644 



PHYSIOLOGY OF GONADS 



endocrine gland made its characteristic 

 steroid by some unique biosynthetic mecha- 

 nism, one that was independent of those in 

 other glands. However, there is now abun- 

 dant evidence that the biosynthetic paths 

 in the several steroid-secreting glands have 

 many features which are similar or identi- 

 cal. 



It is now well established that proges- 

 terone is not simply a female sex hormone 

 produced by the corpus luteum, but a com- 

 mon precursor of adrenal glucocorticoids 

 such as Cortisol and adrenal mineralocorti- 

 coids such as aldosterone, androgens, and 

 estrogens. The adrenal cortex, ovary, testis, 

 and placenta have in common many en- 

 zymes for the biosynthesis of steroids. An- 

 drogenic tumors of the human ovary, for ex- 

 ample, have been shown to produce 

 testosterone and its metabolites. The trans- 

 plantation of an ovary into a castrate male 

 mouse will result in the maintenance of the 

 male secondary sex characters, which sug- 

 gests that the normal ovary can also synthe- 

 size androgens. 



A. CHOLESTEROL 



The early work of Bloch (1951), Rilling, 

 Tchen and Bloch (1958), and of Popjak 

 (1950) showed that labeled acetate is con- 

 verted to labeled cholesterol. The pattern of 

 the labeling present in the cholesterol syn- 

 thesized from acetate-1-C^^ or acetate-2-C^'' 

 as precursor led to speculations as to how 

 the steroid nucleus is assembled. Further 

 work (Langdon and Bloch, 1953) revealed 

 that squalene and certain branched-chain, 

 unsaturated fatty acids are intermediates 

 in this synthesis. The current hypothesis, 

 which is supported by a wealth of experi- 

 mental evidence, states that two moles of 

 acetyl coenzyme A condense to form aceto- 

 acetyl coenzyme A, which condenses with a 

 third molecule of acetyl coenzyme A to form 

 yS-hydroxy-^-methyl glutaric acyl coenzyme 

 A (Fig. 11.1). The coenzyme A group is 

 removed and the hydroxymethyl glutaric 

 acid is reduced to mevalonic acid. Mevalonic 

 acid, 3-hydroxy-3-methylpentano-5-lactone, 

 is metabolized to a 5-carbon isoprenoid 

 compound and three moles of these condense 

 to form a 1 5-carbon hydrocarbon. The head- 

 to-head condensation of two molecules of 

 this 15-carbon compound yields the 30- 



carbon equalene. This is metabolized, by 

 way of lanosterol and the loss of three 

 methyl groups, to cholesterol, which seems 

 to be the common precursor of all of the 

 steroid hormones (Tchen and Bloch, 1955; 

 Clayton and Bloch, 1956). 



The question of whether cholesterol is 

 an obligate intermediate in the synthesis of 

 steroid hormones has not been definitely 

 answered. There is clear evidence that cho- 

 lesterol is converted to steroids without first 

 being degraded to small units and subse- 

 quently reassembled. Werbin and LeRoy 

 (1954) administered cholesterol labeled 

 with both carbon-14 and tritium (H^) to 

 human subjects and isolated from their 

 urine tetrahydrocortisone, tetrahydrocorti- 

 sol, androsterone, etiocholanolone and 11- 

 ketoetiocholanolone. These substances, 

 known to be metabolites of steroid hor- 

 mones, were labeled with both C^^ and H^ 

 and the labeled atoms were present in the 

 ratio expected if they were derived directly 

 from cholesterol. Experiments by Dorfman 

 and his colleagues (Caspi, Rosenfeld and 

 Dorfman, 1956) also provide evidence for 

 the synthesis of steroids via cholesterol. 

 Cortisol and 11-desoxycortisol were isolated 

 from calf adrenals perfused with acetate-1- 

 C^^ and from a patient with an adrenal tu- 

 mor to whom acetate- 1-C^^ had been ad- 

 ministered. It is known that cholesterol 

 synthesized from acetate-l-C^'* is labeled in 

 carbon 20 but not in carbon 21. The Cortisol 

 and 11-desoxycortisol also proved to be la- 

 beled in carbon 20 but not in carbon 21. 

 This evidence does not, of course, exclude 

 biosynthetic paths for the steroids other 

 than one by way of cholesterol, but it does 

 suggest that cholesterol is at least an im- 

 portant precursor of them. Direct evidence 

 that cholesterol is synthesized from squalene 

 in man is provided by the experiments of 

 Eidinoff, Knoll, Marano, Kvamme, Rosen- 

 feld and Hcllman (1958), who prepared tri- 

 tiated squalene and administered it orally 

 to human subjects. They found that the 

 cholesterol of the blood achieved maximal 

 specific aeti\'ity in 7 to 21 liours. 



B. PROCiE.STERONE 



Cholesterol undergoes an oxidative cleav- 

 age of its side chain to yield isocaproic 

 acid and pregnenolone (Fig. 11.2). The lat- 



