STEROID SEX HORMONES 



647 



D. ESTROGENS 



A-4-Androstenedione and testosterone are 

 precursors of the estrogens. Baggett, Engel, 

 Savard and Dorfman (1956) demonstrated 

 the conversion of testosterone to estradiol- 

 17/? by slices of human ovary. Ryan (1958) 

 found that the enzymes to carry out this 

 conversion are also present in the human 

 placenta, located in the microsomal fraction 

 of placental homogenates. Homogenates of 

 stallion testis convert labeled testosterone 

 to labeled estradiol and estrone. Slices of 

 human adrenal cortical carcinoma also have 

 been shown to convert testosterone to es- 

 tradiol and estrone, and Nathanson, Engel 

 and Kelley (1951) found an increased uri- 

 nary excretion of estradiol, estrone, and es- 

 triol following the administration of adreno- 

 corticotrophic hormone to castrate women. 

 Thus it seems that ovary, testis, placenta, 

 and adrenal cortex have a similar biosyn- 

 thetic mechanism for the production of es- 

 trogens and androgens. The first step in 

 the conversion of testosterone or A-4-andro- 

 stenedione to estrogens is the hydroxylation 

 at carbon 19, again by an enzymatic process 

 which requires molecular oxygen and 

 TPNH. Meyer (1955) first isolated and 

 characterized 19-hydroxy-A-4-androstene- 

 3,17-dione from a perfused calf adrenal. 

 When this was incubated with dog placenta 

 it was converted to estrone. The steps in the 

 conversion of the 19-hydroxy-A-4-andro- 

 stenedione to estrone appear to be the in- 

 troduction of a second double bond into ring 

 A, the elimination of carbon 19 as form- 

 aldehyde, and rearrangement to yield a 

 phenolic ring A. The requirements for the 

 aromatization of ring A by a microsomal 

 fraction of human placenta were studied by 

 Ryan (1958). West, Damast, Sarro and 

 Pearson (1956) found that the administra- 

 tion of testosterone to castrated, adrenalec- 

 tomized women resulted in an increased 

 excretion of estrogen. This suggests that 

 tissues other than adrenals and gonads, pre- 

 sumably the liver, can carry out this same 

 series of reactions. 



E. BIOSYNTHESIS OF OTHER STEROIDS 



To complete the picture of the interrela- 

 tions of the biosyntheses of steroids, it 

 should be noted that other evidence shows 



that progesterone is hydroxylated at carbon 

 21 to yield desoxycorticosterone and this is 

 subsequently hydroxylated at carbon 11 to 

 yield corticosterone. Desoxycorticosterone 

 may undergo hydroxylation at carbon 18 

 and at carbon 11 to yield aldosterone, the 

 most potent salt-retaining hormone known 

 (Fig. 11.2). 



Dehydroepiandrosterone is an androgen 

 found in the urine of both men and women. 

 Its rate of excretion is not decreased on 

 castration and it seems to be synthesized 

 only by the adrenal cortex. It has been 

 postulated that pregnenolone is converted 

 to 17-hydroxy pregnenolone and that this, 

 by cleavage of the side chain between car- 

 bon 17 and carbon 20, would yield dehydro- 

 epiandrosterone. 



F. INTERCONVERSIONS OF STEROIDS 



The interconversion of estrone and estra- 

 diol has been shown to occur in a number 

 of human tissues. A diphosphopyridine nu- 

 cleotide-linked enzyme, estradiol- 17/3 de- 

 hydrogenase, which carries out this reaction 

 has been prepared from human placenta 

 and its properties have been described by 

 Langer ancl Engel (1956). The mode of 

 formation of estriol and its isomer, 16-epi- 

 estriol, is as yet unknown. 



There are three major types of reactions 

 which occur in the interconversions of the 

 steroids: dehydrogenation, "hydroxylation," 

 and the oxidative cleavage of the side chain. 

 An example of a dehydrogenation reaction 

 is the conversion of pregnenolone to proges- 

 terone by the enzyme 3-/3-ol dehydrogenase, 

 which requires diphosphopyridine nucleo- 

 tide (DPN) as hydrogen acceptor. This im- 

 portant enzyme, which is involved in the 

 synthesis of progesterone and hence in the 

 synthesis of all of the steroid hormones, is 

 found in the adrenal cortex, ovary, testis, 

 and placenta. Other dehydrogenation reac- 

 tions in which DPN is the usual hydrogen 

 acceptor are the readily reversible conver- 

 sions of A-4-androstenedione ^ testoster- 

 one, estrone ^ estradiol, and progesterone 

 :;^ A-4-3-ketopregnene-20-a-ol. This latter 

 substance, and the enzymes producing it 

 from progesterone, have been found by Zan- 

 der (1958) in the human corpus luteum and 

 placenta. 



The oxidative reactions leading to the 



