Metabolism of dihydrotestosterone to 5α-androstane-3α,17β-dioI glucuronide is greater in the peripheral compartment than in the splanchnic compartment

Duffy, Daniel M.; Legro, Richard S.; Chang, Luke L. Y.; Stanczyk, Frank Z.; Løbo, Rogerio A.

doi:10.1016/s0015-0282(16)57848-0

Cited by 19 publications

(6 citation statements)

References 11 publications

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“…Metabolism of DHT was substantially greater in adipose tissue compared with T, and there was little conversion of T to DHT in muscle. Metabolism of intravenously administered DHT compared with transdermally applied DHT revealed that skin is a major site of peripheral DHT metabolism to 3 α -androstanediol, whereas intravenously-administered DHT yielded greater concentrations of 3 α -androstanediol-glucuronide (45). Splanchnic tissues have a high capacity to metabolize DHT to DHT-glucuronide, which has importance when oral androgens like T undecanoate (TU) are administered (46).…”

Section: Overview Of Dht Biochemistry/physiologymentioning

confidence: 99%

Dihydrotestosterone: Biochemistry, Physiology, and Clinical Implications of Elevated Blood Levels

Swerdloff¹,

et al. 2017

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Benefits associated with lowered serum DHT levels after 5α-reductase inhibitor (5AR-I) therapy in men have contributed to a misconception that circulating DHT levels are an important stimulus for androgenic action in target tissues (e.g., prostate). Yet evidence from clinical studies indicates that intracellular concentrations of androgens (particularly in androgen-sensitive tissues) are essentially independent of circulating levels. To assess the clinical significance of modest elevations in serum DHT and the DHT/testosterone (T) ratio observed in response to common T replacement therapy, a comprehensive review of the published literature was performed to identify relevant data. Although the primary focus of this review is about DHT in men, we also provide a brief overview of DHT in women. The available published data are limited by the lack of large, well-controlled studies of long duration that are sufficiently powered to expose subtle safety signals. Nonetheless, the preponderance of available clinical data indicates that modest elevations in circulating levels of DHT in response to androgen therapy should not be of concern in clinical practice. Elevated DHT has not been associated with increased risk of prostate disease (e.g., cancer or benign hyperplasia) nor does it appear to have any systemic effects on cardiovascular disease safety parameters (including increased risk of polycythemia) beyond those commonly observed with available T preparations. Well-controlled, long-term studies of transdermal DHT preparations have failed to identify safety signals unique to markedly elevated circulating DHT concentrations or signals materially different from T.

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Section: Overview Of Dht Biochemistry/physiologymentioning

confidence: 99%

Dihydrotestosterone: Biochemistry, Physiology, and Clinical Implications of Elevated Blood Levels

Swerdloff¹,

et al. 2017

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“…The isoforms are NAD(P)(H)-dependent and convert 5α-dihydrotestosterone (17beta-hydroxy-5alpha-androstan-3-one [5α-DHT]) to yield 5α-androstane-3α, 17β-diol; [3α-Diol]). At present, different isoforms of 3α-HSD have been found in liver, prostate, mammary glands, uterus, brain, and skin [78,79]. In the oxidation direction, only AKR1C2, which is found in the brain, is able to convert 3α-Diol to 5α-DHT.…”

Section: Hypothesismentioning

confidence: 99%

Proposed mechanism for sperm chromatin condensation/decondensation in the male rat

Chapman

Michael

2003

Reprod Biol Endocrinol

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Condensation of sperm chromatin occurs after spermatozoa have left the caput epididymis and are in transit to the cauda epididymis, during which time large numbers of disulfide bonds are formed. The formation of these disulfide bonds requires the repeated oxidation of the cofactor, NAD(P)H. To date, the means by which this oxidation is achieved has yet to be elucidated. Spermatozoa lose the bulk of their cytoplasm prior to leaving the testis; and, as a result, any shuttle systems for removing and transferring reducing equivalents into the mitochondria are unlikely to be operational. In an apparent preparation for the loss of cytoplasm, however, the following events occur during spermatogenesis. First, androgen-binding protein (ABP) is produced by the Sertoli cells of the testis; second, high affinity binding sites for ABP are inserted into the membrane surrounding the nucleus; and third, a nuclear location is acquired for the enzyme, 3α-hydroxysteroid dehydrogenase (3α-HSD).We propose that after the loss of cytoplasm, the nuclear region of spermatozoa is directly accessible to constituents contained in the lumen of the caput epididymis. As a consequence, luminal ABP attaches itself to the nuclear membrane via its binding sites, and is internalized. After internalization, ABP exerts its principle function, which is to bind to luminal 5α-dihydrotestosterone (5α-DHT), thereby ensuring its availability to the enzyme, 3α-HSD. In the conversion of 5α-DHT to 3α-androstanediol (3α-Diol), NAD(P)H is oxidized. Spermatozoa that reach the cauda epididymis have fully condensed chromatin. In addition, the nuclear region retains appreciable amounts of 5α-DHT and 3α-Diol, both bound to ABP. During fertilization, the bound 3α-Diol is converted back to 5α-DHT, reducing equivalents are transferred to NAD(P) + , and disulfide bonds are broken.IVF clinics report that spermatozoa with incompletely condensed chromatin have a low percentage of fertilization. If our proposed mechanism for chromatin condensation/decondensation is borne out by further research, IVF clinics might consider preincubating spermatozoa with 5α-DHT in order to increase the efficiency of fertilization.

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“…The aim of this study was to determine whether clinical and anthropometric body size measurements were associated with serum hormone (testosterone, estradiol and androstanediol glucuronide (3-alpha-diol-G)) and sex-hormone binding globulin (SHBG) levels within a representative sample of US men aged 20-99 years. SHBG is the major carrier of testosterone and estradiol in circulation and was used to calculate levels of free testosterone and free estradiol; 3-alpha-diol-G, a major metabolite of dihydroxytestosterone, is a correlate of tissue androgen levels [11]. …”

mentioning

confidence: 99%

Relationship of sex steroid hormones with body size and with body composition measured by dual-energy X-ray absorptiometry in US men

Trabert

Graubard

Nyante

et al. 2012

Cancer Causes Control

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Purpose To evaluate the association of body size – captured via whole body dual-energy x-ray absorptiometry (DXA) and physical measurement – with serum sex steroid hormones and sex hormone binding globulin (SHBG) we utilized cross-sectional data and serum samples from the National Health and Nutrition Examination Survey (NHANES; 1999-2004). Methods Testosterone, androstanediol glucuronide (3-alpha-diol-G), estradiol and SHBG were measured via immunoassay in serum samples from a total of 898 adult men (ages 20-90) participating in the morning examination. As part of the NHANES data collection DXA scans and measurements of weight, height and waist circumference were performed by trained staff. Linear regression was used to estimate associations between body size and hormone levels adjusted for potential confounders and NHANES sampling procedures. Results Total bone area (cm2) was inversely associated with total testosterone (ng/mL) [beta=-0.12; p-value<0.01], while bone mineral density (g/cm2) was inversely associated with SHBG (nmol/L) [beta=-17.16; p-value=0.01]. Increased percent body fat was associated with lower concentrations of total testosterone [beta=-0.16; p-value<0.01] and SHBG [beta=-1.11; p-value<0.01] and higher concentrations of free estradiol (fg/mL) [beta=12.52; p-value<0.01]. Conclusions Clinical measures of body fat (measured via DXA scan) and anthropometric measures of body fat (BMI and waist circumference) provided similar inferences regarding the association between increased body fat and hormone levels in men. Increased body fat was associated with lower circulating levels of testosterone (total and free) and SHBG and higher circulating levels of free estradiol in men, while decreased bone mineral density was associated with higher circulating levels of SHBG.

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Metabolism of dihydrotestosterone to 5α-androstane-3α,17β-dioI glucuronide is greater in the peripheral compartment than in the splanchnic compartment

Cited by 19 publications

References 11 publications

Dihydrotestosterone: Biochemistry, Physiology, and Clinical Implications of Elevated Blood Levels

Dihydrotestosterone: Biochemistry, Physiology, and Clinical Implications of Elevated Blood Levels

Proposed mechanism for sperm chromatin condensation/decondensation in the male rat

Relationship of sex steroid hormones with body size and with body composition measured by dual-energy X-ray absorptiometry in US men

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