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Drug Metabolism and Disposition: the... Apr 2023Testosterone exhibits high variability in pharmacokinetics and glucuronidation after oral administration. Although testosterone metabolism has been studied for decades,...
Testosterone exhibits high variability in pharmacokinetics and glucuronidation after oral administration. Although testosterone metabolism has been studied for decades, the impact of UGT2B17 gene deletion and the role of gut bacterial -glucuronidases on its disposition are not well characterized. We first performed an exploratory study to investigate the effect of UGT2B17 gene deletion on the global liver proteome, which revealed significant increases in proteins from multiple biological pathways. The most upregulated liver proteins were aldoketoreductases [AKR1D1, AKR1C4, AKR7A3, AKR1A1, and 7-dehydrocholesterol reductase (DHCR7)] and alcohol or aldehyde dehydrogenases (ADH6, ADH1C, ALDH1A1, ALDH9A1, and ALDH5A). In vitro assays revealed that AKR1D1 and AKR1C4 inactivate testosterone to 5-dihydrotestosterone (5-DHT) and 3,5-tetrahydrotestosterone (3,5-THT), respectively. These metabolites also appeared in human hepatocytes treated with testosterone and in human serum collected after oral testosterone dosing in men. Our data also suggest that 5-DHT and 3α, 5-THT are then eliminated through glucuronidation by UGT2B7 in UGT2B17 deletion individuals. Second, we evaluated the potential reactivation of testosterone glucuronide (TG) after its secretion into the intestinal lumen. Incubation of TG with purified gut microbial -glucuronidase enzymes and with human fecal extracts confirmed testosterone reactivation into testosterone by gut bacterial enzymes. Both testosterone metabolic switching and variable testosterone activation by gut microbial enzymes are important mechanisms for explaining the disposition of orally administered testosterone and appear essential to unraveling the molecular mechanisms underlying UGT2B17-associated pathophysiological conditions. SIGNIFICANCE STATEMENT: This study investigated the association of UGT2B17 gene deletion and gut bacterial -glucuronidases with testosterone disposition in vitro. The experiments revealed upregulation of AKR1D1 and AKR1C4 in UGT2B17 deletion individuals, and the role of these enzymes to inactivate testosterone to 5-dihydrotestosterone and 3, 5-tetrahydrotestosterone, respectively. Key gut bacterial species responsible for testosterone glucuronide activation were identified. These data are important for explaining the disposition of exogenously administered testosterone and appear essential to unraveling the molecular mechanisms underlying UGT2B17-associated pathophysiological conditions.
Topics: Male; Humans; Dihydrotestosterone; Glucuronidase; Testosterone; Liver; Glucuronosyltransferase
PubMed: 36623880
DOI: 10.1124/dmd.122.000975 -
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 -
FASEB Journal : Official Publication of... May 2022Wound healing is a complex process involving multiple independent and overlapping sequential physiological mechanisms. In addition to cutaneous injury, a severe burn...
Wound healing is a complex process involving multiple independent and overlapping sequential physiological mechanisms. In addition to cutaneous injury, a severe burn stimulates physiological derangements that induce a systemic hypermetabolic response resulting in impaired wound healing. Topical application of the anti-androgen drug, flutamide accelerates cutaneous wound healing, whereas paradoxically systemic dihydrotestosterone (DHT) improves burn wound healing. We developed and characterized a PCL scaffold that is capable of controlled release of androgen (DHT) and anti-androgen (F) individually or together. This study aims to investigate whether local modification of androgen actions has an impact on burn injury wound healing. In a full-thickness burn wound healing, mouse model, DHT/F-scaffold showed a significantly faster wound healing compared with F-scaffold or DHT-scaffold. Histology analysis confirmed that DHT/F-scaffold exhibited higher re-epithelization, cell proliferation, angiogenesis, and collagen deposition. Dual release of DHT and F from PCL scaffolds promoted cell proliferation of human keratinocytes and alters the keratinocyte cell cycle. Lastly, no adverse effects on androgen-dependent organs, spleen and liver were observed. In conclusion, we demonstrated DHT plus F load PCL scaffolds accelerated burn wound healing when loading alone did not. These findings point to a complex role of androgens in burn wound healing and open novel therapeutic avenues for treating severe burn patients.
Topics: Androgen Antagonists; Androgens; Animals; Burns; Dihydrotestosterone; Flutamide; Humans; Mice; Polyesters; Tissue Scaffolds; Wound Healing
PubMed: 35394674
DOI: 10.1096/fj.202101803R -
Journal of Andrology 1992Androgen action in sexual tissues, especially skin and the prostate, is expressed by dihydrotestosterone (DHT) acting at the nuclear level. Dihydrotestosterone in the... (Review)
Review
Androgen action in sexual tissues, especially skin and the prostate, is expressed by dihydrotestosterone (DHT) acting at the nuclear level. Dihydrotestosterone in the circulation and target tissues is almost solely derived from the peripheral conversion of secreted testosterone (T) in men and androstenedione in women. The general pathway is testosterone----DHT in equilibrium with androstanediol (3 alpha diol). However, a number of studies suggest that blood DHT or 3 alpha diol are not reliable indicators of peripheral DHT formation. This is particularly suggested by discrepancies in the specific activity of DHT in blood and urine following infusion of labeled DHT, suggesting that total body DHT formation is not reflected by blood levels. Thus, DHT should be thought of as a paracrine hormone formed and acting primarily in target tissues. 3 alpha androstanediol glucuronide (3 alpha diol G) is a major metabolite of DHT. An important site of its formation is the skin. Levels in blood and urine are increased in hirsutism and acne, and blood levels closely parallel pubertal development. 3 alpha diol G levels are especially increased in adrenal disorders of androgenicity such as andrenogenital syndrome; it is also a good marker of response to therapy. Levels are reduced in various forms of male pseudohermaphroditism. 3 alpha androstanediol glucuronide appears to be the best marker available of DHT formation in target tissues such as skin.
Topics: Dihydrotestosterone; Humans
PubMed: 1551803
DOI: No ID Found -
Endocrinology Jul 2022Polycystic ovary syndrome (PCOS) is the most prevalent endocrinopathy in women. A common symptom of PCOS is hyperandrogenism (AE); however, the source of these androgens...
Polycystic ovary syndrome (PCOS) is the most prevalent endocrinopathy in women. A common symptom of PCOS is hyperandrogenism (AE); however, the source of these androgens is uncertain. Aldo-keto reductase family 1 member C3 (AKR1C3) catalyzes the formation of testosterone (T) and 5α-dihydrotestosterone (DHT) in peripheral tissues, which activate the androgen receptor (AR). AKR1C3 is induced by insulin in adipocytes and may be central in driving the AE in PCOS. We elucidated the conversion of both classical and 11-oxygenated androgens to potent androgens in a model of PCOS adipocytes. Using high-performance liquid chromatography (HPLC) discontinuous kinetic assays to measure product formation by recombinant AKR1C3, we found that the conversion of 11-keto-Δ4-androstene-3,17-dione (11K-4AD) to 11-ketotestosterone (11K-T) and 11-keto-5α-androstane-3,17-dione (11K-5AD) to 11-keto-5α-dihydrotestosterone (11K-DHT) were superior to the formation of T and DHT. We utilized a stable isotope dilution liquid chromatography high resolution mass spectrometric (SID-LC-HRMS) assay for the quantification of both classical and 11-oxygenated androgens in differentiated Simpson-Golabi-Behmel syndrome adipocytes in which AKR1C3 was induced by insulin. Adipocytes were treated with adrenal derived 11β-hydroxy-Δ4-androstene-3,17-dione (11β-OH-4AD), 11K-4AD, or Δ4-androstene-3,17-dione (4AD). The conversion of 11β-OH-4AD and 11K-4AD to 11K-T required AKR1C3. We also found that once 11K-T is formed, it is inactivated to 11β-hydroxy-testosterone (11β-OH-T) by 11β-hydroxysteroid dehydrogenase type 1 (HSD11B1). Our data reveal a unique role for HSD11B1 in protecting the AR from AE. We conclude that the 11-oxygenated androgens formed in adipocytes may contribute to the hyperandrogenic profile of PCOS women and that AKR1C3 is a potential therapeutic target to mitigate the AE of PCOS.
Topics: Adipocytes; Aldo-Keto Reductase Family 1 Member C3; Androgens; Androstenes; Dihydrotestosterone; Female; Humans; Insulin; Polycystic Ovary Syndrome; Testosterone
PubMed: 35560164
DOI: 10.1210/endocr/bqac068 -
The Journal of Clinical Investigation Oct 1979Previous studies have suggested that dihydrotestosterone accumulation in the prostate may be involved in the pathogenesis of prostatic hyperplasia in man and dog....
Previous studies have suggested that dihydrotestosterone accumulation in the prostate may be involved in the pathogenesis of prostatic hyperplasia in man and dog. However, the fact that the administration of 10 mg dihydrotestosterone/d to castrated, mongrel dogs (0.5 mg/kg body wt) causes little growth in the prostate, whereas identical doses of 3alpha- androstanediol regularly induce prostatic hyperplasia (> 14 g weight) has raised the possibility that the dihydrotestosterone accumulation may be the result rather than the cause of the pathology. To investigate the mechanism of this phenomenon, we measured the levels of dihydrotestosterone and 3alpha-androstanediol in prostates from 75 dogs. In both naturally occurring and 3alpha-androstanediol-induced prostatic hyperplasia, the levels of dihydrotestosterone were high (>5 ng/g), whereas in immature glands and glands from dihydrotestosterone-treated animals, levels were similar (2.1 and 2.6 ng/g, respectively). 3alpha-Androstanediol levels were no different in animals treated with dihydrotestosterone or 3alpha-androstanediol.Therefore, because exogenous 3alpha-androstanediol is a better precursor of prostatic dihydrotestosterone than exogenous dihydrotestosterone itself, the effects of treatment with larger doses (2.5 mg/kg per d) of dihydrotestosterone and 3alpha-androstanediol for 12 wk were examined. In these amounts, dihydrotestosterone was as effective as 3alpha-androstanediol in inducing the development of prostatic hyperplasia and in elevating prostatic dihydrotestosterone concentration. Because dihydrotestosterone accumulates in spontaneous prostatic hyperplasia, because the administration of sufficient amounts of dihydrotestosterone to the castrated dog can induce the development of prostatic hyperplasia, and because 3alpha-androstanediol induces the development of hyperplasia via conversion to dihydrotestosterone, we conclude that accumulation of dihydrotestosterone is the cause of canine prostatic hyperplasia.
Topics: Androstenediols; Animals; Castration; Dihydrotestosterone; Dog Diseases; Dogs; Male; Prostate; Prostatic Hyperplasia; Testosterone; Time Factors
PubMed: 90055
DOI: 10.1172/JCI109536 -
Asian Journal of Andrology Jul 2007The epididymis is critically dependent on the presence of the testis. Although several hormones, such as retinoids and progestins, and factors secreted directly into the... (Review)
Review
The epididymis is critically dependent on the presence of the testis. Although several hormones, such as retinoids and progestins, and factors secreted directly into the epididymal lumen, such as androgen binding protein and fibroblast growth factor, might play regulatory roles in epididymal function, testosterone (T) and its metabolites, dihydrotestosterone (DHT) and estradiol (E2), are accepted as the primary regulators of epididymal structure and functions, with the former playing the greater role. To ascertain the molecular action of androgens on the epididymis, three complementary approaches were pursued to monitor changes in gene expression in response to different hormonal milieux. The first was to establish changes in gene expression along the epididymis as androgenic support is withdrawn. The second was to determine the sequence of responses that occur in an androgen deprived tissue upon re-administration of the two metabolites of T, DHT and E2. The third was to study the effects of androgen withdrawal and re-administration on gene expression in immortalized murine caput epididymidal principal cells. Specific responses were observed under each of these conditions, with an expected major difference in the panoply of genes expressed upon hormone withdrawal and re-administration; however, some key common features were the common roles of genes in insulin like growth factor/epidermal growth factor and the relatively minor and specific effects of E2 as compared to DHT. Together, these results provide novel insights into the mechanisms of androgen regulation in epididymal principal cells.
Topics: Androgens; Animals; Dihydrotestosterone; Embryo, Mammalian; Epididymis; Estradiol; Female; Gene Expression Regulation; Humans; Leydig Cells; Male; Placenta; Pregnancy; Rats; Rats, Inbred BN; Testosterone
PubMed: 17589794
DOI: 10.1111/j.1745-7262.2007.00316.x -
American Journal of Physiology.... Dec 2019Androgens exert important effects both in androgen-responsive tissues and in the intestinal tract. To determine the impact of the gut microbiota (GM) on intestinal...
Androgens exert important effects both in androgen-responsive tissues and in the intestinal tract. To determine the impact of the gut microbiota (GM) on intestinal androgen metabolism, we measured unconjugated (free) and glucuronidated androgen levels in intestinal contents from the small intestine, with a low bacterial density, and from cecum and colon, with a high bacterial density. Using a specific, sensitive gas chromatography-tandem mass spectrometry method, we detected high levels of glucuronidated testosterone (T) and dihydrotestosterone (DHT) in small intestinal content of mice of both sexes, whereas in the distal intestine we observed remarkably high levels of free DHT, exceeding serum levels by >20-fold. Similarly, in young adult men high levels of unconjugated DHT, >70-fold higher than in serum, were detected in feces. In contrast to mice with a normal GM composition, germ-free mice had high levels of glucuronidated T and DHT, but very low free DHT levels, in the distal intestine. These findings demonstrate that the GM is involved in intestinal metabolism and deglucuronidation of DHT and T, resulting in extremely high free levels of the most potent androgen, DHT, in the colonic content of young and healthy mice and men.
Topics: 3-Oxo-5-alpha-Steroid 4-Dehydrogenase; Androgens; Animals; Cecum; Colon; Dihydrotestosterone; Feces; Female; Gas Chromatography-Mass Spectrometry; Gastrointestinal Microbiome; Gene Expression; Germ-Free Life; Humans; Intestinal Mucosa; Intestine, Small; Male; Mice; Testosterone; Young Adult
PubMed: 31689143
DOI: 10.1152/ajpendo.00338.2019 -
Molecules (Basel, Switzerland) Feb 2024β-Nicotinamide mononucleotide (NMN) has shown promising effects on intestinal health, and it is extensively applied as an anti-aging and Alzheimer's disease...
β-Nicotinamide mononucleotide (NMN) has shown promising effects on intestinal health, and it is extensively applied as an anti-aging and Alzheimer's disease therapeutic, due to its medicinal properties. The effects of NMN on the growth of mouse hair were observed after hair removal. The results indicated that NMN can reverse the state of hair follicle atrophy, hair thinning, and hair sparsity induced by dihydrotestosterone (DHT), compared to that of minoxidil. In addition, the action mechanisms of NMN promoting hair growth in cultured human dermal papilla cells (HDPCs) treated with DHT were investigated in detail. The incubation of HDPCs with DHT led to a decrease in cell viability and the release of inflammatory mediators, including interleukin-6 (IL-6), interleukin-1Beta (IL-1β) and tumor necrosis factor Alpha (TNF-α). It was found that NMN can significantly lower the release of inflammatory factors induced by DHT in HDPCs. HDPCs cells are protected from oxidative stress damage by NMN, which inhibits the NF-κB p65 inflammatory signaling pathway. Moreover, the levels of androgen receptor (AR), dickkopf-1 (DKK-1), and β-catenin in the HDPCs were assessed using PCR, indicating that NMN can significantly enhance the expression of VEGF, reduced IL-6 levels and suppress the expression of AR and DKK-1, and notably increase β-catenin expression in DHT-induced HDPCs.
Topics: Animals; Mice; Humans; beta Catenin; Nicotinamide Mononucleotide; Interleukin-6; Hair; Hair Follicle; Dihydrotestosterone; Cell Proliferation; Oxidative Stress
PubMed: 38398550
DOI: 10.3390/molecules29040798 -
European Thyroid Journal Jun 2023There is increasing evidence that thyroid hormones (THs) work in an integrative fashion with androgen receptors (ARs) to regulate gonadal differentiation and... (Review)
Review
There is increasing evidence that thyroid hormones (THs) work in an integrative fashion with androgen receptors (ARs) to regulate gonadal differentiation and reproductive function. Studies reveal that THs have interactions with the AR promoter region and increase AR expression. THs also have a role in the regulation of enzymes involved in the biosynthesis of androgens, such as 5α-reductase, which is essential in the conversion of testosterone into its active form, 5α-dihydrotestosterone. Additionally, the presence of androgen response elements in the promoter regions of TH-related genes, such as deiodinases and TH receptor isoforms, has been identified in some vertebrates, indicating a mutual interaction between THs and ARs. Since the androgen signaling pathway, mediated by ARs, plays a key role in the formation and progression of prostate cancer (PCa), the existence of crosstalk between THs and ARs supports the epidemiologic and experimental evidence indicating a relationship between the high incidence of PCa and hyperthyroidism. This article aims to review the role of androgen-TH crosstalk in PCa and its implication in clinical management. As life expectancy is growing these days, it can increase the number of patients with PCa and the critical relevance of the disease. In order to gain better knowledge about PCa and to improve clinical management, it is essential to get better insight into the key factors related to the formation and progression of this cancer.
Topics: Male; Animals; Humans; Androgens; Prostatic Neoplasms; Thyroid Hormones; Receptors, Androgen; Dihydrotestosterone
PubMed: 36930264
DOI: 10.1530/ETJ-22-0228