THE HISTOGENESIS OF TISSUES SENSITIVE TO OESTROGENS (1940)

Summary 1. Oestrogens stimulate growth not only of the epithelial and fibro‐muscular tissues of the male and female urogenital tracts, but also of certain non‐reproductive tissues (e.g. skin, nasal mucosa, gums). Under normal physiological conditions oestrogenic sensitivity manifests itself histologically both in the orderly proliferation of cylindrical secretory cells (for convenience this response is referred to as “glandular”), and in the proliferation, cornification and desquamation of stratified squamous epithelium (for convenience called “squamous response”). 2. In the main the glandular response is confined to tissues (e.g. uterus, hydatids of Morgagni) which are undoubtedly derived from the Mullerian duct. The squamous response, on the other hand, occurs in tissues which are stated to be derived from the Mullerian and Wolffian ducts, the urogenital sinus (entoderm) and the skin (ectoderm). 3. Presumed Müllerian tissues (e.g. uterus and vagina) are thus capable of both the glandular and squamous types of response. Exmifiation of the embryo‐logical evidence on the development of the vagina in various species, and of evidence derived from the study of natural and experimental intersexuality, suggests, however, that the vaginal epithelium is ultimately derived from the urogenital sinus. It is likely that in cases where the Mullerian ducts contribute to the development of the upper part of the vagina, the Mullerian epithelium is as a rule finally replaced hy sinus epithelium. 4. It is suggested that true Müllerian tissue responds to oestrogens by glandular proliferation, and that epithelial metaplasia and stratification in the reproductive tract in response to oestrogenic stimulation, whatever be its histochemical basis, may in general be regarded anatpmically as a primary response of tissue in whose development oestrogen‐sensitive sinus epithelium has either played a direct or an indirect part. 5. The process of metaplasia whereby the squamous response spreads to parts of the urogenital tract in which it does not normally appear is examined. The points at which the glandular epithelium of organs opening into what was originally the urogenital sinus meets squamous epithelium derived from the sinus are unstable zones of transition, and even in normal circumstances there may be a tendency for stratified squamous epithelium to replace epithelium which is normally cylindrical (in the same way as the originally Mullerian vaginal epithelium appears to be replaced during development by cells from the urogenital sinus). This tendency is increased under the influence of oestrogenic stimulation. 6. Derivatives of the oestrogen‐sensitive sinus may themselves be insensitive. 7. The changes which oestrogens produce in the genital and circumgenital skin of monkeys may be regarded as the peripheral part of a total oestrogen‐sensitive epithelial zone. The most sensitive part of this zone in the female is the vagina, and to some extent, the response, under normal conditions, diminishes progressively the further one proceeds from the very sensitive central area. 8. In species of monkey in which the female has a sexual skin, oestrogenic stimulation causes stratified squamous prolifkration of the male urethral epithelium. In male monkeys in which stratified proliferation of the urethral epithelium has not been observed, the corresponding females have no external sexual skin. 9. Ectodermal elements appear to be involved in the development of the caudal part of the urogenital sinus. 10. It is therefore concluded that although there are developmental distinctions between various urogenital tissues that respond to oestrogenic stimulation, the embryological components of the urogenital system intermix, during development, at their points of contact. Thus the caudal ends of the mesodermal Mullerian and Wolffian ducts are invaded by epithelium from the primarily entodermal urogenital sinus, and the caudal part of the sinus, in turn, is infiltrated with ectodermal cells from the cloacal region. This represents a morphogenetic reflexion of the fact that the oestrogenic responses of the circumgenital and genital skin grade, without any sharp interruption, in the female into those of the vagina, and in the male into those of the urethra, and that the responses of these two organs in turn may extend into organs which open into them.