5/3-Androsterone conjugates

A series of conjugated polyenes capped with chromophores and containing an androstane spacer were synthesized by Wittig or Wittig-type olefinations from epi-androsterone 5150. For example, vinyl carboxaldehyde 52, prepared from 51 in 60% yield as shown in equation 32, was treated with 9-anthrylmethylphosphonium bromide and n-butyllithium to give diene 53. Exocyclic diene 53 was subsequently oxidized to vinyl carboxaldehyde 54. The androsterone vinyl aldehyde intermediate could either be treated with a tetraphenylporphyrinpolyenyl phosphonium ylide, or, as shown below, the phosphonium salt of the androsterone (55) could be reacted with TPP polyeneal 56. The desired all-(E) isomer, 57, was obtained from the ( )/(Z)-isomeric mixture by chromatographic purification. 

The major pathway for the degradation of testosterone in humans occurs in the liver, with the reduction of the double bond and ketone in the A ring, as is seen in other steroids with a A4-ketone configuration in the A ring. This leads to the production of inactive substances such as androsterone and etiocholanolone that are then conjugated and excreted in the urine. 

Although it has been stated that only phenols are conjugated with sulfuric acid,1 three urinary steroid sulfate esters (androsterone sulfate, dehydro-epi-androsterone sulfate, and A 6-aZZo-pregnene-3(/3)-ol-20-one sulfate) have been isolated in which the sulfuric acid is esterified by an alcoholic hydroxyl group.111 It is true that no alcohol administered to... 

Disposition in the Body. Testosterone is the androgenic hormone formed in the testes. In man, it is metabolised to 5a-androstane-3a,17)5-diol, androsterone, etiocholanolone, and 5a-androstene-3,17-dione. In the horse, the major metabolites are 5a-androstane-3)5,17a-diol, which is excreted in the urine as the glucuronide conjugate, and the 17)5-epimer which is excreted in the urine as the sulphate conjugate. 

Metabolic studies carried out with isotopically labeled dehydroepi-androsterone sulfate [312] showed that this conjugated steroid may follow an indirect metabolic pathway initiated by the hydrolysis of the sulfate group. In the course of the metabolism the conjugated steroid thus becomes a free steroid first and the free steroid may undergo further metabolism. On the other hand, dehydroepiandrosterone sulfate may follow a direct metabolic pathway without a break of the ester group. 

B Steroids containing at least one ketone group without conjugation, e.g., estrone and androsterone. 

Adrenal androgens also have a complex metabolic fate DHEA-S is formed in the adrenal cortex or by sulfokinases in the liver and kidney from DHEA and excreted by the kidney. DHEA and DHEA-S can be metabolized by 7a-and 16a-hydroxylases. 17p-Reduction of both compounds forms A -5-androstenediol and its sulfate. Androstenedione can be metabolized to androsterone after 3a- and 5a-reduction. 5P-Reduction results in the formation of etiocholanolone (see Eigure 51-7). These metabolites are conjugated to glucuronides and sulfates, which are then excreted in the urine. 

Testosterone circulating in the blood is mainly metabolized in the liver to androstenedione which is converted via intermediates into androsterone and its 3 isomer. These are then excreted in urine as glucuro-nides or sulfate conjugates. 

Effective Adsorption of Dehydroepi-androsterone (DHA) Sulfate and Other 17-Ketosteroid Conjugates from Urine by Amberlite Clin. Biochem. 4(4) 287-296 (1971) ... 

Data obtained in vivo (Baulieu et al, 1965) have shown (Fig. 9) that after an injection of radioactive dehydroepiandrosterone and dehydroe-piandrosterone sulfate, the free compound is transformed more rapidly and more eflBciently into androsterone and etiocholanolone than the sulfo conjugate, the latter being apparently protected from rapid liver catabolism. 

The transformation products introduced during acid hydrolysis are products of dehydration, halogenation, and rearrangement. Dehydration may occur at sites distant from the carbon atom involved in the conjugate as in the formation of A <">-androstene-3a-ol-17-one and -etiocholene-3a-ol-17-one from the corresponding ll 3-hydroxy compounds (83). It may also occur during the course of the hydrolysis of a sulfate ester as in the conversion of androsterone sulfate to A -androstene-17-one (126). 

About 30 years ago, the two most important forms of steroid conjugates were isolated, one linked to sulfuric acid (androsterone sulfate, isolated by Venning et o/., 1942), and the other linked to glucuronic acid (pregnanediol glucuronide, isolated by Odell and Martian, 1936, and estriol glucuronide, isolated by S. L. Cohen et al., 1936). 

The saturated Cai compounds are then either conjugated with glucuronic acid and appear in urine as the glucuronides, or they are further broken down. The side chain is split off particularly easily from 17-hydroxy compounds. The products are 17-keto steroids, androsterone, etiocholanolone, and. others, which are also excreted as glucuronides (more rarely as sulfates). The amount of 17-keto steroids in urine can be estimated easily with Zimmermann s color reaction it is useful for the diagnosis of adrenal cortical activity. One should be aware, however, that only a part of the corticosteroid excretion is measured, together vith testosterone inactivation products. Normally, about 10-20 mg per day of 17-keto steroids are excreted. 

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