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This review has characterized the current state of knowledge of four clinical situations in which an interrelationship of gynecology, endocrinology and carbohydrate metabolism is recognized. The literature contains conflicting descriptions of changes in glucose homeostasis during the menstrual cycle and while using birth control pills. Physiologic changes in receptor number have been demonstrated in each of these situations, so failure to observe differences using glucose tolerance testing may reflect an in vivo homeostatic response to changes in these hormone levels. Thus, in vivo identification of alterations in carbohydrate metabolism induced by endogenous or exogenous steroids may require utilization of models that prevent these homeostatic mechanisms. The association between hyperandrogenism and hyperinsulinism has been better characterized, but the relationship is complicated by the frequent coexistence of obesity. The association may be due to insulin-stimulated ovarian androgen production, and insulin insensitivity may reflect a postreceptor defect. Insulin and its metabolic effects have also been implicated in ovulatory dysfunction in women with diabetes mellitus and identified as a factor affecting all levels of the hypothalamic-pituitary-ovarian axis. A clearer understanding of these relationships and their application to clinical management await further study.
After castration, the rat dorsolateral prostate M-40 mRNA initially decreased then rebounded to precastrated levels. The cellular site of M-40 expression and its renewed expression after castration was defined by in situ hybridization histochemistry. In situ hybridization with either a 32P-labeled or biotin-labeled M-40 cDNA probe demonstrated that M-40 mRNA levels were higher in the lateral than dorsal prostate. A second androgen regulated gene, RWB, also was highly expressed in the lateral prostate. The biotinylated cDNA probes provided microscopic resolution of the expressing cells, revealing two distinct morphologies of lateral epithelium which expressed both the M-40 and RWB mRNA. These morphologies appeared in ducts which contained either epithelial cell sheets that were highly convoluted or thinner epithelial cells with a minimal degree of convolution. The RWB mRNA decreased in both cell populations in response to androgen withdrawal. The decline and reappearance of M-40 mRNA also appeared in both epithelial cell types. These data demonstrated that after castration the M-40 mRNA initially decreased as expected for an androgen sensitive gene and then progressed to a fully inducible state. The mechanism of this progression remains to be elucidated.
Prostatic epithelial cells undergo rapid proliferation and lose their ability to synthesize and secrete prostate-specific antigen (PSA) and prostatic acid phosphatase (PAP) under standard tissue culture conditions. Herein, we compared the morphology, growth, secretory activity, and intermediate filament expression of human prostatic epithelial cells cultured on either standard tissue culture plastic or reconstituted basement membrane. Epithelial cells grown on plastic exhibited a 10-fold increase in proliferation and a higher percentage of cells in the S-phase of the cell cycle compared to cells cultured on basement membrane. However, cells grown on basement membrane secreted markedly higher levels of PSA and PAP. The basement membrane-induced enhancement of secretory activity was potentiated by dihydrotestosterone (DHT) and prostate stromal cell conditioned medium. Morphological studies showed that cells plated on basement membrane formed organoid-like clusters and maintained several aspects of differentiated epithelium including abundant secretory vesicles, microvilli, and desmosomes with associated cytoskeletal elements. Cultivation of epithelial cells on basement membrane components also suppressed the expression of vimentin, a mesenchymal intermediate filament polypeptide. However, cytokeratin expression was abnormal in cells grown on either surface. These results indicate that the differentiated properties of prostatic epithelial cells are promoted by cultivation on reconstituted basement membrane in the presence of DHT and stromal cell conditioned medium.
To examine the developmental expression and regulation of P450SCC and P450(17 alpha) in the rat placenta, trophoblast and decidual tissue were removed by dissection from conceptuses obtained from rats on selected days of pregnancy. Total cellular and poly(A)+ RNA and microsomal and mitochondrial fractions were isolated and analyzed for the presence of P450(17) alpha and P450SCC messenger RNA (mRNA) and protein by Northern and Western blot analysis. P450(17) alpha and P450SCC mRNA were detected in the trophoblast but not in the decidual tissue. Western blot studies demonstrated that the immunoreactive P450(17) alpha in the rat placenta is a 79-kilodalton protein, having a slower mobility in sodium dodecyl sulfate-polyacrylamide gel electrophoresis than has been reported for other tissue. Antiserum preabsorbed with pure P450(17) alpha was unable to detect this protein, and immunoprecipitation indicated that it is associated with enzyme activity. Development studies have revealed that the two steroidogenic enzymes are differentially expressed during the progression of pregnancy. Whereas P450SCC mRNA and protein increase abruptly between days 10-12 of pregnancy, decline thereafter, and remain low, those of P450(17) alpha increase slowly and progressively, peaking on day 18 and declining just before parturition. It is the changes in P450(17) alpha and not that of P450SCC which appear to be intimately linked to the previously reported changes in placental production of androgen. To examine whether P450(17) alpha and/or P450SCC became expressed from midpregnancy because of the rapid decline in LH that occurs at this stage, pregnant rats were treated with low but sustained levels of human CG (hCG) in order to prevent the drop in LH activity. hCG treatment caused a remarkable down regulation in the expression of both P450SCC and P450(17) alpha message and protein. In summary, the results of this investigation have established, for the first time, the presence of messages for both P450(17) alpha and P450SCC in the trophoblast tissue forming the rat placenta. The results have revealed that these two enzymes are differentially expressed during the progression of pregnancy and that the expression of their genes is down-regulated by LH/hCG.
A functional model of adult human prostate epithelium is described. This model shows that stromal cells, but not an androgenic stimuli, are required for architectural organisation of prostate epithelium. Within an organised structure, androgenic stimulation is required for the establishment of secretory epithelial cell morphology and associated function. In the absence of stromal cells but in the presence of androgens architectural organisation and secretory function are lost. Epithelial parenchymal units (organoids) from human prostate tissue were isolated, cultured within a three-dimensional collagen matrix, and xenografted subcutaneously into athymic mouse hosts. The grafted gels were rapidly invaded by host fibroblasts. Epithelial organisation initially disappeared but was re-established concurrently with the stromal cell invasion. In intact male hosts, cuboidal and columnar cells that expressed human prostate-specific secretory markers were found. In castrated male and in female hosts epithelial structures were lined with flattened epithelium with no secretory function. This phenomenon could be reversibly replicated by treating intact male hosts with the anti-androgen Flutamide. Gels containing organoids grafted within 0.45 microns Millipore chambers were not invaded by stromal cells and rapidly lost all epithelial organisation and secretory function. When organoids cocultured with human foreskin fibroblasts were grafted within chambers, structural organisation of the epithelium was supported. These results indicate that both heterologous human fibroblasts and mouse stromal cells are capable of permissively supporting adult human prostate epithelial function.
A cDNA representing a 5.2-kb defective, endogenous murine leukemia proviral sequence (EPI-EPS) was isolated from a C57BL/6 mouse cDNA epididymal library. Northern blot analysis demonstrated that EPI-EPS was predominantly expressed in the C57BL/6 mouse epididymis and vas deferens with 10-fold lower expression in the seminal vesicle, kidney, and submandibular gland. Analysis of tissues from other inbred strains of mice as well as the wild mouse, Mus musculus musculus, showed a similar pattern of tissue expression. EPI-EPS expression was also highly androgen regulated in both the reproductive and nonreproductive tissues of the C57BL/6 strain. However, a differential response to testosterone replacement was observed between tissues. Expression of EPI-EPS mRNA in the epididymis and vas deferens exhibited only a partial recovery to precastration levels after testosterone replacement; in the kidney and submandibular gland there was a complete recovery of EPI-EPS expression. Finally, EPI-EPS expression was also highly restricted in the female tissues, with expression limited to the oviduct and uterus. EPI-EPS, however, was not estrogen regulated in the female. These results suggest that a proviral sequence, EPI-EPS, is expressed in M. m. musculus and several inbred strains of mice due to its integration near a highly tissue-specific and androgen-regulated genetic locus.
A series of enzymatic steps in the testis lead to the conversion of cholesterol to the male sex steroid hormones, testosterone and 5 alpha-dihydrotestosterone. Mutations in any one of these steps are presumed to alter or block the development of the male phenotype. Most of the genes encoding the enzymes involved in this pathway have now been cloned, and mutations within the coding regions of these genes do, in fact, block development of the male phenotype.