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Testosterone Replacement, Low T, HCG, & Beyond
Testosterone and Men's Health Articles
Androgen synthesis and action
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<blockquote data-quote="madman" data-source="post: 224400" data-attributes="member: 13851"><p><strong>Fig. 3. <u>Classic and alternative androgen biosynthesis pathways</u>. <u>A</u>. <u>The classic pathway of testosterone (T) biosynthesis</u>, is metabolically active in endocrine organs such as the human testis Leydig cells. Cholesterol is transported to the inner mitochondrial membrane by steroidogenic acute regulatory protein (StAR). At the inner mitochondrial membrane, cholesterol is then converted to pregnenolone (PREG) by the side-chain cleavage catalytic unit consisting of the enzyme cytochrome P450 side-chain cleavage (CYP11A1), ferrodoxin (FDX1) and ferrodoxin-reductase (FDXR). PREG is then sequentially converted to 17a-hydroxypregnenolone (17OHPREG) and dehydroepiandrosterone (DHEA) by cytochrome P450 17a-hydroxylase/17,20-lyase (CYP17A1) supported by cytochrome P450 oxidoreductase (POR) in the first hydroxylase step and cytochrome b5 (CYB5) in the second lyase step. Following the biosynthesis of DHEA, both androstenediol and androstenedione (A4) are biosynthesized by the enzyme 17b-hydroxysteroid dehydrogenase (AKR1C3/HSD17B3) and 3b-hydroxysteroid dehydrogenase (HSD3B2), respectively. Thereafter, both metabolites are converted to T via the same enzymes. Small amounts of T or A4 may also be converted to estrogens (estradiol and estrone, respectively) in the testis by aromatase (CYP19A1). Secreted T is then partially converted to dihydrotestosterone (DHT) in peripheral tissues by steroid-5a-reductases (SRD5A1/2). <u>B</u>. <u>The alternative backdoor pathway</u>. In this pathway, 17a-hydroxyprogesterone (17OHPROG/ 17OHP4) or progesterone (PROG/P4) serve as a substrate for 5a-reduction (by SRD5A1) to enter the backdoor pathway to DHT synthesis. SRD5A1 converts 17OHPROG to 17a-hydroxy-dihydroprogesterone (17OH-DHP, 5a-pregnan-17a-ol-3,20-dione) and the 3a-hydroxysteroid dehydrogenase activity of AKR1C2/4 will yield 17a-hydroxy-allopregnanolone (17OH-ALLO); this metabolite is then converted to androsterone by CYP17A1. Further conversion by AKR1C3/HSD17B3 leads to androstanediol and by AKR1C2/4 or retinol-like dehydrogenase (RoDH) to DHT. <u>C</u>. <u>The alternative C11-oxy pathway</u>. The starting point of this pathway is the 11b-hydroxylation of A4 and T (by 11b-hydroxylase (CYP11B1)) yielding 11b-hydroxyandrostenedione (11OHA4) and 11b-hydroxytestosterone (11OHT), which are then metabolized by SRD5As to 11b-hydroxy-5a-androstane-3,17-dione (11OH5aDIONE) and 11b-hydroxydihydrotestosterone (11OHDHT, 5a-androstan-11b,17b-diol-3-one), respectively. Alternatively,11OHA4 can also be metabolized to 11-ketoandrostenedione (11KA4) by 11b-hydroxysteroid dehydrogenase (HSD11B). 11KA4 is reversibly metabolized to 11-ketotestosterone (11KT) by HSD17Bs, and the latter to the 11-ketoandrostanolone (11KDHT) by SRD5A. Furthermore, 11OH5aDIONE can be converted to 11K5aDIONE, and 11OHDHT to 11KDHT by HSD11B. 11K5aDIONE and 11KDHT are both reversibly metabolized to 11-ketoandrosterone (11KAST, 5aandrostan-3a-ol-11,17-dione) and 11keto-5a-androstane-3a,17b-diol (11K3aDIOL) by AKR1C2/4, while 11OH5aDIONE is also reversibly metabolized to 11b-hydroxyandrosterone (11OHAST, 5a-androstan-3a,11b-diol-17-one), and 11OHDHT to 11OH-3a-androstanediol (11OH3aDIOL) by AKR1C2/4. Finally, 11OHAST and 11OH3aDIOL are metabolized to 11KAST and 11K3aDIOL by HSD11B. <u>D</u>. <u>The alternative C11-oxy backdoor pathway</u>. In this pathway, the 11b-hydroxylation (CYP11B) of PROG/P4 and 17OHPROG/17OHP4 is the starting point. From P4, 11OHP4 is reversibly metabolized to 11-ketoprogesterone (11KP4, 4-pregnen-3,11,20-trione) by HSD11B, whereafter both 11KP4 and 11OHP4 are metabolized by SRD5A to either 5a-Pregnanetrione (11KDHP4, 5a-pregnan-3,11,20-trione) or 11OH-dihydroprogesterone (11OHDHP4, 5a-pregnan-11b-ol-3,20-dione), respectively, with these metabolites also interconverted by HSD11B. Next, 11KDHP4 and 11OHDHP4 are reversibly metabolized to alfaxalone (5a-pregnan-3a-ol-11,20-dione) and 3a,11b-dihydroxy-dihydroprogesterone (3a,11b-diOH-DHP4), respectively, by AKR1C2/4, and these metabolites may be converted to 11OHAST and 11KAST by CYP17A1. On the other hand, from 17OHP4, 21-deoxycortisol (21dF,11b,17a-dihydroxypregn-4-ene-3,20-dione) is reversibly metabolized to 21-deoxycortisone (21dE, 17a-hydroxypregn-4-ene-3,11,20-trione) by HSD11B. Then, 21dF and 21dE are converted by SRD5A to 5a-pregnan-11b,17a-diol-3,20-dione (11OHPdione, 5a-pregnan-11b,17a-diol-3,20-dione) and 5a-pregnan-17a-ol-3,11,20- trione (11KPdione, 5a-pregnan-17a-ol-3,11,20-trione), respectively, with these metabolites also interconverted by HSD11B. Thereafter, 11OHPdione and 11KPdione can be metabolized by AKR1C2/4 to 5a-pregnan-3a,11b,17a-triol-20-one (11OHPdiol) and 5apregnan-3a,17a-diol-11,20-dione (11KPdiol), respectively (with these metabolites also metabolized by HSD11B). Finally, 11OHAST and 11KAST are biosynthesized by CYP17A1 from the latter metabolites, and in the final steps of this pathway, 11KAST is converted to 11K3aDIOL (by HSD17Bs), followed by the production of 11KDHT (by AKR1C2/4 or RoDH).</strong></p><p><strong>[ATTACH=full]22001[/ATTACH]</strong></p><p><strong>[ATTACH=full]22002[/ATTACH]</strong></p></blockquote><p></p>
[QUOTE="madman, post: 224400, member: 13851"] [B]Fig. 3. [U]Classic and alternative androgen biosynthesis pathways[/U]. [U]A[/U]. [U]The classic pathway of testosterone (T) biosynthesis[/U], is metabolically active in endocrine organs such as the human testis Leydig cells. Cholesterol is transported to the inner mitochondrial membrane by steroidogenic acute regulatory protein (StAR). At the inner mitochondrial membrane, cholesterol is then converted to pregnenolone (PREG) by the side-chain cleavage catalytic unit consisting of the enzyme cytochrome P450 side-chain cleavage (CYP11A1), ferrodoxin (FDX1) and ferrodoxin-reductase (FDXR). PREG is then sequentially converted to 17a-hydroxypregnenolone (17OHPREG) and dehydroepiandrosterone (DHEA) by cytochrome P450 17a-hydroxylase/17,20-lyase (CYP17A1) supported by cytochrome P450 oxidoreductase (POR) in the first hydroxylase step and cytochrome b5 (CYB5) in the second lyase step. Following the biosynthesis of DHEA, both androstenediol and androstenedione (A4) are biosynthesized by the enzyme 17b-hydroxysteroid dehydrogenase (AKR1C3/HSD17B3) and 3b-hydroxysteroid dehydrogenase (HSD3B2), respectively. Thereafter, both metabolites are converted to T via the same enzymes. Small amounts of T or A4 may also be converted to estrogens (estradiol and estrone, respectively) in the testis by aromatase (CYP19A1). Secreted T is then partially converted to dihydrotestosterone (DHT) in peripheral tissues by steroid-5a-reductases (SRD5A1/2). [U]B[/U]. [U]The alternative backdoor pathway[/U]. In this pathway, 17a-hydroxyprogesterone (17OHPROG/ 17OHP4) or progesterone (PROG/P4) serve as a substrate for 5a-reduction (by SRD5A1) to enter the backdoor pathway to DHT synthesis. SRD5A1 converts 17OHPROG to 17a-hydroxy-dihydroprogesterone (17OH-DHP, 5a-pregnan-17a-ol-3,20-dione) and the 3a-hydroxysteroid dehydrogenase activity of AKR1C2/4 will yield 17a-hydroxy-allopregnanolone (17OH-ALLO); this metabolite is then converted to androsterone by CYP17A1. Further conversion by AKR1C3/HSD17B3 leads to androstanediol and by AKR1C2/4 or retinol-like dehydrogenase (RoDH) to DHT. [U]C[/U]. [U]The alternative C11-oxy pathway[/U]. The starting point of this pathway is the 11b-hydroxylation of A4 and T (by 11b-hydroxylase (CYP11B1)) yielding 11b-hydroxyandrostenedione (11OHA4) and 11b-hydroxytestosterone (11OHT), which are then metabolized by SRD5As to 11b-hydroxy-5a-androstane-3,17-dione (11OH5aDIONE) and 11b-hydroxydihydrotestosterone (11OHDHT, 5a-androstan-11b,17b-diol-3-one), respectively. Alternatively,11OHA4 can also be metabolized to 11-ketoandrostenedione (11KA4) by 11b-hydroxysteroid dehydrogenase (HSD11B). 11KA4 is reversibly metabolized to 11-ketotestosterone (11KT) by HSD17Bs, and the latter to the 11-ketoandrostanolone (11KDHT) by SRD5A. Furthermore, 11OH5aDIONE can be converted to 11K5aDIONE, and 11OHDHT to 11KDHT by HSD11B. 11K5aDIONE and 11KDHT are both reversibly metabolized to 11-ketoandrosterone (11KAST, 5aandrostan-3a-ol-11,17-dione) and 11keto-5a-androstane-3a,17b-diol (11K3aDIOL) by AKR1C2/4, while 11OH5aDIONE is also reversibly metabolized to 11b-hydroxyandrosterone (11OHAST, 5a-androstan-3a,11b-diol-17-one), and 11OHDHT to 11OH-3a-androstanediol (11OH3aDIOL) by AKR1C2/4. Finally, 11OHAST and 11OH3aDIOL are metabolized to 11KAST and 11K3aDIOL by HSD11B. [U]D[/U]. [U]The alternative C11-oxy backdoor pathway[/U]. In this pathway, the 11b-hydroxylation (CYP11B) of PROG/P4 and 17OHPROG/17OHP4 is the starting point. From P4, 11OHP4 is reversibly metabolized to 11-ketoprogesterone (11KP4, 4-pregnen-3,11,20-trione) by HSD11B, whereafter both 11KP4 and 11OHP4 are metabolized by SRD5A to either 5a-Pregnanetrione (11KDHP4, 5a-pregnan-3,11,20-trione) or 11OH-dihydroprogesterone (11OHDHP4, 5a-pregnan-11b-ol-3,20-dione), respectively, with these metabolites also interconverted by HSD11B. Next, 11KDHP4 and 11OHDHP4 are reversibly metabolized to alfaxalone (5a-pregnan-3a-ol-11,20-dione) and 3a,11b-dihydroxy-dihydroprogesterone (3a,11b-diOH-DHP4), respectively, by AKR1C2/4, and these metabolites may be converted to 11OHAST and 11KAST by CYP17A1. On the other hand, from 17OHP4, 21-deoxycortisol (21dF,11b,17a-dihydroxypregn-4-ene-3,20-dione) is reversibly metabolized to 21-deoxycortisone (21dE, 17a-hydroxypregn-4-ene-3,11,20-trione) by HSD11B. Then, 21dF and 21dE are converted by SRD5A to 5a-pregnan-11b,17a-diol-3,20-dione (11OHPdione, 5a-pregnan-11b,17a-diol-3,20-dione) and 5a-pregnan-17a-ol-3,11,20- trione (11KPdione, 5a-pregnan-17a-ol-3,11,20-trione), respectively, with these metabolites also interconverted by HSD11B. Thereafter, 11OHPdione and 11KPdione can be metabolized by AKR1C2/4 to 5a-pregnan-3a,11b,17a-triol-20-one (11OHPdiol) and 5apregnan-3a,17a-diol-11,20-dione (11KPdiol), respectively (with these metabolites also metabolized by HSD11B). Finally, 11OHAST and 11KAST are biosynthesized by CYP17A1 from the latter metabolites, and in the final steps of this pathway, 11KAST is converted to 11K3aDIOL (by HSD17Bs), followed by the production of 11KDHT (by AKR1C2/4 or RoDH). [ATTACH type="full"]22001[/ATTACH] [ATTACH type="full"]22002[/ATTACH][/B] [/QUOTE]
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Testosterone Replacement, Low T, HCG, & Beyond
Testosterone and Men's Health Articles
Androgen synthesis and action
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