Disease relevance of dihydrotestosterone

• Male pseudohermaphroditism presumably due to target organ unresponsiveness to androgens. Deficient 5alpha-dihydrotestosterone binding in cultured skin fibroblasts [1].
• Maximum specific 5alpha-dihydrotestosterone (DHT) binding activity (Bmax) had been measured in intact confluent monolayers representing fibroblast strains derived form nongenital and genital (labium majus) skin of normal individuals and of 11 patients fulfilling the clinicogenetic criteria of complete testicular feminization (TF) [1].
• Androgen [5alpha-dihydrotestosterone (DHT)] stimulation of LNCaP prostate cancer cells, which have constitutive phosphatidylinositol 3-kinase (PI3K)/Akt pathway activation due to PTEN loss, caused increased expression of cyclin D1, D2, and D3 proteins, retinoblastoma protein hyperphosphorylation, and cell cycle progression [2].
• Inhibition of cell cycle kinetics and proliferation by the androgen 5 alpha-dihydrotestosterone and antiestrogen N,n-butyl-N-methyl-11-[16' alpha-chloro-3',17 beta-dihydroxy-estra-1',3',5'-(10')triene-7' alpha-yl] undecanamide in human breast cancer ZR-75-1 cells [3].
• The androgen receptor (AR), when complexed with 5alpha-dihydrotestosterone (DHT), supports the survival and proliferation of prostate cells, a process critical for normal development, benign prostatic hypertrophy, and tumorigenesis [4].

Psychiatry related information on dihydrotestosterone

• Hemispheric specialization for the control of copulation in the young chick and effects of 5 alpha-dihydrotestosterone and 17 beta-oestradiol [5].
• Four experiments were conducted using male rats to determine whether testosterone (T), or its neural metabolites estradiol (E2) and 5 alpha-dihydrotestosterone (DHT), influence the expression of locomotor activity, which is thought to depend in part on the activation of mesolimbic dopaminergic neurons [6].

High impact information on dihydrotestosterone

• Testosterone and the nonaromatizable androgen, 5alpha-dihydrotestosterone, produced similar effects suggesting that estrogenic metabolites of androgens are not critical for masculinization and defeminization in rhesus monkeys [7].
• Mutations of the androgen receptor that impair the action of 5 alpha-dihydrotestosterone and testosterone result in abnormal male sexual development [8].
• The dissociation rates of 5 alpha-dihydrotestosterone and E2 from SHBG in serum appear to increase with time in frozen serum samples, and this factor may effect measurements of the distribution of these steroids in serum [9].
• Furthermore, the effects of 17beta-estradiol could not be mediated by the AR, and the effects of 5alpha-dihydrotestosterone were increased rather than decreased in ER-inactivated mice [10].
• We further showed that endogenous PSA expression in LNCaP cells can be induced by 5alpha-dihydrotestosterone, and the addition of the Smad3 further induces PSA expression [11].

Chemical compound and disease context of dihydrotestosterone

• These data indicate that 1) DHT and E2 enhance prostate epithelial cells growth, but reduce cell growth when combined; 2) DHT extenuates the inhibitory effects of melatonin on epithelial cell growth; and 3) E2 acts to inactivate melatonin receptors and consequently responses in human epithelial benign prostatic hyperplasia cells [12].
• Human prostate and human prostate cancer LNCaP cells express steroid conjugating uridine diphospho-glucuronosyltransferase (UGT) enzymes, and it was shown that the level of UGT activities and transcripts is down-regulated by androgens, especially dihydrotestosterone (DHT) [13].
• Optic nerve head (ONH) astrocytes from patients with glaucomatous optic neuropathy exhibit increased production of 5alpha-androstane-3alpha,17beta-diol (3alpha-diol), a neuroactive metabolite of 5alpha-dihydrotestosterone (5alpha-DHT) [14].
• A combined light-microscopic and stereologic analysis of the canine prostate was performed under the following experimental conditions: intact and castrated dogs, spontaneous benign prostatic hyperplasia, intact and castrated dogs after treatment with testosterone, 5 alpha-dihydrotestosterone or 3 alpha-androstanediol in combination with estradiol [15].
• Induction of benign prostatic hyperplasia in intact dogs by near-physiological levels of 5 alpha-dihydrotestosterone and 17 beta-estradiol [16].

Biological context of dihydrotestosterone

• Transfection of a mutated androgen receptor cDNA containing a termination codon at position 794 into eukaryotic cells resulted in formation of a normal amount of receptor protein, as indicated by immunoblotting, but the expressed protein does not bind 5 alpha-dihydrotestosterone [8].
• In vitro, 5 alpha-dihydrotestosterone modulates cell growth and stimulates acid phosphatase production [17].
• Here, we report that androgens, such as the aromatizable androstenedione and the non-aromatizable 5alpha-dihydrotestosterone, inhibit MCF-7 cell proliferation [18].
• DHT treatment increased mTOR activity as assessed by phosphorylation of the downstream targets p70 S6 kinase and 4E-BP1, and mTOR inhibition with rapamycin blocked the DHT-stimulated increase in cyclin D proteins [2].
• In addition, BAG-1L significantly reduced the concentrations of 5alpha-dihydrotestosterone (DHT) required for AR activity but did not induce ligand-independent transactivation [19].

Anatomical context of dihydrotestosterone

• Reversal of these events by administration of a single dose of 5 alpha-dihydrotestosterone to adult rats castrated 144 hr previously was accompanied by a differential early enhancement of chromatin-associated CK-2 activity, with a concomitant decrease in the CK-2 activity present in the cytosol [20].
• HPLC analysis of telencephalon and hypothalamus extracts combined with testosterone radioimmunoassay revealed the existence of two peaks coeluting with testosterone and 5alpha-dihydrotestosterone [21].
• Subcellular colocalization studies with fluorescence staining indicate SV can colocalize with AR in the presence of 5 alpha-dihydrotestosterone in COS-1 cells [22].
• In normal HOSE cell cultures/lines, 5alpha-dihydrotestosterone was found to be more effective than testosterone in stimulating cell growth, but in OCa cell lines, 5alpha-dihydrotestosterone and testosterone are equally potent [23].
• Because normal and malignant ovarian epithelial cells are growth inhibited by transforming growth factor (TGF) beta, we tested the ability of 5alpha-dihydrotestosterone (DHT) to modulate this response and the expression of TGF-beta receptor types I and II [24].

Associations of dihydrotestosterone with other chemical compounds

• Her cultured genital (labial) skin fibroblasts have normal testosterone 5 alpha-reductase activity, and metabolize 5 alpha-dihydrotestosterone (DHT) normally, but they do not augment (up-regulate) their basal androgen-receptor binding activity during prolonged incubation with DHT [25].
• The crystal structure of the N-terminal G domain of SHBG in complex with 5alpha-dihydrotestosterone at 1.55 A resolution reveals both the architecture of the steroid-binding site and the quaternary structure of the dimer [26].
• Unlike the estrogen receptor, however, this protein also binds progesterone, R5020, testosterone, and 5 alpha-dihydrotestosterone with similar affinities and in a competitive manner [27].
• Initial treatment of these animals with 5 alpha-dihydrotestosterone, followed by actinomycin D, resulted within 2-3 hr in a more than 2-fold increase in hepatic alpha 2u globulin compared to animals treated with the androgen alone [28].
• However, a low level of androgenic stimulation may continue, even after castration, by the conversion of adrenal androgens to 5alpha-dihydrotestosterone (DHT) in the prostate tumor cells [29].

Gene context of dihydrotestosterone

• To directly compare the effect of ER activation on bone in vivo with the effect of AR activation, 9-month-old orchidectomized wild-type and ER-inactivated mice were treated with the nonaromatizable androgen 5alpha-dihydrotestosterone, 17beta-estradiol, or vehicle [10].
• In fluorescence recovery after photobleaching analysis, mobility of the N-CoR was reduced by 5alpha-dihydrotestosterone (DHT)-bound AR [30].
• These findings are consistent with a role for increased DHT levels in the prostate through increased activity of the SRD5A2 locus in prostate cancer progression, in a subset of patients [31].
• Involvement of p27Kip1 in G1 arrest by high dose 5 alpha-dihydrotestosterone in LNCaP human prostate cancer cells [32].
• As well, Western blot analysis demonstrated a diminution of UGT2B17 protein level in response to DHT and EGF [13].

Analytical, diagnostic and therapeutic context of dihydrotestosterone

• This loss is prevented by an intraperitoneal injection of 17beta-hydroxy-5-alpha-androstan-3-one (5-alpha-dihydrotestosterone) [33].
• The cytosol activity can be stimulated almost immediately (within 10 min) after an intravenous injection of low dose (15 mug per rat) of 5-alpha-dihydrotestosterone into the castrated rat [33].
• The levels of the receptor proteins in R-3327 tumors are higher in tumors borne by male than by female animals, and castration of males decreases the amount of 17beta-hydroxy-5alpha-androstan-3-one binding [34].
• Oligonucleotide microarrays showed that DHT-stimulated rapid increases in multiple genes that regulate nutrient availability, including transporters for amino acids and other organic ions [2].
• However, by electrophoretic mobility shift assay we found that 5alpha-dihydrotestosterone repressed formation of NFkappaB middle dotNFkappaB response element complex formation [35].

References