HORMONES IN DIFFERENTIATION OF SEX 



143 



1937a, b; Deanesly, 1938; for further dis- 

 cussion see Ponse, 1948). A striking case of 

 adrenal disturbance induced by a sex hor- 

 mone appears in frog tadpoles completely 

 inasculinized by large doses of estradiol. 

 Histologically, the change takes the form 

 of a massive hyperplasia of the adrenal 

 cortical or interrenal tissue (Padoa, 1938, 

 1942; Witschi, 1953; Segal, 1953) which 

 may attain 10 times the normal volume. 

 In this remarkable case, however, the mas- 

 culinization of the ovaries is not caused by 

 the adrenal hyperplasia, because in hypo- 

 physectomized tadpoles the hyperplasia 

 does not occur but the paradoxical mascu- 

 linizing effect still persists. Nevertheless, 

 when excessive doses of sex hormones can 

 induce glandular disturbances of this order, 

 the possibility remains that they may be 

 only secondarily involved in the appearance 

 of paradoxical effects.-^ 



Perhaps the simplest explanation of the 

 paradoxical effects of high dosages lies, 

 however, in the possibility that, when pres- 

 ent in excess, a hormone may be trans- 

 formed in the organism into one of opposite 

 type. In this event two hormones are in fact 

 acting simultaneously and the specificity 

 of the administered substance is not in 

 question. This possibility was first sug- 

 gested by findings in the adults of several 

 mammalian species, including man. Treat- 

 ment with large amounts of testosterone 

 may be followed by excretion of consider- 

 able quantities of estrogen in the urine, 

 which disappears when the male hormone 

 is withdrawn (for the older literature see 

 Burrows 1949, Ch. VI). This may occur in 

 normal males, in castrates or in eunuchoid 

 types. In female subjects the estrogen thus 

 produced is sufficient to stimulate female 

 characters or functions, e.g., a marked hy- 

 perplasia of the vaginal epithelium appears. 

 Without the knowledge that estrogen is be- 

 ing produced this would be regarded as a 

 typical paradoxical effect. Conversion of 

 testosterone to estrone or estradiol also 



-^ For fuller discussions of various forms of para- 

 doxical effects and their interpretations see Gallien 

 (1944, 1950, 1955), Wolff (1947), Ponse (1948), 

 Padoa (1950), Jost (1948a) and Burns (1949, 

 1955b). 



takes place in ovariectomized and adrenal- 

 ectomized women (West, Damast, Sarro and 

 Pearson, 1956). It is evident that neither 

 gonads nor adrenals are necessary for such 

 conversions, which may even occur in vitro 

 (Baggett, Engel, Savard and Dorfman, 

 1956; Wotiz, Davis, Lemon and Gut, 1956). 

 Finally, it has been established that the in- 

 jected male hormone is the actual source of 

 the estrogen by the use of testosterone la- 

 beled with C'^ (Baggett, Engel, Savard and 

 Dorfman, 1956; Wotiz, Davis, Lemon and 

 Gut, 1956; Heard, Jellinek and O'Donnell, 

 1955; for a recent review of this subject see 

 Dorfman, 1957). Although it may be tech- 

 nically difficult to demonstrate such con- 

 versions in embryonic organisms, there are 

 no grounds for supposing that they cannot 

 occur. 



XI. Time of Origin and the Source 

 of Gonad Hormones 



Evidence that the embryonic gonads be- 

 gin to produce their hormones early in the 

 course of sexual differentiation comes from 

 many sources. In the more strongly modi- 

 fied freemartins, conditions indicate that the 

 hormone of the male twin must have been 

 active at an early stage. The ovaries of the 

 female are severely inhibited with almost 

 complete suppression of cortical differentia- 

 tion (Willier, 1921). Lillie (1917) suggested 

 that in such cases the first action of the 

 male hormone might be to produce, in ef- 

 fect, a "castration" of the female twin by 

 suppression of the ovarial cortex. It now ap- 

 pears from the results of actual castration 

 experiments that this point is probably not 

 significant as there is nothing to indicate 

 that the ovary is active endocrinologically 

 at such an early stage (Bascom, 1923) . 



In amphibians, either after parabiosis or 

 transplantation of the gonad priraordium, 

 changes in the gonads can be detected very 

 early in relation to the onset of sex differen- 

 tiation, and in some circumstances reversal 

 occurs by direct differentiation as a gonad 

 of opposite sex. The gonads involved are 

 as a rule widely separated and the hor- 

 monal nature of the transforming agent in 

 these cases is beyond question. Similar 

 indications are found in birds. Embrv- 



