142 



BIOLOGIC BASIS OF SEX 



with a crystalline hormone; and in the 

 manner in which many accessory sex struc- 

 tures or their primordia respond to the ap- 

 proiH'iate hormone, both in vivo and in vitro. 

 It should be emphasized further that para- 

 doxical effects seldom appear to the ex- 

 clusion of normal responses, but usually as 

 accompanying phenomena. For example, 

 large doses of testosterone propionate pro- 

 duce strong hypertrophy of the entire male 

 genital system in opossum embryos as ex- 

 pected; however, they also cause hyper 

 trophy of the Miillerian duct derivatives, a 

 response that disappears at low dosages al- 

 though the effect on male structures remains. 

 In the interpretation of paradoxical ef- 

 fects the problem of direct vs. indirect ac- 

 tion arises. It may be argued tentatively 

 that in sufficient concentration hormones of 

 either type stimulate the primordia of the 

 other sex by direct action ; both sets of pri- 

 mordia are capable of responding but at 

 different thresholds, those of heterotypic 

 structures being very high. Such a situation 

 would permit selective action at ordinary or 

 "physiologic" levels and at the same time 

 account for the appearance of paradoxical 

 effects at higher concentrations. As a mat- 

 ter of fact, the dosages which elicit para- 

 doxical responses are as a rule so far above 

 physiologic levels as to have doubtful sig- 

 nificance for normal differentiation. Evi- 

 dence favoring the thesis of direct action has 

 been cited and in one case at least a typical 

 paradoxical effect has been produced in 

 vitro. Large doses of testosterone propionate 

 have a strong feminizing (i.e., inhibitory) 

 action on the syrinx of the duck in vitro 

 (Wolff and Wolff, 1952a). However, the 

 presumption that the paradoxical action 

 must have been exerted directly does not 

 establish its nature. The high concentration 

 of male hormone obviously has an adverse 

 effect, resembling the inhibitory effect of 

 the female hormone, but the inhibition is 

 possibly of a general nature rather than 

 specific. First attempts to culture the syrinx 

 on a simple synthetic medium also resulted 

 in atypical differentiation (Wolff, Haffen 

 and Wolff, 1953) due apparently to nutri- 

 tive deficiencies. High concentrations of 

 hormones ?>? vitro mav onlv create general 



conditions unfavorable for normal growth 

 and differentiation. 



On the other hand, paradoxical effects are 

 certainly in some cases not mediated di- 

 rectly but are of secondary origin. The fem- 

 inization of the testes that occurs in certain 

 amphibians after treatment with male hor- 

 mones (p. 94; for a summary see Gallien, 

 1955) is an example. An early disturbance 

 of mesonephric development interferes sub- 

 sequently with differentiation of the medul- 

 lary sex cords, thus preventing testicular 

 development. After metamorphosis, when 

 the hormone is withdrawn, a certain recov- 

 ery occurs and development is resumed, but 

 in the virtual absence of the medullary 

 component only the cortical rudiment de- 

 velops. It should be noted, however, that 

 during the hormone phase of this experi- 

 ment there is inhibition of the cortex as well 

 as suppression of the medulla, and it is only 

 after the male hormone is withdrawn that 

 development of the cortex is resumed. Al- 

 though the paradoxical effect on the medulla, 

 is pronounced it is indirect, and it does not 

 occur alone but in conjunction with a par- 

 tial atresia of the cortex. Thus the picture 

 is more complicated than first appears. 



On the other hand, the correlation be- 

 tween the appearance of paradoxical effects 

 and the use of high dosages suggests other 

 possibilities as to the manner in which such 

 effects are mediated. It is a familiar fact in 

 endocrine physiology that prolonged treat- 

 ment with sex hormones disturbs the nor- 

 mal endocrine balances and may influence 

 the activity of other glands. It is possible 

 that certain paradoxical effects may origi- 

 nate in this way. As yet there is no direct 

 evidence of this in embryonic organisms but 

 it is well known that under abnormal or 

 pathologic conditions both the gonads and 

 the adrenal glands of adult animals are 

 capable of producing the hormones of the 

 other sex. This is the case for certain tu- 

 mors of the gonads and adrenal cortex, and 

 it is characteristic of the adrenal hyper- 

 plasias which produce the adrenogenital 

 syndrome in fetal and postnatal life. It is 

 also well established that under abnormal 

 physiologic conditions ovaries may produce 

 considerable amounts of androgen (cf. Hill, 



