The steroidogenic pathway in Leydig cells involves the conversion of cholesterol to pregnenolone, which then leads to the production of progesterone. Progesterone can be converted to 17(OH) progesterone type III through the action of 17-hydroxylase. Testosterone (T) is formed from androstenedione, which is produced from progesterone. Dihydrotestosterone (DHT) is derived from testosterone through the action of 5α-reductase. Estradiol-17β (E2) is formed from testosterone in adipose tissue, mediated by the enzyme CYP19. Testosterone can bind to androgen-binding protein (ABP) in the seminiferous tubules or circulate in the peripheral circulation bound to sex hormone–binding globulin (SHBG). DHT can also bind to androgen receptor (AR). The binding of testosterone or DHT to their respective receptors can cause dissociation of the receptor from a specific gene's promoter. The activation of the androgen-AR complex involves chaperone proteins, nuclear translocation of testosterone and DHT, dimerization, binding to an AR, and recruitment of coactivator proteins and general transcription factors. The ability of testosterone and DHT to activate the androgen-AR complex may differ in different cell types and is influenced by the presence of different coactivator proteins. The binding of testosterone or DHT to AR can have various effects, including feedback suppression of gonadotropin secretion, imprinting male pattern of gonadotropins, sex drive, and behavior. Some effects of testosterone are mediated by dihydrotestosterone (DHT) and estradiol (E2) after their production from testosterone. Testosterone binds to serum proteins in the peripheral circulation, with approximately 60% binding to sex hormone–binding globulin (SHBG), 38% binding to albumin, and about 2% remaining as free hormone. Testosterone and its metabolites are primarily excreted in urine, with approximately 50% of excreted androgens found as urinary 17-ketosteroids. The majority of the remaining excreted androgens are conjugated or exist as diol or triol derivatives. Adrenal androgens contribute to the production of urinary 17-ketosteroids, with only about 30% originating from the testis. Androgens are conjugated with glucuronate or sulfate in the liver and are then excreted in urine.
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.