Urodynamic findings in men operated on for an undescended testicle.

OBJECTIVE: To test the hypothesis that men with a history of undescended testicle have voiding problems similar to those in rodents exposed to excessive amounts of oestrogens during development, although the role of oestrogen in the failure of the human testicle to descend remains controversial. PATIENTS AND METHODS: Thirteen men (mean age 45 years) previously operated on for an undescended testicle (testis-retention, TR group) and 12 age-matched men operated on for inguinal hernia or appendicitis (control group) participated in a urodynamic examination, transrectal ultrasonography (TRUS) of the prostate, and blood tests for hormones and prostate-specific protein. They also completed a questionnaire on urinary symptoms. RESULTS: The free maximum flow rate was significantly lower and the detrusor pressure at maximum flow (P(det)Q(max)) slightly higher in the TR than the control group. Three men in the TR group (and none of the controls) had bladder outlet obstruction (BOO), whereas voiding was not obstructed among 11 control men (and five men in the TR group). The hormone concentrations of the groups did not differ significantly but the prostates were significantly smaller in the TR group. The testosterone concentrations and the ratio between 17beta-oestradiol (E2) and free testosterone (E2/fT) influenced prostate size significantly. An exploratory analysis suggested that E2/fT may influence the maximum detrusor pressure and P(det)Q(max). CONCLUSION: Men born with an undescended testicle had smaller prostates but more often had BOO than did the controls. The results suggest that an imbalance between the actions of oestrogen and testosterone may influence the initiation and continuance of BOO among cryptorchid men.

Neonatal exposure to diethylstilbestrol permanently alters the basal and 17 beta-estradiol induced expression of c-fos proto-oncogene in mouse urethroprostatic complex.

Perinatal estrogen exposure induces permanent structural and functional changes in the male reproductive tract. We have studied the effect of neonatal estrogenization on the estrogen-responsive c-fos proto-oncogene expression in mouse prostate. Fos is involved in growth and differentiation, and may play a central role in regulating diverse estrogen-related cellular differentiation. In adult control mouse prostate, basal c-fos mRNA expression is very low. Neonatal treatment with diethylstilbestrol on days 1-3 (neoDES) results in permanently increased fos expression in the prostatic urethra and all prostatic lobes. In adult castrated animals, estradiol induces a rapid transient increase in c-fos expression in the prostatic urethra, with maximum induction being higher in neoDES animals. In situ hybridization and immunohistochemistry show that in neoDES mice fos transcripts and protein are localized primarily in the epithelium of posterior periurethral prostatic collecting ducts. These are the sites previously reported to show the most pronounced morphological changes after estrogen treatment. Our results indicate that neonatal estrogenization affects both basal and estrogen stimulated c-fos mRNA levels in the prostate of mature mice, which supports the hypothesis that estrogen-induced morphological changes in mouse prostate may involve altered c-fos expression.

Dietary soybean may be antiestrogenic in male mice.

We tested whether dietary soybeans alter prostatic growth and development of prostatic dysplasia in mice that were treated with a synthetic nonsteroidal estrogen, diethylstilbestrol during the first 3 d after birth. Soybeans were chosen because they contain substantial amounts of isoflavonic estrogens. The presence of estrogenic isoflavonoids in soybean-containing feed was confirmed by measuring the excretion of seven different plant estrogens in the urine of normal adult male mice. Estrogenicity of dietary soybean was confirmed by the growth response in uteruses of immature mice. In addition to their estrogenic effect, antiestrogenic properties of soybeans on uterine growth were observed in the presence of a more potent estrogenic growth stimulator, diethylstilbestrol in feed. In neonatally estrogenized male mice, soybean feeding reduced the prostatic growth inhibition due to diethylstilbestrol and, in preliminary experiments, delayed the development of dysplastic changes in the prostate. The number of animals showing severe dysplasia in prostatic epithelium was significantly lower in 9-mo-old animals given soybean-containing feed from fertilization onwards, but in 12 mo-old animals the difference was less obvious and was not significant. Our findings suggest an antiestrogenic action for dietary soybean in male mice, which may be important for the hormonal regulation of normal as well as neoplastic prostatic growth.

Interaction of male and female sex hormones in cultured rat prostate.

The organ culture of the rat ventral prostate was chosen as a model to determine whether any of the estrogen effects in vivo on the prostate are direct and expressed at the hormone concentrations normally found in the male. During 2 weeks of culture, estradiol at the high concentration of 10(-5) M blocked the androgenic activation of [3H]thymidine incorporation into DNA. The inhibition was localized in epithelium. Protein content of testosterone-treated explants and the accumulation of prostatein in the medium were considerably decreased, indicating inhibition of secretion. Antiandrogenic effects were not seen in morphology of estrogen-treated explants. The lower concentrations (from 10(-9) M to 10(-6) M) of estradiol increased the volume density of epithelium from day 7 onwards. The height of epithelium was concomitantly increased. The volume density of epithelium as well as the percentage of acini with metaplastic changes were significantly increased. These epithelial changes were less pronounced in the presence of androgen, suggesting that physiological concentrations of androgen prevent the expression of estrogen action in the morphology of the prostate. A change in staining with peanut (PNA)- and wheat germ agglutinin (WGA)-lectins indicated defective secretory capacity in metaplastic epithelium. In spite of the increased protein content in the explants, no constant pattern of the changes in prostatein accumulation could be recorded. Although the concentrations of estrogen required to induce squamous metaplasia were still unphysiological, the occurrence of this abnormal differentiation of the prostatic epithelium suggests that the cooperative action of estrogen is involved in androgen-dependent normal epithelial growth and possibly also in promoting growth of prostatic neoplasia.

Effect of glucose on the major testosterone-maintained protein in the cultured rat ventral prostate.

The effect of glucose on the androgen-maintained protein synthesis was studied in the cultured rat ventral prostate. The explants were cultivated for 5 days in the glucose-free medium containing 10% fetal calf serum with or without 10 mM glucose and 10(-7) M testosterone. In some experiments tunicamycin, a specific inhibitor of protein glycosylation was added to the glucose-containing medium. The morphological integrity of the tissue was maintained in all the mediums used. At the end of the culture, the explants were incubated with [35S]methionine. Soluble radioactive proteins were separated by the SDS-polyacrylamide gel electrophoresis and analyzed further by the fluorography. Glucose was necessary for the testosterone-maintained accumulation of three components (Mr less than 14,000) of the major prostatic secretory protein. The electrophoretic migration, glycosylation pattern and immunological data (not shown) indicated that it was the well-known prostatic binding protein. On the other hand, two prominent polypeptides (Mr 70,000 and 100,000) appeared in the absence of glucose. Glucose starvation and the inhibition of glycosylation with tunicamycin caused similar effects on the labelling of the newly-synthesized soluble proteins. The mechanisms of glucose maintenance of the major prostatic protein and suppression of two high molecular weight proteins seemed to be different, although glycosylation was probably involved in both glucose effects.

Indirect androgenic control of citrate accumulation in rat ventral prostate.

Androgenic control of citrate metabolism was studied by measuring the conversion of (2-14C)acetate or (6-14C)glucose to (14C)citrate and 14CO2 in the ventral prostate of the rat. The decarboxylation of (2-14C)acetate showed that androgen preferentially increased (14C)citrate oxidation, probably to meet the increased energy demands of cellular synthetic reactions. This led to the decreased accumulation of (14C)citrate from (2-14C)acetate. On the other hand, both the production of (14C)citrate and the formation of 14CO2 from (6-14C)glucose were decreased by castration and increased by testosterone, this being mainly due to the androgenic control of pyruvate dehydrogenase. These changes were more marked and rapid than those in oxygen consumption, in (2-14C)acetate oxidation, or in the total content of prostatic citrate that was maintained by testosterone. Glucose as the main source of citrate in testosterone-treated rats can thus be replaced by alternative substrates in castrated rats. The rate of citrate accumulation could be more dependent on the number of secretory cells than their hormonal activation.

Development of human fetal prostate in culture.

The direct influence of androgens on prostatic development was studied by culturing explants of urogenital sinuses of human embryos and fetuses aged 6 to 13 weeks in the presence of either (10(-7) mol/l testosterone or dihydrotestosterone for 6 days. The differentiation of prostatic epithelial cells started both in control and androgen-treated explants in the ninth week, and androgens accelerated the differentiation of the secretory pathway organelles in the epithelial cells. The amount of granular endoplasmic reticulum and the number of Golgi complexes increased in the presence of androgens, especially in the older fetuses. Incipient secretory activity appeared in some cells during the culture and the differentiation occurred sooner in the androgen-treated explants than in the controls or in vivo. The differentiation and maintenance of the urogenital mesenchyme was also better in the presence of the hormone. The direct epitheliomesenchymal cell contacts seen earlier in vivo were also seen during the differentiation in vitro. These contacts may indicate an inductive role of the mesenchyme in the glandular morphogenesis. Androgens were not able to induce the epithelial differentiation in vitro before the first signs of mesenchymal differentiation were evident in vivo. The results suggest either that the mesenchymal changes are not solely determined by androgens or that the early explants may require additional factors for proper differentiation.