HO 3˜-HSD CYP17 (17-hydroxylase) CH3 CH3 CH3 C O CH3 OH Pregnenolone OH CH3 CH3 CH3 O C O CH3 CH3 CH3 O H C O Progesterone 17(OH) Progesterone Type III 17˜-HSD Into seminiferous tubule T + ABP T • ABP (predominantly as T) SHBG + T CH3 CH3 O O Androstenedione CH3 CH3 O OH Testosterone (T) CH3 CH3 O OH Dihydrotestosterone (DHT) Into peripheral circulation CYP19 (adipose tissue) 5°-Reductase (genital skin, prostate) Estradiol-17˜Leydig cell HO SHBG • T •Fig. 44.8 SteroidogenicpathwayinLeydigcells(thefirststepofconvertingcholesteroltopregnenoloneisomitted).Testosteroneissequesteredbybindingtoandrogen-bindingprotein(ABP)withintheseminiferoustubulesorcirculateswithintheperipheralcirculationboundtosexhormone–bindingglobulin(SHBG)andcanbeperipherallyconvertedtodihydrotestosterone(DHT)orestradiol-17β (E2).(ModifiedfromWhiteBA,PorterfieldSP.Endocrine Physiology. 4thed.Philadelphia:Mosby;2013.) binding or DHT-AR binding causes dissociation of the vicinity of a specific gene’s promoter. It remains unclear how chaperone proteins, followed by nuclear translocation of testosterone and DHT differ in their ability to activate the the androgen-AR complex, dimerization, binding to an AR in the context of different cell types, although the pres-androgen response element (ARE), and recruitment of ence of different coactivator proteins in different cell types coactivator proteins and general transcription factors to the is probably involved. Such coactivator proteins would have
Feedback suppression of gonadotropin secretion
Imprint male pattern of gonadotropins, sex drive, behavior • Fig. 44.9 Spectrum of effects of testosterone (T). Note that some effects result from the action of testosterone itself, whereas others are mediated by dihydrotestosterone (DHT) and estradiol (E2) after they are produced from testosterone. VLDL, LDL, HDL, very-low-density, low-density, and high-density lipoproteins, respectively.
different affinities for the testosterone-induced configuration of the AR versus the DHT-induced configuration of the AR.
Transport and Metabolism of Androgens
As testosterone enters the peripheral circulation, it binds to and quickly reaches equilibrium with serum proteins. About 60% of circulating testosterone is bound to sex hormone–binding globulin (SHBG), 38% is bound to albumin, and about 2% remains as “free” hormone. Testosterone and its metabolites are primarily excreted in urine. Approximately 50% of excreted androgens are found as urinary 17-ketosteroids, with most of the remainder being conjugated androgens or diol or triol derivatives. Only about 30% of the 17-ketosteroids in urine are from the testis; the rest are produced from adrenal androgens. Androgens are conjugated with glucuronate or sulfate in the liver, and these conjugated steroids are excreted in urine.