Urinogenital System 



485 



velop as a result of indirect action on the 

 gonad, depressing or abolishing an in- 

 hibitory mechanism. When, however (as 

 frequently happens under experimental con- 

 ditions), the parts in question are differ- 

 entiated precociously, or show marked hyper- 

 trophy in comparison with normal struc- 

 tures, direct stimulation by the introduced 

 hormone is indicated (Fig. 190). Direct ac- 

 tion is also indicated when castration effects 

 are prevented by hormones (p. 483). The 

 differentiation of structures of the second 

 class probably always involves direct action. 



Specificity of Hormone Action. Evidence 

 has been presented showing that, on the 

 whole, the actions of hormones are specific 

 in the sense that a given type of hormone has 

 a stimulatory action on structures of the 

 proper sex, while inhibiting various hetero- 

 typic structures. Specificity of action has 

 been denied, however, largely on the basis 

 of paradoxical effects, various examples of 

 which have been cited. [For a summary of 

 the paradoxical effects of various steroid 

 hormones see Wolff, Strudel and Wolff 

 ('48).] To be valid this argument must as- 

 sume that such effects are the result of direct 

 action of the hormone on heterotypic sex 

 primordia. But in some of the best known 

 cases of paradoxical effects it is probable 

 that the action is mediated indirectly, and 

 in many instances excessive dosage is the 

 determining factor. It must be recalled that 

 under certain conditions gonads also exert 

 paradoxical effects in which the action in- 

 volves production of the hormone of the other 

 sex (for examples see Ponse, '48; Hill, '50). 



The paradoxical effects of high dosages are 

 well known. For example, in opossum em- 

 bryos receiving large doses of male hormone 

 extreme stimulation of male structures is 

 also accompanied by hypertrophy of Miil- 

 lerian dvict derivatives in both sexes. The 

 latter effect declines rapidly with dosage, 

 and below a certain level disappears com- 

 pletely, although male structures are still 

 stimulated (Burns, '42, '45a). A similar 

 situation appears in many experiments with 

 amphibians. [For paradoxical effects on the 

 gonads see Padoa ('36, '38, '42); Gallien 

 ('41, '44); Vannini ('46); and for the Miil- 

 lerian dvicts, Mintz ('47).] Large doses of 

 female hormone have a strong masculinizing 

 effect on gonads, but low doses are feminiz- 

 ing only. Indeed, the same substance (es- 

 tradiol), in the same dosage, may have 

 opposite effects depending on the solvent. In 

 aqueous solution there is a masculinizing 

 effect and in oil an orthodox action (Gallien, 



'41). The rate of utilization — in effect a 

 difference in dosage — is evidently the deter- 

 mining factor. 



The question remains as to how the para- 

 doxical effects of large dosages are exerted. 

 If, for example, female primordia can re- 

 spond directly to a sufficient concentration 

 of male hormone, only a difference in 

 threshold between male and female pri- 

 mordia is involved, and to this extent the 

 hormone is "ambisexual." But when the 

 dose required to elicit a paradoxical response 

 so far exceeds physiological limits, the result 

 has little significance for normal differentia- 

 tion. There is, however, much evidence sug- 

 gesting that paradoxical effects are exerted 

 indirectly. Masculinization of gonads by 

 large doses of female hormone is known in 

 some cases to be associated with strong hy- 

 perplasia of the interrenal (adrenal cortical) 

 tissue (e.g., Padoa, '38, '42; Witschi, '51b), 

 a potential sovirce of androgen; and in vari- 

 ous mammals (see Burrows, '45) treatment 

 with large doses of male hormone is followed 

 by excretion of estrogens, in both intact and 

 castrate individuals. This phenomenon has 

 not as yet been demonstrated in embryos 

 but the possibility must always be consid- 

 ered. On the whole, the evidence provided 

 by paradoxical effects seems at present in- 

 conclusive and greatly outweighed by the 

 many unqvialified examples of specific action. 



Embryonic versus Adult Hormones. The re- 

 sults of parabiosis and various types of gonad 

 grafting in amphibian and bird embryos 

 demonstrate that embryonic gonads produce 

 sex-differentiating substances which are 

 transported and act in the manner of hor- 

 mones (cf. also the freemartin). The results 

 of embryonic castration confirm this view in 

 the strongest possible manner. A question as 

 to the nature of embryonic hormones, and 

 their relation to adult sex hormones, is nat- 

 urally posed. The appearance of paradoxical 

 effects, and the fact that steroid hormones do 

 not in all cases produce complete and inte- 

 grated transformations, have led to the view 

 that embryonic hormones are chemically and 

 physiologically different. But when the re- 

 sponses of sex primordia to steroid hormones 

 are compared with those produced by em- 

 bryonic gonads in various types of grafting 

 experiments, no essential differences appear. 

 There is in most cases a high degree of 

 specificity in the responses to steroid hor- 

 mones, and the mechanism of action (stim- 

 ulation-inhibition) seems identical for many 

 structures. The significance of paradoxical 

 effects has been discussed. 



