our data suggest that the occurrence of progestogens and androgens is highly conserved in plants, and their biosynthesis might favor a route using the Δ pathway.
Topics: Androgens; Dihydrotestosterone; Embryophyta; Progestins; Tandem Mass Spectrometry; Testosterone
PubMed: 37559351
DOI: 10.1111/nph.19163 -
Problemy Endokrinologii Mar 2021Today the problem of hyperandrogenism in women is a widely studied and discussed while same issue in relation to men is barely raised. In clinical practice,...
BACKGROUND
Today the problem of hyperandrogenism in women is a widely studied and discussed while same issue in relation to men is barely raised. In clinical practice, hyperandrogenism can be the cause of a number of diseases.
AIM
Provide characterization the variations of physiological hyperandrogenism in men.
MATERIALS AND METHODS
Сontinuous cross-sectional study of 100 men with hyperandrogenism. The study assessed the volume and structure of the prostate, the volume of the testicles; the levels of luteinizing hormone (LH), total testosterone, sex hormone binding globulin (SHBG) were determined with further calculation of the level of free testosterone according to Vermeullen, and dihydrotestosterone (DHT). Based on the results of the analysis of the hormonal status of patients with hyperandrogenism, 4 groups of patients were formed: 1-patients with increased total testosterone and SHBG levels; 2-patients with elevated total testosterone levels and normal SHBG levels; 3-patients with an increased level of total testosterone, DHT with a normal level of SHBG; 4-patients with an increased level of DHT with normal levels of total testosterone and SHBG. The difference between groups of patients was determined, a p-value <0.05 was considered statistically significant.
RESULTS
The age and volume of the prostate in group 1 patients were statistically significantly higher than in the other groups. This group, despite the high level of total testosterone, was not characterized by complaints of acne. Group 2 patients complained of acne more often, but the prevalence of this symptom even in this group was statistically significantly lower than in group 3 patients. At the same time, the frequency of occurrence of alopecia was statistically significantly lower in group 2 than in patients of both groups 3 and 4. Patients of group 3 had the most striking clinical manifestations of hyperandrogenism. Group 4 was characterized by alopecia.
CONCLUSION
An increase of androgen levels can be detected at any age. At the same time, in men of the older age group, an increase in the level of total testosterone may be due to an increase in the secretion of SHBG and not be accompanied by an increase in the level of free testosterone. In young patients, the clinical manifestations of hyperandrogenism may differ: patients with elevated DHT levels are characterized by androgenic alopecia; acne is common in men with elevated total and free testosterone levels, and increased DHT exacerbates the problem.
Topics: Aged; Cross-Sectional Studies; Dihydrotestosterone; Humans; Hyperandrogenism; Male; Sex Hormone-Binding Globulin; Testosterone
PubMed: 34004108
DOI: 10.14341/probl12732 -
Experimental Gerontology Mar 2023The effect of androgens on the cardiovascular system in humans is ambiguous. Moreover, still little is known about the effects of the most potent androgen,... (Comparative Study)
Comparative Study
INTRODUCTION
The effect of androgens on the cardiovascular system in humans is ambiguous. Moreover, still little is known about the effects of the most potent androgen, dihydrotestosterone, on arterial stiffness and endothelial function. The aim of this study was to evaluate whether age-dependent alterations in serum concentration of dihydrotestosterone and its circulating metabolite are accompanied by changes in endothelial function and arterial stiffness.
METHODS
In 12 young and 11 older men, basal serum concentrations of testosterone, dehydroepiandrosterone sulfate (DHAE-S), androstenedione (AE), dihydrotestosterone (DHT) and androstanediol glucuronide (ADG) were analyzed in relation to vascular status including cIMT - carotid intima media thickness, cAI - central augmentation index, crPWV - carotid radial pulse wave velocity, SI - stiffness index, endothelial and inflammatory markers.
RESULTS
Although concentration of testosterone was not different between young and older group, it was demonstrated that DHT, DHEA-S, AE and ADG were significantly lower in older men in comparison to young men (p < 0.01). Interestingly the most surprising difference was found for DHT concentration, that was as much as 61 % lower in aged men that displayed significantly higher values of cIMT, AI, crPWV and SI (p < 10), suggestive of arterial stiffness. Furthermore, DHT was negatively correlated to all arterial wall parameters (cAI, crPWV, SI and cIMT), c-reactive protein (CRP) and hyaluronic acid (HA) concentration, as well as positively correlated to markers of endothelial function (MNA and 6-keto-PGF) in all studied individuals (n = 23).
CONCLUSIONS
We have shown that ageing leads to a significant decrease in DHT concentration that is accompanied by impaired arterial wall characteristics and worsened endothelial function. Therefore more attention should be paid to the DHT, DHEA-S and ADG concentrations as a biomarkers for vascular dysfunction in ageing men.
Topics: Aged; Humans; Male; Androgens; Androstenedione; Carotid Arteries; Carotid Intima-Media Thickness; Dehydroepiandrosterone; Dihydrotestosterone; Pulse Wave Analysis; Vascular Stiffness; Adult; Aging
PubMed: 36693531
DOI: 10.1016/j.exger.2023.112104 -
The Journal of Clinical Endocrinology... Apr 2022Many effects of testosterone are mediated through dihydrotestosterone (DHT) and estradiol.
CONTEXT
Many effects of testosterone are mediated through dihydrotestosterone (DHT) and estradiol.
OBJECTIVE
To determine the relative contributions of each hormone to the observed effects of testosterone treatment in older men with hypogonadism.
METHODS
Using data from the Testosterone Trials, we assessed the association of changes in total testosterone, estradiol, and DHT levels over 12 months of testosterone treatment with hemoglobin, high-density lipoprotein (HDL) cholesterol, volumetric bone mineral density (vBMD) of lumbar spine, sexual desire, and prostate-specific antigen (PSA). We used random forests to model the associations of predicted mean changes in outcomes with change in each hormone at low, mean, or high change in the other 2 hormones. Stepwise regression models were run to confirm the findings of random forests.
RESULT
Predicted increases in hemoglobin and sexual desire were greater with larger increases in estradiol and were larger with high change in DHT compared with low change in DHT. Greater increases in estradiol were associated with larger decreases in HDL cholesterol; this association did not vary according to changes in DHT or testosterone. Change in vBMD was most robustly associated with change in estradiol and was greater with high change in testosterone and DHT. There was no consistent relation between change in PSA and change in any hormone.
CONCLUSION
Change in estradiol level was the best predictor not only of the change in vBMD and sexual desire but also of the changes in hemoglobin and HDL cholesterol. Consideration of testosterone, estradiol, and DHT together offers a superior prediction of treatment response in older hypogonadal men than testosterone alone.
Topics: Aged; Cholesterol, HDL; Dihydrotestosterone; Estradiol; Humans; Male; Prostate-Specific Antigen; Testosterone
PubMed: 35041751
DOI: 10.1210/clinem/dgac028