Steroid metabolism in human fetal skin

摘要

Hydroxysteroid dehydrogenases (HSDs) were first described in human skin by Baillie et al (80). The enzymes were found to be present in the sebaceous glands, and their distribution within these glands has been described. These observations were based on enzyme histochemical methods, and are supported by a large body of biochemical evidence of in vitro steroid metabolism by skin. In vitro incubation studies using skin from subjects in extrauterine life with radioactive steroid substrates have shown the organ to be active in metabolising androgens. Less information is available on the metabolism of oestrogens, progesterone and corticosteroids, but skin has been shown to transform them. The objects of the first part of the study to be described were to investigate the presence and distribution of hydroxysteroid dehydrogenase activity in human fetal skin using an established histochemical technique, and to relate the findings to maturity and sex of the fetus, and the known pattern of activity in skin from subjects in extrauterine life. The localisation of such activity within the skin and within different active components of the skin, would be ascertained. The second part of the study planned the in vitro incubation of skin from freshly stillborn fetuses with radioactive steroid substrates, followed by isolation and identification of the radiometabolites produced, in an attempt to confirm the biochemical reactions implied by the results of the histochemical part of the study, and to elaborate more extensively the pathways of metabolism of androgens by the organ. Two hundred and five specimens of skin from 51 human fetuses ranging from 6 to 41 weeks were incubated to demonstrate the presence of HSDs by histochemical methods. Histochemically demonstrable HSD was noted in fetal skin, and when present was seen only within the acini of the sebaceous glands and in the secretory duct. 17beta-HSD activity was first demonstrated at 16 weeks gestation, when fully functional sebaceous glands were first noted. Demonstrable 3beta- and 16beta-HSD did not appear in the glands until 22 to 24 weeks. There were differences between the fetal pattern of enzyme activity and that already known in skin from subjects in extrauterine life. The change-over to the latter pattern occurred at 38 weeks gestation. No correlation was noted between the pattern of HSD activity and sex of the fetus or body site. In abnormal fetuses the HSD activity and pattern were unaffected providing the architecture of the skin was normal. This was not the case in anencephaly and the abnormal skin architecture noted was accompanied by a marked reduction in activity of the three HSDs under consideration. Twenty four in vitro incubations were performed with skin from 6 fetuses in the three trimesters of human pregnancy, using [3H]-testosterone, [3H]-DHA and [3H]-androstenedione as substrate. The major radiometabolites isolated and identified were androstenedione, 5beta-androstane-3,17-dione,androsterone, epiandrosterone, 5beta-dihydrotestosterone,5beta-androstane-3beta, 17beta-diol, 5beta-androstane-3beta, 17beta-diol, and 5-androstene-3beta,17beta-diol and testosterone from DHA incubations. The data obtained indicated the presence of the following steroid enzymes: 3beta-HSD, 3beta-HSD, 3beta-HSDA4-5 isomerase, 17beta-HSD and an active 5beta-reductase.The latter was particularly active in scrotal skin. The results also confirmed the presence and specificity of the 3beta- and 17beta-HSD demonstrated histochemically, but indicate a degree of insensitivity of the histochemical method. Finally, the results of both these integral parts of the study are discussed, and then significance indicated. It is concluded that human fetal skin is ndoubtedly involved in steroid metabolism, and androgen metabolism in particular. An attempt is made to place the results of these observations in their proper perspective, in terms of fetal skin physiology, and androgen metabolism in the fetus more generally. In terms of steroid metabolism, speculation is made as to the possibility of fetal skin being an excretory route or detoxication centre for steroids, and the role of steroid metabolic activity in the local stimulation and control of fetal sebaceous glands.