Screening for Zinner Syndrome in Patients With a Congenitally Solitary Kidney: Lessons Learned.

PURPOSE: We determined if serial screening ultrasounds are beneficial in evaluating for the development of Zinner syndrome in males with a congenital solitary kidney. MATERIALS AND METHODS: All patients included had their congenital solitary kidney diagnosed at <20 years of age and had to be ≥20 at their last visit. Individuals were seen annually, with pelvic ultrasounds to screen for mesonephric duct cysts obtained at birth and every year of age, divisible by 5. RESULTS: At a median follow-up of 38 years of age (range 20-57), 17% (20/121) developed Zinner syndrome, with 60% (12/20) developing clinical symptoms. The yield for screening ultrasound studies was significantly higher in patients ≤20 years of age at 3.5% (12/340), compared to 0.33% (1/296) in patients >20 years of age (P = .004). Serial ultrasounds reveal the onset of lower urinary tract and cyst-related pain symptoms are associated with the growth of the seminal vesicle cyst to ≥5 cm (P = .0198). Of symptomatic patients, 75% (8/12) had abnormal uroflows. Complete urodynamic studies revealed findings consistent with bladder outlet obstruction in 38% (3/8), equivocal for obstruction in 24% (2/8), and detrusor underactivity in 38% (3/8). Cyst excision effectively resolved voiding symptoms that were obstructive in etiology but failed to resolve symptoms in patients with detrusor underactivity. CONCLUSIONS: Serial ultrasound evaluations reveal that cyst growth to ≥5 cm in size is highly related to the onset of clinical symptoms, with the resolution of voiding symptoms by cyst excision directly associated with urodynamic findings.

Erectile dysfunction in patients undergoing multiple attempts at hypospadias repair: Etiologies and concerns.

INTRODUCTION: One-third of adult patients presenting for the repair of persistent penile defects after failing multiple hypospadias repair attempts during childhood will complain of erectile dysfunction (ED). The goal of this paper is to identify possible etiological causes of its onset. MATERIALS AND METHODS: Five selection criteria were used for entrance into the study: 1) Patients had to have failed ≥ three prior hypospadias repair attempts. 2) Present for evaluation between 18 and 40 years of age. 3) No known congenital or medical anomaly could be present that could have predisposed to erectile dysfunction. 4) Sexual history inventory for men (SHIM-5 score) completed. 5) All patients with moderate to severe ED (SHIM scores ≤ 16) underwent psychological screening; individuals with good quality spontaneous or self-stimulated erections, experiencing major life events, or had documented psychological problems were excluded from the study. One hundred consecutive patients meeting these criteria were assessed. We evaluated multiple factors to discern if they were associated with the onset of ED: the initial location of the urethral meatus, if a corporoplasty was performed, the type of corporoplasty used, if the urethral plate was divided or resected, the use of a ventral corporal graft, the total number of open reparative procedures performed before referral, the number of direct visual internal urethrotomies (DVIU) performed, the length of a urethral stricture at the time of the referral and whether lichen sclerosus was present. Statistical evaluations used chi-square analysis, two-tailed t-tests, or a logistic regression model where indicated, p-values < 0.05 were considered significant. RESULTS: 37% (37/100) of our patients complained of moderate to severe ED (SHIM score ≤16). Statistical analysis comparing patients with ED to those without ED (63%:63/100), revealed patients with ED were older, median age 34 yrs (range 20-40) vs 26 yrs (range 18-40) p = 0.0212, had undergone division of the urethral plate 70.3% (26/37) vs 47.6% (30/63), p = 0.0276, had placement of a ventral corporal graft, 24% (8/33) vs 1.5% (1/67), p = 0.0003 or had undergone repetitive DVIU's to manage urethral stricture disease, median number 4 (range 0-15) vs 0 (range 0-6), p < 0.0001, see table. CONCLUSIONS: The early onset of ED in patients that failed multiple attempts at hypospadias repair in childhood is associated with advancing age, division of the urethral plate, and prior ventral corporal grafting. Especially significant is the association of ED to the use of repetitive internal urethrotomy to manage urethral stricture disease.

Augmentation cystoplasty and risk of neoplasia: fact, fiction and controversy.

PURPOSE: We determined if ileal/colonic bladder augmentation performed in patients with congenital bladder abnormalities is an independent risk factor for bladder malignancy. MATERIALS AND METHODS: We reviewed a registry of patients with bladder dysfunction due to neurological abnormalities, exstrophy and posterior urethral valves. Individuals treated with augmentation cystoplasty were matched (1:1) to a control group treated with intermittent catheterization based on etiology of bladder dysfunction, gender and age (±2 years). RESULTS: We evaluated 153 patients with an ileal/colonic cystoplasty and a matched control population. There was no difference (p=0.54) in the incidence of bladder cancer in patients with augmentation cystoplasty (7 patients [4.6%]) vs controls (4 [2.6%]). In addition, there was no difference between the 2 groups regarding age at diagnosis (51 vs 49.5 years, p>0.7), stage (3.4 vs 3.8, p>0.5), mortality rate (5 of 7 [71%] vs 4 of 4 [100%], p>0.4) or median survival (18 vs 17 months, p>0.8). Irrespective of augmentation status patients with a history of renal transplant on chronic immunosuppression had a significantly higher incidence of bladder cancer (3 of 20 [15%]), compared to patients who were not immunosuppressed (8 of 286 [2.8%], p=0.03). CONCLUSIONS: In patients with congenital bladder dysfunction ileal/colonic bladder augmentation does not appear to increase the risk of bladder malignancy over the inherent cancer risk associated with the underlying congenital abnormality. In addition, immunosuppression irrespective of bladder treatment is an independent risk factor for malignancy in this patient population.

Cancer screening in the pediatric cancer patient: a focus on genitourinary malignancies, and why does a urologist need to know about this?

INTRODUCTION: The long-term survival of a patient with childhood cancer now exceeds 80%. Unfortunately, as survivorship improves, the long-term consequences of the treatments used have become manifest. Specifically, the finding that development of a subsequent malignant neoplasm (SMN) is the leading cause of late mortality is concerning. In cancer survivors who are at high risk for developing an SMN, cancer screening protocols have well-documented survivorship benefits. Regrettably, 50% of these high-risk patients are non-compliant with these protocols, with studies revealing that inadequate patient compliance is in part because of insufficient knowledge of the physician regarding its need. DISCUSSION: Urologists are in a unique position to correct this deficiency. Characteristically, survivors of childhood cancer present to urologists as an adult with complaints of infertility, erectile dysfunction, androgen deprivation, lower urinary tract symptoms or for follow-up of a urinary diversion. The urologist because of their specialty should be able to treat the patients presenting complaint, identify the high-risk patient, and re-establish them on their surveillance protocol. SCREENING RECOMMENDATIONS FOR HIGH-RISK PATIENTS: The risk for developing an SMN is unequally expressed and is temporally biphasic. A minimal 10-year follow-up time span is recommended for patients who received alkylating agents or topoisomerase inhibitors. These agents can induce hematologic malignancies classically within the first 3-5 years after chemotherapy completion, with minimal risk existing after 10 years. Lifelong follow-up for SMN development is recommended under five distinct circumstances; if a genetic predisposition to tumor formation exists, a persistent post-treatment non-malignant mass is present if chemotherapy was received before 2 years of age, if the initial type of tumor predisposes to SMN, or if the patient received radiation therapy. CONCLUSION: The urologists ability to identify the patient at high risk for developing an SMN and return them to a surveillance protocol is crucial for appropriate patient management.

Mortality following augmentation cystoplasty: A transitional urologist's viewpoint.

INTRODUCTION: Three complications have been hypothesized to increase patient mortality following enterocystoplasty: spontaneous bladder perforation, bladder neoplasia, and chronic renal failure (CRF). The present study examined risk of their occurrence and discussed ways to improve the quality of care. MATERIALS AND METHODS: The present transitional clinic followed 385 patients with a history of bladder augmentation using either ileal, sigmoid, or ascending colon. The median age was 37 years (range 16-71). Median follow-up interval after augmentation was 26 years (range 2-59). DISCUSSION: Spontaneous rupture of the bladder occurred in 3% (13/385), with one associated death (0.25%, 1/385). Spontaneous bladder rupture significantly correlated with substance abuse, non-compliance with catheterization, and mental/physical disabilities that required the use of surrogates to perform and monitor intermittent catheterization (P < 0.01). Of the 203 patients that were followed for ≥10 years, 4% (8/203) developed a bladder tumor. In comparison, 2.5% (5/203) of an age-matched control population, managed by anticholinergics and intermittent catheterization, developed a bladder tumor. Therefore, enterocystoplasty cannot be associated with an increased risk of cancer development (P = 0.397). Chronic renal failure ≥ Stage 3 arose in 15% (58/385), and 1% (4/385) of the patients died as a result of this complication. Obese patients (BMI ≥30) catheterizing per urethra were more likely to be non-compliant with catheterization and develop CRF compared with obese patients with a continent catheterizable stoma (P > 0.001). These findings suggest that compliance with intermittent catheterization and renal preservation are enhanced by the presence of a catheterizable abdominal stoma. CONCLUSION: The individual's intellectual and physical capability to obey medical directives, refrain from high-risk habits, maintain a healthy weight, and comply with long-term follow-up visits were all critical to the enduring success of bladder augmentation.

Systematic review of bladder cancer outcomes in patients with spina bifida.

BACKGROUND: In patients with congenital bladder anomalies, bladder augmentation is used as a last resort to reduce intravesical pressure, but concerns about malignant transformation in augmented patients were first raised in the 1980s. The best evidence to date indicates that augmentation does not appear to increase the risk of bladder cancer in spina bifida patients. To date, oncologic outcomes from patients with spina bifida with and without augmentation have only been available in small case reports. OBJECTIVE: To systematically evaluate factors in myelomeningocele patients with bladder cancer, including bladder augmentation, that contribute to overall survival (OS). STUDY DESIGN: A systematic review using PubMed was conducted by cross referencing terms 'myelomeningocele,' 'cystoplasty,' 'bladder cancer' and respective synonyms according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. Inclusion criteria were studies with patients with an underlying diagnosis of myelomeningocele and bladder cancer with data on age, stage, and mortality status. Studies were excluded for spinal cord injury, history of tuberculosis or schistosomiasis, or prior ureterosigmoidostomy. RESULTS: Fifty-two patients were identified from 28 studies with a median age at bladder cancer diagnosis of 41 years (range 13-73); 37 (71%) presented with stage III or IV bladder cancer. Overall survival at 1 year and 2 years was 48.5% and 31.5%, respectively. Overall survival was different between those with and without augmentation (P = 0.009) by log-rank analysis. No between-group differences in OS were seen based on age, management with indwelling catheter, diversion with ileal conduit or being on a surveillance program. Only stage remained a significant predictor of OS on multivariate analysis (HR 2.011, 95% CI 1.063-3.804, P = 0.032). Secondary analysis was performed after removing patients with gastric augmentation (n = 8), and no difference in OS was seen between patients with (n = 8) and without augmentation (n = 36, P = 0.112). Of augmented patients, latency to development of bladder cancer was variable (Summary Figure). DISCUSSION: Bladder cancer is a deadly diagnosis in patients with congenital bladder anomalies like spina bifida, and while overall prevalence of the two conditions occurring together is low, bladder cancer will go on to affect 2-4% of spina bifida patients. The present study examined overall survival, and further characterized outcomes in these patients. Presence of a bladder augment did not appear to worsen overall survival. CONCLUSIONS: Patients with myelomeningocele who developed bladder cancer had aggressive disease. Augmentation did not worsen OS, based on cases reported in the literature. Risk of bladder cancer should be discussed with all myelomeningocele patients.

Reversal of flutamide-induced cryptorchidism by prenatal time-specific androgens.

The recent discovery of time-specific antiandrogens (flutamide) to induce undescent of the testes has provided us the ability to study androgen therapy for cryptorchidism in the first specific antiandrogen animal model for testicular descent. Postpartal administration of pharmacological doses of testosterone, dihydrotestosterone, or human chorionic gonadotropin failed to reverse antiandrogen-induced cryptorchidism. Reduction in the frequency of testicular undescent occurred only when these agents were administered before parturition. Indeed, statistically significant reductions in the incidence of undescended testes occurred only when androgens were administered simultaneously with the antiandrogens on gestational days 16-17. However, the successful ability of prenatal dihydrotestosterone or testosterone to prevent cryptorchidism was associated with significant complications of prenatal androgen therapy. Specifically, 100% (46 of 46) of the animals that had inhibition of flutamide-induced cryptorchidism manifested findings of hypogonadotropic hypogonadism. The findings of descended diminutive testes and epididymis in these latter animals did, however, substantiate that testicular weight does not play a significant role in descent of this organ. In summary, these studies delineate a narrow window of time in which androgens act to effect testicular descent that is independent of testicular size.

Time-specific androgen blockade with flutamide inhibits testicular descent in the rat.

Inhibition of androgen action by flutamide, a nonsteroidal antiandrogen, blocked testicular descent in 40% of the testes exposed to this agent continuously from gestational day 13 through postpartal day 28. By contrast, only 11% of the testes failed to descend when blocked by 5 alpha-reductase inhibitors during the same period. Flutamide administration over narrower time intervals (gestational day 13-15, 16-17, or 18-19) revealed maximal interference with testicular descent after androgen inhibition during gestational days 16-17. No significant differences in testicular or epididymal weights were evident between descended and undescended testes; furthermore, no correlation was detected between the presence of epididymal abnormalities and testicular descent. These findings indicate that androgen inhibition during a brief period of embryonic development can block testicular descent. The mechanism through which this inhibition occurs remains to be elucidated.

Localization of the androgen receptor in the developing rat gubernaculum.

The distribution of androgen receptor expression within the developing rat gubernaculum was examined at different times during fetal and neonatal development using polyclonal antibodies directed at the amino-terminus (amino acids 1-21) and the carboxy-terminus (amino acids 898-917) of the androgen receptor. These studies reveal a high level expression of androgen receptor in the undifferentiated cells that comprise the mesenchymal core of the gubernaculum in early development. However, during the morphological alterations of the gubernaculum into a muscular structure, the level of androgen receptor detected in these cells declines, with minimal immunoreactivity present 2 weeks postpartum. Whether the loss of staining of the mesenchyme is related to decreases in androgen receptor expression, death of the mesenchymal cells, or differentiation of these cells into myoblasts remains to be determined.

Androgen receptor expression in the developing rat prostate is not altered by castration, flutamide, or suppression of the adrenal axis.

Mesenchymal epithelial interactions are believed to be important to the growth and development of the neonatal prostate. Prior studies in the rat ventral prostate, using autoradiography and tritiated dihydrotestosterone, indicate that androgen receptors are present in the prostatic stroma on day 3 and are detected in the epithelium by the tenth postnatal day. These findings suggested that androgen stimulation of the prostatic mesenchyme is a crucial step in the growth and development of the prostate. We have examined this developmental program directly using polyclonal antibodies that recognize specific epitopes of the androgen receptor to examine the pattern of androgen receptor expression in intact and neonatally castrate animals. In keeping with previous studies, androgen receptors are present in the prostate stroma at birth and subsequently appear in the prostatic epithelium by the 10th postnatal day. Development of androgen receptor expression in the epithelium was not changed when the animals were castrated at birth, castrated and blocked by flutamide, or castrated and given hydrocortisone to suppress the production of adrenal androgens. These findings suggest that the appearance of androgen receptors in the prostatic epithelium is programmed by androgens before birth or that factors other than testicular or adrenal androgens control the development of epithelial androgen receptors.

Androgen receptor levels in the rat penis are controlled differently in distinctive cell types.

The rat phallus grows during sexual maturation as serum androgen concentrations rise to adult levels, and growth ceases when sexual maturity is attained despite the continued presence of adult serum androgen levels. This cessation of growth is correlated temporally with a diminution in the levels of androgen receptor, as detected by assays of ligand binding. To determine whether the change in androgen receptor content occurs in all cells in the tissue, immunohistochemical studies of the penile androgen receptor were performed in rats of different ages. In immature animals and animals castrated prepubertally, the androgen receptor is detected in virtually all cell types, including the corpus cavernosum penis, the small lateral cavernous bodies, the corpus cavernosum urethra, skin, urethra, and os penis. By contrast, in the mature rat penis minimal androgen receptor is evident within the corporal tissue and os, although immunoreactivity remains detectable in the penile skin and urethra. It is concluded that the cessation of androgen-mediated growth correlates with a decrease in androgen receptor levels in the body of the penis.

Antipeptide antibodies to two distinct regions of the androgen receptor localize the receptor protein to the nuclei of target cells in the rat and human prostate.

We have developed polyclonal antibodies to two synthetic peptides corresponding to the amino-(N-)terminal or carboxyl-(C-)terminal segments of the human androgen receptor (hAR) protein, as deduced from the nucleic acid sequence of the androgen receptor cDNA. Immunoreactive antisera were identified by solid phase enzyme-linked immunosorbent assay and purified by peptide affinity chromatography. Specific immunoreactivity with the hAR was confirmed by immunoblotting, using both a fusion protein produced in E. coli that contains the C-terminal 880-amino acid sequence of hAR and the full-length receptor protein produced in COS cells after transfection with a plasmid containing the entire hAR-coding region. Immunohistological evaluation of rat and human prostatic tissue using anti-C-terminal or anti-N-terminal antibodies demonstrated similar patterns of specific staining of the nuclei of epithelial and stromal cells. Castration resulted in a decrease in the amount of nuclear AR detected in the rat prostate after a short time of exposure to anti-C-terminal antibodies (less than 4 h), but did not alter the level of specific staining obtained with anti-N-terminal antibodies. This decrease in nuclear staining using anti-C-terminal antibodies could be reversed by treating castrated animals with dihydrotestosterone. When longer times of exposure to the primary antibodies were used, high levels of nuclear staining were obtained with both types of antibodies in prostate specimens from castrate as well as as intact rats. This immunohistochemical staining pattern contrasts with receptor measurements in rat prostate homogenates that indicate the partition of AR binding into the low salt (cytosolic) fraction in the castrate animal and into the high salt (nuclear) fraction in the intact animal. Our results suggest that the AR is predominantly a nuclear protein even in the absence of ligand and that dihydrotestosterone serves to tighten its association with the nucleus. These data also suggest that the immunoreactivity of anti-C-terminal antibodies is influenced by the presence of dihydrotestosterone, presumably via an alteration in the physical state of the receptor protein.

Bladder dysfunction and management in multiple sclerosis.

Symptomatic bladder dysfunction occurs at some time in most patients with multiple sclerosis. The relapsing-remitting course and progressive loss of mobility associated with multiple sclerosis make management of urinary urgency and incontinence difficult. Urodynamic evaluation serves as a guideline for appropriate treatment. After accurate diagnosis of bladder dysfunction, a management program is developed with use of fluid schedules, voiding techniques, neuropharmacologic manipulation, intermittent catheterization, surgical treatment, and other adjunctive measures as indicated. The goals of treatment are to protect and preserve renal function, relieve symptomatic voiding dysfunction, and avoid subsequent urinary complications. A management program should be individualized, dynamic, and monitored with periodic, systematic urologic review to maintain these goals.

Nocturnal enuresis: a guide to evaluation and treatment.

Nocturnal enuresis has several possible causes, including genetic inheritance, reduced bladder capacity, sleep disorders, abnormal secretion of antidiuretic hormone, psychologic abnormalities, neurologic dysfunction, bacteriuria, and diet. A through assessment of the patient's voiding history is of major importance in the management of nocturnal enuresis. Whether the patient has monosymptomatic or polysymptomatic nocturnal enuresis must be determined. Treatment options include pharmacotherapy, behavioral modification with an alarm system, or a combination of these modalities. In order for treatment to be successful, the physician, patient, and patient's parents must be involved in the decision-making process.

Current concepts in the pathophysiology of testicular undescent.

At present, we believe that descent of the testes within the human is a complex event mediated by both hormonal and mechanical factors. We hypothesize that descent of the testes occurs as a result of the secretion of an androgen-independent factor from a normal testis (descendin). This paracrine factor is responsible for the rapid proliferation (outgrowth) of the ipsilateral gubernaculum. The development of the gubernaculum results in creating a dilated inguinal canal, the width of which matches the testicular width. Descent of the testes through the inguinal canal is an interplay between abdominal pressure, a patent processus vaginalis, and androgen-induced gubernacular regression. We hypothesize that androgens (under control of an intact hypothalamic pituitary axis) alter the viscoelastic properties of the gubernaculum, reducing the turgidity of the gubernaculum and allowing intra-abdominal pressure to push the testis into the scrotum. Cryptorchidism can therefore result when any one or more of the involved factors malfunction.

Alterations in maternal epidermal growth factor (EGF) effect testicular descent and epididymal development.

OBJECTIVE: (1) To determine the ability of epidermal growth factor (EGF) to reverse antiandrogen-induced cryptorchidism and epididymal abnormalities; (2) to evaluate whether alterations in maternal EGF would result in abnormal testicular descent or mal development of the epididymis. METHODS: Experiment 1: Timed pregnant ICR mice were treated with either flutamide, flutamide plus EGF, or vehicle alone on gestational days 11 through birth. Experiment 2: Maternal EGF was abolished by removing the submandibular glands. Following timed mating, dams were treated with either flutamide, anti-EGF, DHT, or vehicle alone on gestational days 11 through birth. RESULTS: Experiment 1: Treatment with flutamide resulted in a 36 percent (26/72) incidence of undescended testes (UDT), and a 43 percent (31/72) incidence of abnormal epididymides. Rats treated simultaneously with flutamide plus EGF had a reduced incidence of UDT (14%, 6/42) and epididymal anomalies (19%, 8/42); p < 0.01. Experiment 2: The absence of maternal EGF resulted in a significant incidence of cryptorchidism in 11/50 (22%) testes, and epididymal anomalies in 19/50 (38%); p < 0.01. CONCLUSIONS: Our findings suggest that EGF stabilizes the wolffian duct system and partially mediates testicular descent.

Flutamide-induced cryptorchidism in the rat is associated with altered gubernacular morphology.

OBJECTIVES: One of the major controversies regarding descent of the testes is whether androgenic regulation of the gubernaculum testes exists. To determine if antiandrogens can alter the development of the gubernaculum within the fetus, the following experiment was performed. METHODS: Timed pregnant Sprague-Dawley rats were treated with either flutamide, dihydrotestosterone (DHT), or vehicle alone (controls) from gestational day (GD) 15 to 17. Fetal specimens were removed via cesarean section on GD 18 and 20. Serial coronal sections were obtained, and digital microscopy with computer-assisted reconstruction was used to ascertain the morphology of the three components of the gubernaculum, that is, the gubernacular cord and the mesenchymal and muscular components of the gubernacular bulb. RESULTS: Flutamide significantly prevented and DHT significantly enhanced gubernacular cord regression compared with controls (P < 0.01). Flutamide also resulted in a significant inhibition of the gubernacular bulb outgrowth, with diminution of both the mesenchymal and muscular components of the gubernacular bulb. CONCLUSIONS: These data suggest that androgens play an active role in gubernacular cord regression and gubernacular outgrowth within the fetal rodent.

Intestinal metaplasia is not a strong risk factor for bladder cancer: study of 53 cases with long-term follow-up.

OBJECTIVES: Intestinal metaplasia often coexists with adenocarcinoma of the urinary bladder, suggesting to some investigators that it is premalignant. However, the natural history and long-term outcome of intestinal metaplasia in isolation are unknown. We report 53 cases of intestinal metaplasia of the urinary bladder followed for more than 10 years. METHODS: We reviewed the Mayo Clinic surgical pathology files between 1926 and 1996 and all patients with exstrophic bladder recorded in the files of the Hospital for Sick Children (Toronto, Ontario, Canada) and Dallas Children's Hospital (Dallas, Texas) between 1953 and 1987, and identified all patients with intestinal metaplasia of the bladder. RESULTS: A total of 53 cases were identified from both series, and none of the patients developed adenocarcinoma of the bladder. The Mayo Clinic series consisted of 24 patients. Nineteen of the 24 (79.1%) were alive without evidence of cancer (median follow-up 14 years, range 0.9 to 53), and 5 patients died of intercurrent disease (at 0.9, 4, 8, 11, and 53 years after diagnosis) without evidence of bladder cancer. The Dallas Children's Hospital and the Hospital for Sick Children series consisted of 29 patients. Twenty-seven of the 29 (93.1%) were alive without evidence of cancer (median follow-up 13 years, range 3 to 23.9). Two patients died of trauma (at 10.9 and 12 years after diagnosis) and at autopsy had no evidence of bladder cancer. CONCLUSIONS: Intestinal metaplasia of the urinary bladder is not a strong risk factor for adenocarcinoma or urothelial cancer.

Altered brain and pituitary androgen metabolism by prenatal, perinatal or pre- and postnatal finasteride, flutamide or dihydrotestosterone treatment in juvenile male rats.

1. The authors investigated the administration of finasteride, a 5 alpha-reductase inhibitor; flutamide, an androgen receptor blocker and; exogenous dihydrotestosterone (DHT) during intervals covering different portions of the "critical period" of neural development (i.e. prenatal, perinatal or pre- and postnatal development) to determine the long-term effects of these agents on altering androgen metabolism in hypothalamic and pituitary tissue of juvenile (30 day-old) male rats. 2. The efficacy of the treatments and hypothalamic-pituitary axis function was monitored by measuring luteinizing hormone levels by radioimmunoassay. 5 alpha-Reductase and aromatase activity was determined in hypothalamic and pituitary tissue. 3. Significant alterations in pituitary 5 alpha-reductase activity was detected in DHT-treated animals, whereas, hypothalamic 5 alpha-reductase activity was significantly decreased by finasteride treatment and significantly increased by DHT treatment. Hypothalamic aromatase activity was significantly decreased in flutamide-treated animals. 4. These results suggest that: a) prenatal exposure to exogenous DHT stimulates hypothalamic (but inhibits pituitary) 5 alpha-reductase activity long-term and b) basal 5 alpha-reductase activity levels can be inhibited by finasteride treatment in hypothalamic but not in pituitary tissue, suggesting that a different regulatory mechanism exists for 5 alpha-reductase in hypothalamic versus pituitary tissue.

The hormonal control of testicular descent.

Descent of the testes is a complex event mediated by hormonal and mechanical factors. At present we hypothesize that testicular descent occurs as the result of the secretion of descendin from a normal testicle. Descendin secretion results in selective growth of the gubernacular cells. Gubernacular outgrowth results in masculinization of the inguinal canal. At the beginning of testicular descent, the patent processus migrates into the inguinal canal, transmitting intraabdominal pressure to the gubernaculum. The gubernaculum in turn applies traction to the testicle to introduce the testicle into the inguinal canal. Descent of the testes into and through the inguinal canal is an interplay between intraabdominal pressure transmitted by a patent processus vaginalis and androgen-induced gubernacular regression. Specifically, we hypothesize that androgens under control of an intact fetal hypothalamic-pituitary axis alter the viscoelastic properties of the gubernaculum. Reductions in the turgidity of the gubernaculum allow intraabdominal pressure to push the testicle into the scrotum. Functional abnormalities in any of the above factors will result in cryptorchidism.