In Utero and Lactational TCDD Exposure Increases Susceptibility to Lower Urinary Tract Dysfunction in Adulthood.

Benign prostatic hyperplasia, prostate cancer, and changes in the ratio of circulating testosterone and estradiol often occur concurrently in aging men and can lead to lower urinary tract (LUT) dysfunction. To explore the possibility of a fetal basis for the development of LUT dysfunction in adulthood, Tg(CMV-cre);Nkx3-1(+/-);Pten(fl/+) mice, which are genetically predisposed to prostate neoplasia, were exposedin uteroand during lactation to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD, 1 µg/kg po) or corn oil vehicle (5 ml/kg) after a single maternal dose on 13 days post coitus, and subsequently were aged without further manipulation, or at 8 weeks of age were exposed to exogenous 17 ß-estradiol (2.5 mg) and testosterone (25 mg) (T+E2) via slow release subcutaneous implants.In uteroand lactational (IUL) TCDD exposure in the absence of exogenous hormone treatment reduced voiding pressure in adult mice, but otherwise had little effect on mouse LUT anatomy or function. By comparison, IUL TCDD exposure followed by exogenous hormone treatment increased relative kidney, bladder, dorsolateral prostate, and seminal vesicle weights, hydronephrosis incidence, and prostate epithelial cell proliferation, thickened prostate periductal smooth muscle, and altered prostate and bladder collagen fiber distribution. We propose a 2-hit model whereby IUL TCDD exposure sensitizes mice to exogenous-hormone-induced urinary tract dysfunction later in life.

[Vesiculectomy with laparoscopic partial prostatectomy in the treatment of primary adenocarcinoma of the seminal vesicle with carcinomatous transformation of the ejaculatory duct]. / Vesiculectomía con prostatectomía parcial laparoscópica en el tratamiento del adenocarcinoma primario de vesícula seminal con transformación carcinomatosa del conducto eyaculador.

INTRODUCTION: Primary adenocarcinoma of the seminal vesicle is an extremely rare condition. Some cases have been described in relation to congenital seminal vesicle cysts, which is often also associated with agenesia or ipsilateral renal disgenesia. The rareness of this type of lesions makes it difficult to plan a regulated surgical approach for them, although they are often treated by simple exeresis or exenteration, depending on their stage at the beginning. MATERIALS AND METHODS: We present a new surgical technique that consists of radical vesiculectomy associated with laparoscopic partial prostatectomy (total segmentary) of the central area to successfully treat primary seminal vesicle adenocarcinoma in a young man who was diagnosed through an azoospermia study. RESULTS: A study of the scan (MRI) with diffusion and the transrectal biopsy of the mass allowed us to make a thorough preoperative evaluation of the case, confirming the malignity and precociousness of the lesion. The laparoscopic approach allowed us to perform a pelvic lymphadenectomy and transperitoneal exeresis, including the central prostate area and suture of the posterior face of the urethra at the height of the apex of the prostate. The wall of the seminal cyst lesion confirmed infiltrating clear cell adenocarcinoma and non-invasive adenocarcinoma in the prostate segment of the central gland in the light of the ejaculatory conduct with "in situ" growth. Thus, the surgical specimen allowed radical exeresis with negative margins, guaranteeing minimally invasive surgery with preservation of continence and erection. CONCLUSION: We describe a new integral approach for the radical surgery of localized primary adenocarcinoma of the seminal vesicle. Despite its exceptional nature, the case allowed for a double reflection: a) The study of diffusion with MRI may suggest the diagnosis of malignity in this type of lesions; and b) Radical surgical treatment must include exeresis of the central portion of the prostate gland.

[Unilateral agenesis of structures dependent on the mesonephric duct. Presentation of a case]. / Agenesia unilateral de las estructuras dependientes del conducto mesonéfrico. Presentación de un caso.

The mesonefric duct plays an essential role in the development of the genitourinary tract. From that duct derive structures as the ureter, the vas deferens and the seminal vesicles. Also, the ureteral bud interact with the mesonefric blastema and induce its conversion to renal tissue. The origin of these anomalies of the embrionary development is unknown. In some cases, mutations on the gene of the cystic fibrosis (CFRT) could play a role, assuming that there is a relationship between the congenital absence of the vas deferens and the cystic fibrosis. Usually, the absence of these structures has a silent course. Thus, the most important diagnostic factor is the clinical suspicion. The knowledge of this association can lead to the diagnosis of other congenital abnormalities. In addition, it is important to know that these anomalies could be present isolated as expression of other non-urological diseases, specially the cystic fibrosis, the most common hereditary disease between the Caucasian race.

Spontaneous mutation in mice provides new insight into the genetic mechanisms that pattern the seminal vesicles and prostate gland.

The seminal vesicles and prostate gland are anatomically adjacent male sex-accessory glands. Although they arise from different embryonic precursor structures and express distinct sets of secretory proteins, these organs share common features in their developmental biology. A key shared developmental feature is the elaboration of complex secretory epithelia with tremendous surface area from simple precursor structures with juxtaposed epithelial and mesenchymal cells. In this study, new insight into the nature of the biological processes that underlie glandular morphogenesis is achieved by analyzing the phenotypes present in mice that harbor a spontaneous mutation, seminal vesicle shape (svs), previously identified for causing altered seminal vesicle morphology in adults. An examination of seminal vesicle development in svs mice provides the first evidence that the concurrent processes of epithelial branching and epithelial infolding are distinct processes under separate genetic control. It also provides the first direct evidence that the thickness and topology of the smooth muscle layer in the seminal vesicles are determined by interaction with the glandular epithelium during the branching process. In addition, the seminal vesicle phenotype in svs mice is shown to phenocopy the morphologic form present in certain other mammals such as the guinea pig, raising the possibility that the svs mutation is the sort of variant that arises during evolution. By also including an investigation of the prostate gland, this study also identifies previously unrecognized phenotypes in svs prostates, including increased gland size and dramatically reduced levels of branching morphogenesis. Finally, this study advances the goal of identifying the svs gene by mapping the svs mutation relative to known molecular markers and testing Fgfr2 as a candidate gene. The finding that the svs mutation maps to a genomic region syntenic to a region frequently deleted in human prostate tumors, together with the prostatic phenotype present in svs mice, further raises the interesting possibility that the svs mutation will identify a candidate prostate tumor suppressor gene.

Critical windows of vulnerability for effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin on prostate and seminal vesicle development in C57BL/6 mice.

A single maternal dose of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on gestation day (GD) 13 can greatly impair ventral prostate, dorsolateral prostate, anterior prostate, and seminal vesicle development in wild-type C57BL/6 mice. The developmental stages at which these organs are most sensitive to TCDD exposure have now been investigated. Pregnant mice were dosed orally with 5 micro g TCDD/kg or vehicle on GD 13, and their pups were fostered at birth to dams of the same treatment or cross-fostered to dams of the opposite treatment. Additional males had in utero and lactational TCDD exposure following maternal dosing on GD 16. Organ weights and secretory protein, cytokeratin 8, and cyclophilin mRNA expression were determined at 35 days of age. Effects of TCDD on ventral prostate development were due primarily to in utero exposure; the critical window was between GD 13 and birth. Dorsolateral prostate development was inhibited about equally by in utero or lactational exposure, and vulnerability did not begin until GD 16. Anterior prostate development was also affected by both in utero and lactational TCDD exposure, particularly the former. Vulnerability began before GD 16 and continued into postnatal life. Seminal vesicle development was essentially unaffected by in utero or lactational exposure alone but was significantly inhibited by combined exposure, regardless of whether dams were dosed on GD 13 or 16. In summary, the time during which each organ was most vulnerable to TCDD exposure varied from one organ to another. These findings provide insights into the developmental processes that TCDD inhibits in each organ, and demonstrate that TCDD inhibits ventral prostate development before this organ first appears, presumably via effects on the urogenital sinus. The observation that in utero TCDD exposure (alone) inhibited development of each prostate lobe is significant because previous studies have shown that little TCDD is transmitted to mice before birth.

The BMP family member Gdf7 is required for seminal vesicle growth, branching morphogenesis, and cytodifferentiation.

Epithelial-mesenchymal interactions play an important role in the development of many different organs and tissues. The secretory glands of the male reproductive system, including the prostate and seminal vesicles, are derived from epithelial precursors. Signals from the underlying mesenchyme are required for normal growth, branching, and differentiation of the seminal vesicle epithelium. Here, we show that a member of the BMP family, Gdf7, is required for normal seminal vesicle development. Expression and tissue recombination experiments suggest that Gdf7 is a mesenchymal signal that acts in a paracrine fashion to control the differentiation of the seminal vesicle epithelium.

Nkx3.1, a murine homolog of Ddrosophila bagpipe, regulates epithelial ductal branching and proliferation of the prostate and palatine glands.

Nkx3.1 is a homeobox gene related to Drosophila bagpipe. Nkx3.1 is an early marker of the sclerotome and a subset of vascular smooth muscle cells, and at later stages, this gene is expressed in the prostate, palatine glands, kidney, and restricted regions of the central nervous system. In the present study, we determined the chromosomal localization of Nkx3.1 and examined the function of Nkx3. 1 in vivo by using gene targeting technique. Interestingly, Nkx3.1 mapped to the central region of the mouse chromosome 14 and was linked to Nkx2.6, a murine homolog of Drosophila tinman. Homozygous mutant mice for Nkx3.1 were viable and fertile, and the phenotype was, unexpectedly, confined to the prostate and palatine glands. The homozygous mutant mice exhibited defective branching morphogenesis of the prostate and palatine glands. Moreover, epithelial cells of the mutant prostate and palatine glands showed significant hyperplasia. No abnormalities were detected in the sclerotome, blood vessels, kidney, or brain. These results indicate that Nkx3.1 plays a critical role in epithelial branching and proliferation in the prostate and palatine glands. However, we did not observe prostate cancer in homozygous mutant mice up to 2 years of age. Therefore, involvement of NKX3.1 in carcinogenesis in men needs to be carefully determined by further investigation.

Immunohistochemical localization of cyclooxygenase-1 and cyclooxygenase-2 in the human fetal and adult male reproductive tracts.

The first rate-limiting step in the conversion of arachidonic acid to PGs is catalyzed by cyclooxygenase (Cox). Two isoforms of Cox have been identified, Cox-1 (constitutively expressed) and Cox-2 (inducible form), which are the products of two different genes. In this study we describe the immunohistochemical localization of Cox-1 and -2 in the human male fetal and adult reproductive tracts. There was no Cox-1 expression in fetal samples (prostate, seminal vesicles, or ejaculatory ducts), and only minimal expression in adult tissues. There was no expression of Cox-2 in the fetal prostate. In a prepubertal prostate there was some Cox-2 expression that localized exclusively to the smooth muscle cells of the transition zone. In adult hyperplastic prostates, Cox-2 was strongly expressed in smooth muscle cells, with no expression in the luminal epithelial cells. Cox-2 was strongly expressed in epithelial cells of both fetal and adult seminal vesicles and ejaculatory ducts. The Cox-2 staining intensity in the fetal ejaculatory ducts during various times of gestation correlated with previously reported testosterone production rates by the fetal testis. These data indicate that Cox-2 is the predominant isoform expressed in the fetal male reproductive tract, and its expression may be regulated by androgens. The distinct cell type-specific expression patterns of Cox-2 in the prostate (smooth muscle) vs. the seminal vesicles and ejaculatory ducts (epithelium) may reflect the different roles of PGs in these tissues.

[Malformations of Wolffian duct derived male genital organs (epididymis, vas deferens, seminal vesicules, ejaculatory ducts)]. / Malformations des organes génitaux masculins issus du canal de Wolff (épididyme, déférent, vésicule séminale, canal éjaculateur).

OBJECTIVES: To analyse embryological phenomena, in order to define a practical approach to management. METHODS: The authors reviewed the files of eight boys with an abnormality of Wolffian duct derived genital organs, consisting of three cases of vas deferens agenesis, two of which were accompanied by homolateral renal agenesis, one case of ectopic vas deferens with contralateral renal agenesis, three cases of duplicated vas deferens and one congenital seminal vesicle cyst with renal agenesis. DISCUSSION: Congenital malformations of the epididymis consist of cysts and agenesis or partial atresia. Cysts essentially raise a problem of differential diagnosis. Treatment is only required in the case of severe discomfort. Vas deferens agenesis is the commonest lesion, an incidental finding in children. An experimental treatment is proposed in adults. Duplications, interdeferential communications and deferentomegaly are much rarer lesions. Seminal vesicle cysts are well visualized by transrectal ultrasonography and should be treated surgically. Lastly, ejaculatory ducts may present urethroseminal reflux or may be ectopic. CONCLUSION: The possibility of absent or ectopic vas deferens should be considered in the case of unilateral renal agenesis. Vas deferens agenesis justifies examination of the contralateral side and investigation to exclude renal agenesis. Congenital cysts of the epididymis only require surgery when they are symptomatic. The presence of ipsilateral renal agenesis should be investigated in the case of cystic dilatation of the seminal vesicle.

Male accessory sex organ morphogenesis is altered by loss of function of Hoxd-13.

The role of the Hox gene Hoxd-13 in postnatal morphogenesis of the male accessory sex organs was examined by correlating the distribution and temporal regulation of expression in the accessory sex organs of postnatal mice with morphologic abnormalities of Hoxd-13-deficient transgenic mice. Previous studies of Hoxd-13 expression in the perinatal period have shown a broad domain of expression in the lower genitourinary tract, with expression in both mesenchyme and epithelium; focal expression was also noted in the epithelium of the nascent ducts of the developing prostate. Quantitative RT-PCR studies of Hoxd-13 expression in the 5 day mouse confirm widespread expression in the accessory sex organs developing from both the Wolffian duct and the urogenital sinus. Expression is down-regulated with age, and a detailed time course of expression in the developing prostate shows that the level of Hoxd-13 expression correlates with morphogenetic activity in the development of the prostate ductal system. Transgenic Hoxd-13-deficient mice display multiple abnormalities in the male accessory sex organs. The most severe abnormalities were observed in organs exhibiting ductal branching during postnatal development and included diminished mesenchymal folding in the seminal vesicles, decreased size and diminished ductal branching in the ventral and dorsal prostate, and agenesis of the bulbourethral gland. We conclude that Hoxd-13 expression in the postnatal period correlates with a period of intense morphogenetic activity in accessory sex organ development and that the function of Hoxd-13 is evidenced by morphologic abnormalities in accessory sex organs of the Hoxd-13-deficient mutant.

Surgical treatment of bilateral large seminal vesicle cysts associated with unilateral renoureteral agenesis.

A 26-year-old man presented bilateral cysts of the vesicles, larger on the right side, associated with agenesis of right kidney and ureter. Surgical treatment consisted of removal of the right cyst and volume reduction of the left one. The embryological aspects are discussed, together with the clinical findings and the treatment options.

Change in morphological and functional cytodifferentiation induced by seminal vesicle mesenchyme in cell suspensions of rat Dunning prostatic adenocarcinoma cells.

Previous experiments have shown that seminal vesicle mesenchyme (SVM) can induce small 0.5 mm fragments of the rat Dunning tumor (DT) to undergo secretory differentiation with a concomitant reduction in tumorigenesis. In the present experiments Dunning tumor epithelial cells (DTE) were purified from DT cell suspensions by Percoll gradient centrifugation and recombined with neonatal rat SVM. The resultant tissue recombinants (SVM + DTE) were grafted under the renal capsule of male athymic mice and grown for 2 months. Under these conditions SVM induced the DTE to exhibit a highly differentiated secretory phenotype by forming ducts lined with tall columnar epithelial cells or large clear cells with pale cytoplasm. Undifferentiated epithelial cells of the parental DT were rarely observed in these tissue recombinants. The loss of tumorigenicity in SVM + DTE recombinants was associated with a striking reduction of epithelial 3H-thymidine labeling index in SVM + DTE recombinants (DT = 8.31%; SVM + DTE recombinants = 1.10%). Differences in putative secretory proteins were also observed by SDS-PAGE in SVM + DTE recombinants in comparison with DT. Testosterone metabolism was examined in epithelial cells recovered from grafts of DT vs. SVM + DTE tissue recombinants by thin layer chromatography and revealed that the major metabolite produced by DTE was androstenedione, whereas in epithelium isolated from SVM + DTE tissue recombinants the major androgen metabolite was 5alpha-DHT. Thus, after induction by SVM the DTE metabolized androgens in a pattern similar to the normal rat dorsal prostate. The SVM-induced changes in DTE suggest the possibility that emerging or established carcinomas might be regulated at least in part by their connective tissue microenvironment.

Androgen regulation of the rat keratinocyte growth factor (KGF/FGF7) promoter.

Keratinocyte Growth Factor (KGF/FGF7) is a candidate andromedin in normal embryonic development of male accessory sex glands, such as the prostate and seminal vesicles. The expression of KGF mRNA and protein is androgen-responsive. To elucidate the regulation of expression of the KGF gene, we isolated the first two exons of the KGF gene and approximately 15 kb upstream sequences. The major transcription start site was mapped. It is preceded by a CAAT-box and a TATA-box. Transient transfections in LNCaP cells revealed that, upon treatment with the synthetic androgen R1881, KGF promoter activity is upregulated 6 to 11 fold, indicating androgen regulation of the KGF promoter in the region from position - 900 to -1200. The longest construct (BH-pLuc: -4700 to +901) has a much higher basal activity than the shorter constructs, indicating that in the region -4700 to -2700 additional activating sequences are present.

Epithelial development in the rat ventral prostate, anterior prostate and seminal vesicle.

The prostate and seminal vesicle (SV) are androgen-dependent secretory glands of the male genital tract. The epithelial cells of these glands produce the bulk of the seminal secretions. The objective of the present study was to examine the ontogeny of cytokeratin and androgen receptor (AR) expression in the rat SV, anterior prostate (AP) and ventral prostate (VP). The study utilized organ culture to examine the effects of androgens on the development of these markers and castration of adult rats to examine androgenic effects on their maintenance. Tissues were examined from 14 days of gestation to adulthood. The SV was a tubular organ from its inception while the prostate formed from solid epithelial cords. These prostatic buds canalized in a proximal to distal manner starting at day 1 postnatal in the VP and day 5 in the AP. The expression of cytokeratins and AR was visualized by immunocytochemistry. In all three glands keratins 5, 7, 8, 14, 18 and 19 were initially uniformly expressed in all epithelial cells. In the SV, segregation of cytokeratins between the luminal and basal cell types started at 4 days postnatally with keratin 7 localizing to basal cells. Five days after birth, keratins 5 and 14 were also localized to the basal epithelium, while keratins 8 and 18 were only expressed by luminal cells, Keratin 19 was expressed in all epithelial cells throughout development and into adulthood. In the VP and AP the same pattern of cytokeratin segregation occurred as in the SV. Epithelial differentiation occurred in a proximal to distal fashion in the prostate. In the proximal VP ducts keratins 7 and 14 were basally localized by 2 days postnatally, while keratin 5 did not clearly segregate to basal cells until day 9 after birth. In the AP keratin 14 was basally localized by 1 day postnatal but keratin 5 and 7 did not colocalize to the basal cells until days 9 and 12, respectively. AR were expressed in the epithelium of the urogenital sinus from 19 days of gestation. At 19 and 20 days of embryonic development AR-negative prostatic buds were seen emerging from the AR-positive urogenital sinus epithelium. By birth AR were detectable in the epithelium of both prostatic lobes and the SV. The role of androgens in the development of the prostatic and SV epithelium was investigated in a serum-free organ culture system. These experiments showed that differentiation of prostatic and SV luminal and basal epithelial cell types was accelerated as compared to the in vivo situation in the presence of androgens, and did not occur in their absence. Following castration of adult animals the prostate and SV regressed with preferential loss of luminal epithelium. The relative numbers of basal cells was increased, though some flattened cells expressing a luminal cell pattern of cytokeratins were still observed. AR were detected in the prostatic and SV epithelium of long-term castrated animals. In summary, the rat prostate was found to be derived from undifferentiated solid epithelial cords. Canalization occurred concurrent with the differentiation of clear epithelial subtypes. Epithelial AR were expressed from around the time of birth and expression levels increased with age. The SV was canalized from its inception but likewise was derived from an undifferentiated epithelial precursor.

Stromal development in the ventral prostate, anterior prostate and seminal vesicle of the rat.

The prostate and seminal vesicle (SV) are androgen-dependent secretory glands of the male genital tract. They produce the bulk of the seminal secretions. The object of the present study was to examine and document the ontogeny of stromal maturation in the rat anterior and ventral prostate and SV. These organs have a loosely organized cellular mesenchyme during fetal development. During prostatic development the mesenchyme condensed to form smooth muscle sheaths immediately surrounding the epithelium, with looser connective tissue between individual ducts. In the SV, a loose connective tissue layer called the lamina propria lies between the epithelium and developing muscle. Smooth muscle alpha-actin, myosin, desmin, laminin, vinculin, vimentin and androgen receptor (AR) expression were examined by immunocytochemical methods during the pre- and postnatal developmental periods. The first marker to be detected was vimentin, which was initially found throughout the mesenchyme. During development vimentin became mostly restricted to the interductal tissue of the prostate and the lamina propria of the SV. Smooth muscle markers were expressed in an orderly sequence in a proximal to distal manner along prostatic ducts, from the urethra towards the tips. Expression of alpha-actin was followed by vinculin, myosin, desmin, and laminin. These markers became localized to the developing smooth muscle sheaths and were not expressed in the interductal tissue of the prostate or the lamina propria of the SV. Organ culture experiments demonstrated that androgens were required for the differentiation of smooth muscle sheaths. Castration of adult rats demonstrated that androgens were required to maintain smooth muscle differentiation. In castrates, the stroma was relatively thicker but less dense than in intact animals. Following castration, expression of the smooth muscle markers was lost sequentially in the reverse order of their expression during development. In long-term castrates alpha-actin, vimentin and a small amount of vinculin were detected. AR were first detected in the urogenital sinus mesenchyme immediately surrounding the epithelium at 16 days of gestation. As development progressed expression of AR became more widespread, and postnatally was found throughout the mesenchyme. As maturation of smooth muscle occurred, stromal expression of AR became localized to the muscular sheath immediately surrounding the epithelium. In the prostate the interductal connective tissue displayed very low levels of AR expression. In the SV, AR were also observed in the lamina propria. In summary, stromal differentiation and dedifferentiation in the rat prostate and SV were found to be androgen-dependent processes with ordered sequential ontogenic expression of specific markers.

Distinct transcripts are recognized by sense and antisense riboprobes for a member of the murine HSP70 gene family, HSP70.2, in various reproductive tissues.

The expression of hsp70.2, an hsp70 gene family member, originally characterized by its high levels of expression in germ cells in the adult mouse testis, was detected in several other reproductive tissues, including epididymis, prostate, and seminal vesicles, as well as in extraembryonic tissues of mid-gestation fetuses. In addition, hybridization with RNA probes transcribed in the sense orientation surprisingly indicated the presence of slightly larger "antisense" transcripts in several tissues. The levels of antisense transcripts varied among the tissues, with the highest signal detected in the prostate and no signal being detectable in the testis. Consistent with these results, in situ hybridization analysis clearly localized the sense-orientation transcripts to pachytene spermatocytes, while no antisense-orientation transcripts were observed in adjacent sections of the same tubules. Our findings have thus shown that although hsp70.2 was expressed abundantly and in a highly stage-specific manner in the male germ line, it was also expressed in other murine tissues. Furthermore, we have made the surprising observation of antisense transcription of the hsp70.2 gene in several mouse tissues, revealing another level of complexity in the regulation and function of heat shock proteins.

Development of nerves containing nitric oxide synthase in the human male urogenital organs.

OBJECTIVE: To determine the spatial and temporal distribution of nitric oxide synthase (NOS) in the urogenital organs of a series of human male fetuses, using an immunohistochemical technique. MATERIAL AND METHODS: Thirteen pre-natal specimens ranging in gestational age from 13 to 30 weeks were acquired following abortion or miscarriage. The distribution of NOS, which catalyses the production of nitric oxide (NO), was revealed using an indirect immunolabelling technique and compared with the overall innervation of each specimen visualized using the general nerve-marker protein gene product 9.5 (PGP). RESULTS: At 13 weeks of gestation the majority of nerves supplying the developing prostate gland expressed NOS while similar nerves formed a very minor proportion of the total innervation to the urinary bladder and intramural ureters. With increasing gestational age, NOS-containing nerves became more numerous in the lower urinary tract, the majority occurring at the bladder neck and around the prostatic urethra. In contrast, NOS-containing nerves were not detected in the muscle coat of the vas deferens and seminal vesicle until 23 weeks of gestation and at 30 weeks still only formed a small proportion of the intramuscular nerves. From 23 weeks onwards NOS-containing nerves were present occasionally in the dense subepithelial nerve plexuses which developed in the bladder, prostate, vas deferens and seminal vesicle. Also from 23 weeks onwards, many of the epithelial cells lining the vas deferens, seminal vesicle and ejaculatory ducts showed immunoreactivity to NOS but no immunoreactivity was observed in the epithelial lining of the urinary bladder and the intramural ureters. CONCLUSION: Based on the comparative density of NOS-containing nerves and the difference in their temporal development among the various urogenital organs it is apparent that NO plays an increasingly important role in the autonomic control of the lower urinary tract during fetal development but that its involvement in the functional control of the vas deferens and seminal vesicle is relatively minor before birth.

Developmental pattern and regulation by androgens of androgen receptor expression in the urogenital tract of the rat.

Distribution and regulation of androgen receptor expression during fetal and neonatal virilization of the rat fetus was assessed by immunohistochemistry. In mesonephric duct derivatives the androgen receptor expression became evident first in the efferent ductules and epididymis (on fetal day 14), subsequently in the vas deferens and finally in the seminal vesicle. Mesenchymal cells of the urogenital tubercle were positive for androgen receptors from fetal day 14 onwards. In the mesenchymal cells of the prostate anlagen, androgen receptor positive cells were found first on fetal day 16. Administration of 5alpha-dihydrotestosterone to pregnant rats from day 11 to day 20 of gestation caused a stabilization of the wolffian duct in female fetuses. The androgen receptor expression pattern became similar as found in mail fetuses, and showed an increase in density and in frequency of androgen receptor positive cells. Administration of the androgen antagonist flutamide during the same interval caused a reduction in density and frequency of androgen receptor positive cells in male fetuses. These findings indicate that androgens enhance the expression of androgen receptors in the developing rat genital tract by induction of androgen receptor positive cells, and by increasing the frequency. The developmental pattern of androgen receptor expression in the rat mesonephric duct system reflects the androgen-responsiveness of the ducts, and is consistent with induction of the androgen receptor along the ducts by testosterone reaching these structures in an exocrine fashion.

Induction of prostatic morphology and secretion in urothelium by seminal vesicle mesenchyme.

Mesenchymal-epithelial interactions are essential for the development of the male reproductive tract. Tissue recombination experiments have been used to define the characteristics of these interactions. When mesenchyme, embryonic connective tissue, is recombined with epithelium from another organ an instructive induction may occur in which the developmental fate of the epithelium is altered. Instructive inductions are most common when the epithelium that is removed from the mesenchyme and the epithelium that is recombined with the mesenchyme are from the same germ layer. All of the mesenchyme of the male reproductive tract is of mesodermal origin. The epithelia of these organs are derived from either the mesodermal Wolffian duct epithelium or the endodermal urogenital sinus epithelium. Urogenital sinus mesenchyme can instructively induce bladder and urethral epithelium to form prostate (Donjacour, A. A. and Cunha, G. R. (1993) Endocrinol. 132, 2342-2350) and seminal vesicle mesenchyme can instructively induce epithelium from the ductus deferens and ureter (Cunha, G. R., Young, P., Higgins, S. J. and Cooke, P. S. (1991) Development 111, 145-158) to form seminal vesicle. To see whether inductive interactions could occur across germ layers in this system, seminal vesicle mesenchyme, normally associated with a mesodermal epithelium, was recombined with epithelium from neonatal or adult bladder or urethra, which are of endodermal origin. The resulting tissue recombinants were analyzed histologically and by immunocytochemistry and western blotting with antibodies to prostatic and seminal vesicle secretory proteins. Full prostatic differentiation was observed in tissue recombinants made with seminal vesicle mesenchyme plus either adult or neonatal bladder or urethral epithelium.(ABSTRACT TRUNCATED AT 250 WORDS)

Development of peptide-containing nerves in the human fetal vas deferens and seminal vesicle.

OBJECTIVE: To use immunohistochemical methods to study the developing autonomic innervation of the human fetal vas deferens and seminal vesicle. MATERIAL AND METHODS: Thirteen pre-natal specimens ranging in gestational age from 13 to 30 weeks were acquired following abortion or miscarriage. The overall innervation of each specimen was visualized using protein gene product 9.5 (PGP), a general nerve marker, while the onset and development of specific neuropeptide-containing sub-populations were investigated using antisera to neuropeptide Y (NPY), vasoactive intestinal peptide (VIP), substance P (SP), calcitonin gene related peptide (CGRP), bombesin (BOM), somatostatin (SOM), and met-enkephalin (ENK). In addition the occurrence and distribution of presumptive noradrenergic nerves was studied using antisera to dopamine-beta-hydroxylase (D beta H) and tyrosine hydroxylase (TH). RESULTS: At 13 weeks numerous PGP, D beta H, TH, NPY and ENK immunoreactive (-IR) nerve trunks were present in the adventitia of the vas deferens and seminal vesicle but at this stage nerve fibres were not present in the smooth muscle coat of either organ. By 17 weeks, fine PGP-, D beta H, and TH-IR nerve fibres had penetrated the outer aspect of the muscle coat of the seminal vesicle but not the vas deferens. At 20 weeks a branching network of PGP-, D beta H- and TH-IR nerve fibres occurred throughout the full thickness of the muscle coat of the seminal vesicle while similar nerves were present only in the outer half of the muscle coat of the vas deferens. At 23 weeks the full thickness of the muscle coat of the vas deferens was richly innervated by a branching plexus of PGP-IR nerves. Many of these adventitial and intramuscular nerves were immunoreactive for D beta H or TH while some were immunoreactive for either NPY or ENK. Occasional adventitial nerves were immunoreactive for SP or CGRP, these being first observed at 20 weeks. VIP-IR nerves were extremely rare in the muscle coat of either organ, being first observed at 17 weeks in the seminal vesicle and at 20 weeks in the vas deferens where they mainly formed perivascular plexuses. PGP-IR nerves were first observed in the submucosa of the seminal vesicle at 20 weeks and in the vas deferens at 21 weeks. Some of these nerves were perivascular in location while other formed a subepithelial plexus which increased in density with increasing gestational age. At 22 weeks of gestation some of the submucosal nerves were immunoreactive for SP or NPY, while at 30 weeks NPY-IR nerves formed the majority of subepithelial nerves. Occasional VIP-IR subepithelial nerves were first observed at 26 weeks but were extremely rare even at 30 weeks. Submucosal nerves immunoreactive for CGRP, D beta H, TH or ENK did not occur in any of the specimens examined. CONCLUSION: (i) From 13 weeks gestation autonomic nerves develop in the muscle coat of the fetal seminal vesicle and vas deferens, being denser in the seminal vesicle than the vas deferens up to 23 weeks gestation. (ii) The majority of the intramuscular nerves in either organ contain D beta H, TH, NPY and ENK and are presumably noradrenergic in type. (iii) A subepithelial nerve plexus develops around 20 weeks gestation and contains NPY but not VIP, unlike the adult organs. (iv) Scattered neuroendocrine cells immunoreactive for SOM are present in the mucosa of the seminal vesicle from 23 weeks of gestation.