Gerald R. Cunha

Stromal-epithelial interactions--I. Induction of prostatic phenotype in urothelium of testicular feminized (Tfm/y) mice.

Heterotypic tissue recombinants (UGM+/+ + BLETfm) were prepared with embryonic wild-type urogenital sinus mesenchyme (UGM+/+) and epithelium of the urinary bladder (BLETfm) of adult Tfm/Y mice. Following 1 month of growth in male hosts, the recombinants contained prostatic acini containing secretory product. In UGM+/++ BLETfm recombinants, secretory activity, epithelial cytodifferentiation, and DNA synthesis were stimulated by testosterone propionate and antagonized with cyproterone acetate. Total cellular protein synthesis was quantitatively and qualitatively similar to that of the prostate and distinct from that of bladder. These data suggest that Tfm epithelium is capable of expressing a prostatic, androgen-sensitive differentiation when grown in association with wild-type urogenital sinus mesenchyme.

Teratogenic effects of clomiphene, tamoxifen, and diethylstilbestrol on the developing human female genital tract

The potential estrogenicity and teratogenicity of triphenylethylene antiestrogens were examined in 54 genital tracts isolated from 4- to 19-week-old human female fetuses and grown for 1 to 2 months in untreated athymic nude mice or host mice treated by subcutaneous pellet with the antiestrogens clomiphene and tamoxifen or the synthetic estrogen diethylstilbestrol (DES). In specimens grown to a gestational age equivalent of 15 weeks or less, the vagina and urogenital sinus were lined by an immature squamous epithelium, which were similar in both drug-treated and untreated specimens. Proliferation and maturation of the squamous vaginal epithelium were observed in specimens treated with clomiphene, tamoxifen, or DES only when grown to a gestational age equivalent of 16 weeks or more. Formation of endometrial and cervical glands proceeded in 87 per cent (13 of 15) of control specimens grown to a gestational age equivalent of 13 weeks or more in untreated hosts. By contrast, age-matched drug-treated specimens contained glands in only 44 per cent (12 of 27) of specimens. In the developing uterine corpus of untreated controls, the uterine mesenchyme segregated into inner (endometrial stroma) and outer (myometrial) layers; whereas in drug-treated specimens, condensation and segregation of the mesenchyme were greatly impaired. The fallopian tube was also affected by clomiphene and tamoxifen (and to a lesser extent by DES) in that its epithelium was hyperplastic and disorganized. The complex mucosal plications characteristic of the fallopian tube were also distorted in drug-treated specimens. These results emphasize the heretofore unrecognized estrogenicity and potential teratogenicity of triphenylethylene antiestrogens on the developing human genital tract and emphasize the need for caution to prevent inadvertent exposure of the developing fetus to these compounds.

Autoradiographic analysis of nuclear estrogen binding sites during postnatal development of the genital tract of female mice

Autoradiographic analysis of [3H]-estrogen nuclear binding sites was performed on developing genital tracts (uterus, cervix and vagina) of mice 1 to 90 days postpartum. During days 1 to 15 postpartum, nuclear estrogen binding sites were observed exclusively within mesenchymal cells; epithelial cells did not exhibit nuclear labelling. At 18 days postpartum vaginal and cervical epithelial cells exhibited nuclear estrogen binding sites for the first time, whereas the initial appearance of estrogen receptor activity in the epithelium of the uterus was detected at 20 days postpartum. Thereafter, nuclear estrogen binding sites were maintained in both epithelial and stromal cells into adulthood. The acquisition of nuclear binding sites within epithelium of female genital organs at 18 days is discussed in terms of epithelial-mesenchymal interactions and the acquisition of growth responsiveness.

Nuclear estrogen binding sites in human endometriosis

With a technique of in vitro steroid autoradiography, the localization of nuclear estrogen binding sites has been studied in ovarian endometriotic foci from untreated patients in both the follicular and luteal phases of the cycle. Unlike the uterine endometrium, which displays cyclic changes in estrogen binding sites, the endometriotic foci show no such changes in the localization of estrogen binding sites. Throughout the cycle, a marked degree of estrogen binding is present in the stromal cells of the endometriotic foci, while in the uterine endometrium stromal binding sites are seen only during the proliferative phase and not during the secretory phase of the cycle. The glandular epithelium of the endometriotic foci displays a patchy localization of nuclear estrogen binding sites at all stages, while the glandular epithelium of the uterus is strongly positive during the proliferative phase but displays no estrogen binding sites during the secretory phase of the cycle. Thus, the endometriotic foci appear to respond differently to ovarian hormones, both in terms of the modulation of estrogen binding and in terms of glandular histology.

Stromal Influence on Expression of Morphological and Functional Characteristics of Urogenital Epithelia

The etiology of malformations of the genital system is based upon knowledge of normal urogenital morphogenesis, genetics, fetal endocrinology, and molecular biology. From these studies it is known that gonadal sex is determined following fertilization through expression of the H-Y antigen, which induces testicular development in the gonadal anlage (Ohno, 1979; Wachtel, 1980) (Fig. 1). Ovarian development occurs in the absence of the H-Y antigen. Once the gonadal sex is specified, subsequent development of internal and external genitalia, as well as sexual differentiation of certain neural centers within the brain, is determined by hormonal conditions within the fetus (Jost et al, 1977; Price and Ortiz, 1965; Wilson et al., 1980). The fetal testes produce androgens that induce masculine development of the internal and external genitalia (Price and Ortiz, 1965; Jost et al., 1977; Winter et al., 1977). The Mullerian Inhibiting Substance, also produced by the fetal testes, causes regression of the Mullerian ducts in male fetuses (see Donohoe et al., 1976, and chapter 9).