Comments on the Metabolism of Steroid Hormones"

RALPHI. DORFMAN

(Worcester Foundation for Experimental Biology, Shrewsbury, Mass.)

I shall confine my remarks to certain general ciated with various disease states, but qualitative aspects of steroid metabolism, a brief considera differences have not been found. Thus, adrenal tion of cholesterol as a precursor of steroid hor cancer with masculinization is associated with an mones, and the biosynthesis of estrogens. excessive production and excretion of dehydro- epiandrosterone, Cushing's disease is associated GENERALASPECTS with a high production of cortisol usually detected Dr. Gallagher has presented some elegant ex by the excessive amounts of tetrahydrocortisone perimental data indicating that the 11-oxygenated and tetrahydrocortisol in the urine, while the 17-ketosteroids which arise from cortisol are pri adrenogenital syndromeisassociated with excessive marily derivatives of etiocholane (5/3)rather than amounts of pregnanediol and pregnanetriol most androstane (5o), while ring A reduction of 11/3- probably originated from endogenously produced hydroxy-A4-androstene-3,17-dione yields quite a progesterone and 17-hydroxyprogesterone. different picture. The latter steroid, when adminis tered to human subjects, yielded primarily 5a CHOLESTEROLASA PRECURSOROF derivatives. These conclusions, as well as the report STEROIDHORMONES that the 11-oxygen function is not selectively re First experiments demonstrating the possible moved from the intact steroid nucleus, are in ac conversion of cholesterol to steroid hormones (6) cord with our earlier findings (4). Dr. Gallagher's paper points out that, just as have recently been supplemented with definitive studies. Of these, the reports of Werbin and the 11/3-hydroxy group is strongly fixed to the LeRoy (13, 14) have been particularly valuable. steroid nucleus, so is the 17a-hydroxyl group in â‚¬¿21Administration of doubly labeled cholesterol (C14 steroids. This new fact, which is contrary to earlier and H3) to humans yielded doubly labeled tetra reports, is particularly important, because the re hydrocortisone, tetrahydrocortisol, androsterone, lationships between the steroid metabolites in etiocholanolone, and 11-ketoetiocholanolone. These urine and the hormones produced in the adrenal metabolites of steroid hormones were isolated from gland are simplified. For example, if the 17-hy- the urine and found to have the expected ratio of droxyl group could be removed by metabolic reac radioactive carbon to radioactive hydrogen, dem tions, then a metabolite such as pregnanolone onstrating that cholesterol may be converted di could be expected to arise from progesterone and rectly to steroid hormones without prior degrada 17-hydroxyprogesterone. Under these conditions tion to smaller units. In a second series of experi the determination of pregnanolone and pregnane- ments involving the biosynthesis of corticoids from diol would not be particularly helpful. Since, how carboxyl-labeled acetate and the study of carbons ever, the 17a-oxygen function is not lost during 20 and 21 for their C14content, the results are con catabolic reactions, the concentration of pregnano sistent with the idea the hormones may be derived lone and pregnanediol in urine is informative be directly from cholesterol. Thus, cortisol and 11- cause it reflects only one endogenous steroidâ€” deoxycortisol were biosynthesized by a calf adre progesterone. nal perfusion technic and by a patient bearing a It is perhaps worth commenting on the possible malignant adrenal tumor, respectively. If these presence of abnormal steroid hormone metabolites corticoids arose directly from cholesterol, it would in the blood and urine of patients bearing malig be expected that carbon 20 should be radioactive nant tumors or, for that matter, in any diseased while carbon 21 should be free of C14.These ex state. From time to time such hypotheses have been pected results were found (2, 3). Although the evi advanced, but real proof has not been supplied. dence at hand does not exclude pathways in which The available facts suggest that certain quantita cholesterol is not an intermediate, the facts strong tive differences in steroid concentrations are asso- ly suggest that cholesterol is an important precur * Presented at the second meeting of the Scientific Review sor of the steroid hormones. Committee of the American Cancer Society, held at the West- chester Country Club, Rye, New York, December 13 and 14, The conversion of cholesterol to pregnenolone 1956. has been demonstrated by the use of in vitro sys- 535

terns, and the simultaneous isolation of isocaproic exogenous particle, perhaps, such as ethyltoluene. acid points to a direct splitting between carbons 20 This would be consistent with the observation that and 22 of cholesterol. Most recent studies (12) equilin and equilenin derived from carboxyl-la- have implicated 20/3-hydroxycholesterol as an in beled acetate have only four radioactive carbon termediate. It is quite possible that the formation of atoms. The condensation of these two particles pregnenolone from cholesterol involves two prior would yield a Ci9compound which, after hydroxyl- hydroxylations, one at carbon 22 and the other at ation, could yield dihydroequilenin. Reduction of the 20/3position. The 200,22-dihydroxy derivative ring B of dihydroequilenin would yield estradiol- of cholesterol could then be degraded by a desmo- 17/3. This therefore could be considered to be a lase to form pregnenolone. One could further spec possible alternative pathway for the biosynthesis ulate that the 20/3-hydroxycholesterol demon of estradiol-17/3 and estrone. strated by Solomon and co-workers may be a key Salhanick and Berliner (10) have recently dem intermediate in the formation of the C19steroids onstrated the presence of equilenin in human from cholesterol. The 17a-hydroxylation of 20/3- adrenal cancer tissue. This finding is of extreme hydroxycholesterol would proceed to 17a,20/3-di- importance, since it is the first time this class of hydroxycholesterol, which, after attack by a steroids has been found in a natural source other proper desmolase, could yield dehydroepiandros- than the pregnant mare's urine. terone directly. REFERENCES 1. BAGGETT,B.; ENGEL,L. L.; SAVAKD,K.; and DORFMAN, BIOSYNTHESISOFESTROGENS R. I. The Conversion of Testosterone-3-C14 to C14-Estra- After many unproductive years, important ad diol-170 by Human Ovarian Tissue. J. Biol. Chem., 221: vances in estrogen biosynthesis have been made 931-41, 1956. 2. CASPI,E.; ROSENFELD,G.;and DORFMAN,R.I. Degrada during the past few years. One biosynthetic path tion of Cortisol-Cu and Corticosterone-C14 Biosynthesized way, perhaps the principal one, has been estab from Acetate-1-C14. J. Org. Chem., 21:814, 1956. lished and a second indicated. The first biosynthet 3. CASPI,E.; UNGAR,F.; and DORFMAN,R. I. Degradation ic pathway is the formation of estrogens from of 3a,17o,21-Trihydroxypregnan-20-one-C14 Biosynthe androgens. This has been established by the incu sized from Acetate-1-C14 by a Cushing's Patient. J. Org. bation of testosterone-4-C14 with human ovarian Chem., 22:326, 1957. 4. DORFMAN,R. I. In Vivo Metabolism of Neutral Steroid and stallion testicular tissue (1); by in vivostudies Hormones. J. Clin. Endocrinol. & Metabol., 14:318-25, with testosterone-4-C14 in the pregnant mare (8); 1954. and by the incubation of A4-androstene-3,17-dione 5. . Metabolism of Androgens, Estrogens and Corti- with ovarian, placental, and adrenal tissues (9). coids. Am. J. Med., 21:679-87, 1956. 6. DOHFMAN,R. I., and UNGAR,F. Metabolism of Steroid The mechanism of this transformation appears to Hormones. Minneapolis: Burgess Publishing Co., 1953. involve a 19-hydroxyl intermediate, since 19-hy- 7. HEARD,R. D. H.; JACOBS,R.; O'DONNELL,V.; PERÃ“N, droxy-A4-androstene-3,17-dione is efficiently con F. G.; SAFFRAN,J.C.; SOLOMON,S.S.; THOMPSON,L.M.; verted to estrogen. WiLLOUGHBY,H.;and YATES,C. H. The Application of C14 to the Study of the Metabolism of the Sterols and Steroid The possibility of a second mechanism is in Hormones. Recent Prog. Hormone Research, 9:383-408, triguing, particularly because the theoretical path 1954. way leads to highly unsaturated steroids which 8. HEARD,R. D. H.; JELLINCK,P. H.; and O'DONNELL,V.J. may have significance in the induction and/or Biogenesis of Estrogens: the Conversion of Testosterone- 4-C14 to Estrone in the Pregnant Mare. Endocrinology, maintenance of certain human tumors. The evi 57:200-204, 1955. dence for a second pathway of estrogen biosynthe 9. MEYER, A. S. Conversion of 19-Hydroxy-A4-Androstene- sis rests on the following series of experiments: 3,17-dione to Estrone by Endocrine Tissue. Biochim. et when acetate-1-C14 was administered to a pregnant Biophys. Acta, 17:441-42, 1955. mare, the labeled estrone isolated from the urine 10. SALHANICK,H.,and BERLINER,D. L. Isolation of Steroids had a molar specific activity approximately twice from a Feminizing Adrenal Carcinoma (to be published). that of equilin and equilenin; estrone-C14 admin 11. SAVARD,K.; ANDREC,K.; REYNERI, C.; BROOKSBANK, B. W. L.; DORFMAN,R.I.; HEABD,R. D. H.; JACOBS,R.; istered to the pregnant mare was not converted to and SOLOMON,S.S. The Biosynthesis of Estrone and Pro the ring B aromatic estrogens; testosterone-C14 gesterone in the Pregnant Mare (to be published). was converted to estrone-C14 but again not to 12. SOLOMON,S.; LEVTTAN,P.; and LIEBERMAN,S. Possible Intermediates between Cholesterol and Pregnenelone in either equilin or equilenin (7). On the basis of these Corticosteroidogenesis. Proc. Can. Physiol. Soc., 20th facts, it seems quite likely that the ring B unsatu Meeting, p. 54, Montreal, 1956. rated estrogens arise by a pathway independent of 13. WEHBIN,H., and LE ROY,G. V. Cholesterolâ€”a Precursor the route of extradiol-17/3 biosynthesis. of Tetrahydrocortisone in Man. J. Am. Chem. Soc., 76: 5260-61, 1954. The suggestion has been made (5, 11) that the 14. . Cholesterolâ€”a Precursor of Tetrahydrocortisone ring B unsaturated estrogens may arise from a CÃo (THF) and 11-Ketoetiocholanolone in Man. Fed. Proc., isoprenoid residue (derivable from acetate) and an 14:303, 1955.

Ralph I. Dorfman

Cancer Res 1957;17:535-536.

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