Possible Conversion of Adrenal Cortical Steroids to 17-Ketosteroids Some 27 neutral steroids have been isolated from the adrenal cortex

(167). From the available evidence, particularly from studies on urines

XII. BIOCHEMISTRY OF ANDROGENS 527 of patients with increased adrenal cortical activity and isolations from the urines of gonadectomized individuals, it appears that 17-ketosteroids such as androsterone, etiocholanolone, dehydroisoandrosterone, iso-androsterone, and 11-hydroxyandrosterone are derived, at least in part, from some of these adrenal cortical steroids.

The question of 17-ketosteroids arising from C²I compounds of the adrenal cortex is still a question more of speculation than experimental verification. It is well known that the adrenal cortex contains primarily two kinds of compounds: one, the 3(jö)-hydroxyallo, and the second the A⁴-stenone type. It has been suggested by Hirschmann and Hirschmann (112,113) that the A⁵-stenols may be converted by dismutation to 3(/3)-hydroxyallo compounds and A⁴-stenones. The A⁴-stenone would be metabolized in a fashion similar to that of testosterone. However, the question of the fate of the 3(jo)-hydroxyalio compounds is still open.

If we permit ourselves to make three assumptions, the metabolism of adrenal cortical steroids to 17-ketosteroids can be considerably simplified.

These assumptions are as follows: (1) that the body is capable of ruptur-ing the 17,20-glycol or 17,20(o:)-ketol with the formation of a 17-ketone;

(2) that the body is capable of converting a 3(/3)-hydroxyallo compound into a A⁵-stenone; and (3) that the body is capable of reducing the 11-hydroxy group to the hydrocarbon. In some of the following discus-sions all these assumptions are employed. In others the second assump-tion is not utilized.

a. 6-Oxygen Compounds Having a 8(β)-Hydroxyalio Configuration.

Fig. 23 illustrates the possible metabolism of four 5-oxygen-substituted adrenal steroids to 17-ketosteroids. The four compounds differ only in the state of oxidation of the carbons at C-ll and C-20, being hydroxy substitutions or ketones. On removal of the side chain there is formed either 11-hydroxyisoandrosterone ( X X I I I ) or 11-ketoisoandrosterone (LX). Assuming that the 3 (β)-hydroxyalio compounds may be desat-urated to Δ⁵-3(β) hydroxy compounds, 11-hydroxydehydroisoandro-sterone (LXI) and 11-ketodehydroisoandro11-hydroxydehydroisoandro-sterone (LXII) would be formed. Removal of the hydroxy group at C-ll will convert 11-hydroxy-dehydroisoandrosterone (LXI) to 11-hydroxy-dehydroisoandrosterone (III), which can be partly excreted unchanged and partly metabolized to androsterone (I) and etiocholanol-3(a)-17-one (XVIII), probably by way of A⁴ -andro-stenedione-3,17 ( X X I I ) . The latter steroid has previously been discussed as a common intermediate in the metabolism of both dehydroisoandro-sterone (III) and testodehydroisoandro-sterone ( X X V ) .

If the hydroxy group at 11 is not reduced, the 11-hydroxydehydroiso-androsterone (LXI) may be oxidized to A⁴-androstenol-ll-dione-3,17 (LXIII) with subsequent reduction to 11-hydroxyandrosterone (XL), an

androgen isolated from human urine, and etiocholanediol-3(a),ll-one-17 (LXIV), a compound as yet not isolated from urine. Another possibility would be a similar set of metabolic reactions as described except for the presence of an 11-ketone derivative in place of the 11-hydroxysteroid.

The end product under these conditions would be 11-ketoandrosterone

ANDROSTERONE ETI0CH0LAN0L"3K)-0NE-I7 LL-HYDROXYANOROSTERONE ETI0CH0LANE0I0L-3<«O,I|-0NE-17 F I G . 23.—Possible metabolism of adrenal cortical steroids to 17-ketosteroids.

For (L) read (LXIV).

(LXV) and the etiocholanol-3(a)-dione-ll,17 (LXVI). The latter two steroids have not as yet been isolated from urine.

If only two assumptions are made: (1) that the glycol or (ce)-ketol configuration can be ruptured to form 17-ketosteroids and (2) that the 11-oxygen substitution can be reduced to the hydrocarbon, an alterna-tive scheme for the metabolism of the 3(ß)-hydroxyallo compounds can be postulated (Fig. 24). Under these conditions androsterone (I) and

11-hydroxyandrosterone (XL) would be the end metabolites.

XII. BIOCHEMISTRY OF ANDROGENS 529

ANDROSTERONE 11 — HYDROXYANDROSTERONE

F I G . 24.—Possible metabolism of adrenal cortical steroids to 17-ketosteroids.

ANDROSTERONE E T I O C M O L A N O L - 3 H ) - O N E - 1 7 11 "HYDROXY ANDROSTE RONE ETIOCHOLANE0IOL-3(°<),H-ONE - 1 7

F I G . 25.—Possible metabolism of adrenal cortical steroids to 17-ketosteroids.

b. 5-Oxygen-A^A-stenone Compounds. Four adrenal steroids which also contain 5-oxygen substitutions, but having the A⁴-stenone configura-tion, are represented in Fig. 25. The reduction of the aß unsaturated ketone would presumably be effected in a manner similar to that for testosterone ( X X V ) . Postulating reactions at C-ll and on the side chain similar to that discussed previously, the end products should be the same as previously described in Fig. 23.

I X L A N D R O S T E R O N E 1 1 - H Y D R O X Y A N D R O S T E R O N E

F I G . 26.—Possible metabolism of an adrenal cortical steroid to 17-ketosteroids.

c. 5-Oxygen-8(a)-hydroxyallo Compound. One compound isolated from the adrenal cortex contains the saturated 3 (a)-hydroxyalio con-figuration. This compound, allopregnanetetrol-3(a),ll,17(ß),21-one-20 (CXI), would yield, on removal of the side chain, 11-hydroxyandrosterone (XL), which in turn may be reduced at C-ll to androsterone (I) (see Fig. 26).

d. 4-Oxygen Compounds Having 8(β)-Hydroxyalio Configuration.

Fig. 27 lists two steroids (LXXII, L X X I I ) which are 4-oxygen-3(/3)-hydroxyallo compounds. Rupture of the C-17 to C-20 bond would yield isoandrosterone (XIV) and, presumably by the same reaction dis-cussed for the 5-oxygen compounds, isoandrosterone may be metabolized to dehydroisoandrosterone (III), androsterone (I), and etiocholanol-3(a)-one-17 (XVIII).

e. 4-Oxygen-A4-stenone Compounds. Fig. 28 illustrates a problem similar to that of the second group of compounds discussed previously

XII. BIOCHEMISTRY OF ANDROGENS 531

C X X V U I CXXIX

X I V

I S O A N O R O S T E R O N E

Fia. 27.—Possible metabolism of adrenal cortical steroids to 17-ketosteroids.

C=O

X V I I I

I

A N D R O S T E R O N E E T I O C H O L A N O L " * 3 ( O ( ) * * 0 N E ~ I T

F I G . 28.—Possible metabolism of an adrenal cortical steroid to 17-ketosteroids.

and illustrated in Fig. 25. Here we have all factors similar except that we have no oxygen substitution in ring C. The simple removal of the side chain would result in the formation of A⁴-androstenedione-3,17 ( X X I I ) , which in turn should yield androsterone (I) and etiocholano-3(a)-one-17 (XVIII).

0 o o

Δ - A N D R O S T E N E D I O N E - 3 , 1 7 A D R E N O S T E R O N E A N D R 0 S T A N E D I 0 L - 3 ( £ ) , I I - 0 N E - 1 7

F I G . 29.—17-Ketosteroids isolated from adrenal cortical tissue.

L X X X I I I L X X X I V L X X X V

X I V

I S O A N D R O S T E R O N E

F I G . 30.—Possible metabolism of adrenal cortical steroids to 17-ketosteroids.

/. 17-Ketosteroids in Adrenal Cortex. Fig. 29 illustrates three 17-keto-steroids which have been isolated from the adrenal gland. Their possi-ble place in the metabolic scheme has already been suggested. It is worth remembering that Reichstein, who isolated all three of these com-pounds, suggested the possibility that these compounds may not be present in the gland as such, but instead may be formed as a result of the isolation procedures employed.

g. 8-Oxygen Compounds with a 17-Hydroxy Group. Figs. 30 and 31 illustrate 3-oxygen-substituted adrenal steroids with 17-hydroxy groups

XII. BIOCHEMISTRY OF ANDROGENS 533 which should also give rise to 17-ketosteroids. The compounds repre-sented in Fig. 30 have the 3(β)-hydroxyalio configuration, while the compounds represented in Fig. 31 have the A⁴-stenone configuration.

17"ß"-Hydroxyprogesterone ( X X I V ) , a member of the latter group, has been shown to be an androgen.

h. Concerning Metabolism of Desoxycorticosterone and Adrenal Cortical Extracts to 17-Ketosteroids. The administration of desoxycorticosterone to an ovariectomized chimpanzee, to an ovariectomized-adrenalectomized

C H 3 C H »

C = 0 H — C - O H

X V I I I

A N D R O S T E R O N E E T I O C H O L A N O L -3 ( O ( ) - 0 N E- L 7

F I G . 31.—Possible metabolism of adrenal cortical steroids to 17-ketosteroids.

monkey, and to patients suffering from Addison's disease caused distinct increases "in 17-ketosteroid excretion. In the case of the Addison's disease patients, it is difficult to discern whether this increased excretion of 17-ketosteroids was due to the general improvement of the physical status of the patient and the secondary increased production of 17-keto-steroid precursors by the gonads, or whether a real conversion took place.

The former explanation seems more plausible. The experiments on the ovariectomized chimpanzee and on the ovariectomized monkey indicated conversion of 3.2% to 13.8% for desoxycorticosterone to 17-ketosteroids (68).

The administration of adrenal cortical extracts to ovariectomized-adrenalectomized monkeys and to Addison's disease patients also gave rise to an increased 17-ketosteroid excretion. In the monkey, calculated

minimum conversions of the adrenal cortical steroids contained in the extract to 17-ketosteroids ranged from 2.8% to 12.2%. The data for the experiments on humans are difficult to evaluate for the reason previ-ously stated (68).

5. Site of Inactivation of Androgens

When pellets of testosterone or testosterone propionate are implanted in the spleen the androgenic effect on the castrated host is of a low order.

The specific effect is greatly augmented if the spleen carrying the pellets is transplanted and the splenic artery and vein ligated. Thus, it appears that testosterone can be inactivated in the liver. When methyl-testosterone is implanted in the spleen a greater response is elicited (5,13). It has been suggested that both methyltestosterone and testo-sterone are inactivated in the liver and that the two compounds show different activities when administered orally since they are absorbed by different routes from the intestinal tract (4). Methyltestosterone may be absorbed by way of the lacteals and lymphatics, thus avoiding the liver. Previously it was suggested by Miescher and Tschoop (150) that methyltestosterone suffers less destruction by intestinal enzymes than testosterone propionate.

Incubation of testosterone with rabbit liver slices in serum gave rise to A⁴-androstenedione-3,17 and czs-testosterone, and incubation of A⁴-androstenedione-3,17 under similar conditions gave rise to testosterone (38,39).

D . ENZYMIC CHANGES D U E TO BACTERIA AND YEASTS

Mamoli, Ercoli, and co-workers (78-79,129-133,199,213,214) have made extensive studies on the metabolic changes of androgens and related steroids as a result of the action of bacteria, yeasts, and molds.

The work was originally undertaken to study the influence of tissues in vitro on the androgen, but, due to extensive contamination of tissue extracts, observed changes were due to the influence of microorganisms on the steroids.

The influence of fermenting yeast has been studied on A^androstene-dione-3,17 (XCI) by Butenandt, Dannebaum, and Suranyi (20) and on androstanedione-3,17 ( L X X ) by Vercellone and Mamoli (213). Fig. 32 illustrates the changes observed under these experimental conditions.

Both A^androstenedione-S,^ (XCI) and androstanedione-3,17 ( L X X ) have been reduced to androstanediol-3(ß),17(a) (XCII).

Fig. 33 illustrates the changes that were effected principally by Bacillus putrefactus. This organism can produce reductive changes in the steroid nucleus at C-4 to the normal form, and reduce the

XII. BIOCHEMISTRY OF ANDROGENS 535 ketone groups at both C-3 and C-17. Thus, testosterone ( X X V ) may be converted to etiocholanol-17(a)-3-one (XCIII) and etiocholanediol-3(a),17(a) (XCIV). A⁴-Androstanedione has been converted to etio-cholanol-17(a)-3-one (XCIII), etiocholanediol-3(a),17(a) (XCIV), and etiocholanedione-3,17 ( L X X I ) . Finally, it has been demonstrated that androstanedione-3,17 ( L X X ) can be reduced to isoandrosterone ( X I V ) and androstanediol-3(0),17(a) (XCII).

Ο Ο II II

H H

X C I L X X

H

X C I I

F I G . 32.—Conversions under the influence of fermenting yeast.

Corynebacterium mediolanum has been studied with respect to its ability to oxidize the A⁵-stenols grouping to A⁴-stenones. In Fig. 34 the conversions of dehydroisoandrosterone (III) to A⁴ -androstenedione-3,17 ( X X I I ) and A⁵-methylandrostenediol-3(/3), 17(a) (XCV) to methyl-testosterone (XCVI) are illustrated. That this reaction probably also takes place in the animal organism is illustrated by the conversion of dehydroisoandrosterone (III) to androsterone (I) and etiocholanol-3-A⁶-(a)-one-17(XVIII), which probably takes place by way of A⁴ -andro-stenedione-3,17(XXII).

In the presence of yeast which was probably contaminated with bacteria, it has been shown that both dehydroisoandrosterone (III) and androstenediol-3(ß), 17(a) ( X X V I I I ) may be converted to A⁴ -andro-stenedione-3,17 ( X X I I ) . These changes are illustrated in Fig. 35.

VII. Mechanism of Action of Androgens

Although it appears logical to assume that the mechanism of action of androgens involves enzyme or enzyme system relationships, only pre-liminary information on this point is available at the present time. The

principal effects of androgens may be said to involve growth stimulation.

Thus the influences on such specific tissues as seminal vesicles, combs, and prostates are primarily growth phenomena. The nitrogen-retaining properties of the androgens may also be linked to the growth process.

The nitrogen retention found under the influence of androgens is greater

X C I I

F I G . 33.—Conversions under the influence of Bacillus patrefactus (with yeast brei).

than can be expected on the basis of sex-specific tissue. Rather it appears more like a general effect on the growth process of many tissues.

However, a second character of androgen stimulation may be related to the question of blood flow and vascularization. Thus an early change in such an organ as the comb is the increased blood supply to the structure under the influence of the male sex hormone. The mechanism of this increased vascularity has not been elucidated.

Concerning the second phenomenon, that of growth, a number of

XII. BIOCHEMISTRY OF ANDROGENS 537 possible mechanisms may be mentioned. First a system may be visual-ized whereby the androgen acts as a part of an enzyme system favoring, perhaps, growth of the organ. Second, the androgens may act to remove an inhibitor.

X C V X I II

FI G . 34.—Conversions due to Corynebacterium mediolanum.

Ο

X X V I I I

F I G . 35.—Conversions due to yeast contaminated with bacteria.

Although the mechanism of action of androgens is obscure, some of the necessary conditions for this action have been described. Vitamin Ε deficiency in capons has been shown to prevent the full action of andro-gens on the comb. It has been claimed that vitamin Ε enhances the action of small doses of androgens on the capon's comb ( 3 4 ) .

The influence of testosterone propionate on rachitic rats has been studied (37). On a rachitic diet the secondary sex glands become atrophic, and the administration of testosterone propionate for 3 to 21 days produces characteristic responses toward the normal glands. In addition to effects on secondary sex characteristics, there was observed a beneficial effect on the weights of the treated animals but no effect on the bone lesions. On the rachitic diet androgens still exerted their characteristic action.

The relation of the thyroid to the action of androgens on the capon's comb has been studied (34,35). There are claims that the administra-tion of thyroxine either orally or intramuscularly intensifies and prolongs the effect of testosterone on the capon comb, while thyroidectomy reduces the comb sensitivity to androgens.

VIII. Inhibitory Effects of Compounds on Action of Androgens

In document Biochemistry Androgens (Pldal 60-72)