Use of External Controls in Regulatory Decision-Making.

The expanded use of electronic data retrieval systems has greatly expanded the potential sources of real-world data and presents new opportunities for evidence generation outside of the traditional research trial. These data may be used to inform trial design and interpretation as well. Externally controlled trials, such as single-arm and noninferiority designs, have long been used in regulatory decision-making despite the potential flaws based on assumptions of assay sensitivity and constancy.

Erectile dysfunction and sildenafil citrate and cardiologists.

Since the release of sildenafil citrate (Viagra), increasing numbers of patients are seeking treatment for erectile dysfunction (ED). Many of the risk factors for ED are the same as those for cardiac disease. Sildenafil citrate is a highly effective oral agent for ED. It is absolutely contraindicated in patients receiving organic nitrates. The issue of cardiac deaths associated with sildenafil citrate and ways of potentially minimizing these cases are discussed.

Comparison of penile duplex ultrasonography to pudendal arteriography. Variant penile arterial anatomy affects interpretation of duplex ultrasonography.

RATIONALE AND OBJECTIVES: Duplex ultrasonography is currently used as a noninvasive imaging modality for the functional evaluation of penile blood flow in impotent men. However, the accuracy of this test is controversial. The objective of this study was to determine the sensitivity and specificity of duplex ultrasonography, to assess the ultrasonographic parameters most predictive of arterial disease, and to evaluate the causes of misinterpretation of duplex ultrasound studies. METHODS: Duplex ultrasonography and pudendal arteriography were performed on 42 impotent men during a 4-year prospective study. The predictive power of the following ultrasonographic parameters were analyzed: cavernosal arterial diameter, peak blood flow velocity, and pulsations on real-time ultrasonography. RESULTS: The results of both studies were concordant in 81% of the patients with a 77% sensitivity and 85% specificity for ultrasonography when using arteriography as the gold standard. Arterial pulsations and peak blood flow velocity were most predictive, whereas dilation was not helpful. Variant penile arterial anatomy was present in 83% of the patients and was the most frequent cause of misinterpretation of duplex ultrasonography. CONCLUSION: Duplex ultrasonography is a fairly reliable screening test for arterial disease in impotent men. Visualization of arterial pulsations and measurement of peak blood flow velocity are the best predictors of arterial function. Awareness of the potential arterial anomalies may help reduce misinterpretation of ultrasonography. Arteriography is necessary in any patient being considered for penile arterial surgery because of the high frequency of anatomic variations.

Endocrine evaluation of infertile men.

OBJECTIVES: To determine the incidence and type of endocrinologic abnormalities in men undergoing infertility evaluations and the most appropriate testing to detect them. METHODS: A retrospective review of consecutive patients attending two infertility centers was performed. Results of endocrine testing were compared to medical history and physical and laboratory findings to determine whether endocrinologic screening could be limited to a specific subpopulation. RESULTS: Only 99 of the 1035 patients (9.6%) had abnormal endocrine studies upon repetitive testing. The majority of these patients had an isolated elevation of serum follicle stimulating hormone (FSH) levels. Only 1.7% had a clinically significant endocrinopathy that would have had an effect upon disease management. Screening with serum testosterone and FSH levels alone was just as effective as a complete hormonal panel of testosterone, FSH, luteinizing hormone, and prolactin for the detection of clinically significant endocrinopathy. Only 1 patient with a clinically significant endocrinopathy would not have been identified if hormonal screening was limited to only those patients with a sperm density of less than 10 x 10(6)/mL. CONCLUSIONS: Endocrinopathies are a rare cause of male infertility. Endocrine screening of men with sperm counts of less than 10 million/mL with serum testosterone and FSH levels alone will detect the vast majority of clinically significant endocrinopathies.

Antegrade ejaculatory duct recanalization and dilation.

Ejaculatory duct obstruction is a rare but correctable cause of male infertility. Standard therapy is transurethral resection of the ejaculatory ducts, which is frequently complicated by seminal vesicle urinary reflux and is contraindicated when the obstruction is located outside the prostate gland. Herein, we report a minimally invasive technique that successfully dilated the ejaculatory duct without complications in a patient with unilateral, complete ejaculatory duct obstruction located outside the prostate.

Placebo-controlled study of oral terbutaline and pseudoephedrine in management of prostaglandin E1-induced prolonged erections.

Prolonged erections, priapism, secondary to pharmacologic stimulation are usually treated by drainage of the corporeal bodies and irrigation with a sympathomimetic. To study the efficacy of oral medical therapy in the treatment of priapism, 75 patients with pharmacologically induced (prostaglandin E1) prolonged erections were randomized to receive terbutaline, pseudoephedrine, or placebo. Detumescence occurred in 36 percent, 28 percent, and 12 percent, respectively. Terbutaline was significantly better than placebo (p < 0.05) in achieving detumescence. The results of this study suggest that oral terbutaline should be considered in the initial management of pharmacologically induced prolonged erections.

Distribution of intraprostatic hyperchoice lesions in infertile men.

OBJECTIVES: To determine whether intraprostatic hyperechogenic lesions seen on transrectal ultrasonography are related to infertility. METHODS: The transrectal ultrasonographic studies of 58 infertile men and 12 fertile controls who all had intraprostatic hyperechoic lesions were reviewed to determine the anatomic distribution of hyperechoic lesions within the prostate and their relationship to the ejaculatory ducts. RESULTS: Hyperechoic lesions were located in the region of the verumontanum in 62% of the fertile control subjects and only 22% of infertile patients (P < 0.05). In contrast, hyperechoic lesions were present in the region of the ejaculatory ducts in 75% of the infertile men and only 39% of the fertile controls (P < 0.05). CONCLUSIONS: Hyperechogenic lesions located within the verumontanum appear to be a normal finding in fertile men, whereas lesions located in the region of the ejaculatory ducts are more likely to be associated with infertility.

Incidence of varicoceles in men with primary and secondary infertility.

OBJECTIVES: To determine whether varicoceles are more prevalent in men with secondary infertility than in men with primary infertility. METHODS: The records of 2188 consecutive men attending three infertility centers were reviewed to determine the incidence of varicoceles in men with primary and secondary infertility. In addition, other factors affecting both male and female infertility were assessed in these patients. RESULTS: The incidence of varicoceles was not significantly different between the 1447 men with primary infertility versus the 741 men with secondary infertility: 44% and 45%, respectively. The incidence of vasal agenesis was significantly greater in men with primary infertility (P < 0.001). In addition, the female partner was significantly older in couples with secondary infertility (P < 0.001). CONCLUSIONS: These findings do not support the conclusion that varicoceles have a progressive adverse effect on fertility over time and suggest that further study is needed to determine whether varicocele repair is indicated in patients with normal semen parameters.

Puboprostatic ligament sparing improves urinary continence after radical retropubic prostatectomy.

OBJECTIVES: To determine whether a puboprostatic ligament-sparing technique of prostatic apical dissection provided improved urinary continence after radical retropubic prostatectomy. METHODS: A total of 43 men with clinically localized prostate cancer underwent radical retropubic prostatectomy (standard apical dissection in 25, puboprostatic ligament-sparing technique in 18). Patients were evaluated by independent observer questionnaire to determine their continence status. The questionnaire was tested in a control group of 25 men who had not undergone prostate surgery. The overall continence rate and time to achieve continence was compared between the two surgical groups. In addition, the clinical and pathologic stages and both the rate and location of positive margins were assessed. RESULTS: Mean patient age and serum prostate-specific antigen values were not significantly different between the two groups. Clinical and pathologic stages were also similar. The mean follow-up period for the puboprostatic ligament-sparing group was 35 weeks compared with 57 weeks for the standard group (P < 0.05). The median time until continence was achieved after surgery was significantly shorter (P = 0.01) for the puboprostatic ligament-sparing group than for the standard method (6.5 and 12 weeks, respectively). However, the overall continence rate at 1-year follow-up for the two groups was similar (100% and 94%, respectively). The positive margin rate and location of positive margins were not different with the puboprostatic ligament-sparing technique. CONCLUSIONS: The puboprostatic ligament-sparing technique improves the rapidity of return of urinary continence after radical prostatectomy without significantly enhancing overall continence or interfering with the therapeutic efficacy of the procedure.

Effectiveness of laparoscopic varicocelectomy.

Laparoscopic varicocelectomy is a new technique which has been described in a limited number of clinical reports. We reviewed the results of 46 patients undergoing laparoscopic repair of 75 varicoceles over a two-year period to assess the effectiveness of this operative technique. The internal spermatic artery was preserved in 80 percent of the varicoceles and two arteries were present in 5 percent. Our ability to preserve the internal spermatic artery improved significantly with the use of the intraoperative Doppler probe after the first six months of performing this operation (p < 0.01). Nineteen infertile patients had a minimum follow-up of twelve months with seminal improvement in 68 percent and a pregnancy rate of 26 percent. Complications occurred in 2 patients (4%), inferior epigastric vessel bleeding in one, and genitofemoral nerve injury in the other. There was one persistent varicocele (1%). Our results with laparoscopic varicocelectomy are comparable with those reported with standard open surgical approaches.

Association of antisperm antibodies with chronic nonbacterial prostatitis.

Antisperm antibodies are significant in male factor infertility. The prevalence of antisperm antibodies in the infertile population is approximately 10 percent, and it is not cost-effective to test for these antibodies in every male partner of an infertile marriage. Earlier studies have demonstrated a higher prevalence of antisperm antibodies among men with a history of bacterial prostatitis or urethritis. Because of this established association, we measured the prevalence of serum antisperm antibodies, using a gel agglutination assay, in 28 men with chronic nonbacterial prostatitis and in age-matched control group of 69 men without a history of prostatitis. The prevalence was 25 percent (test subjects) and 7.2 percent (controls) (p less than 0.05). This finding indicates that nonbacterial prostatitis is a risk factor for the presence of serum antisperm antibodies and that subfertile men with a history of nonbacterial prostatitis should be tested for these antibodies.

Effect of obesity and fertility status on sex steroid levels in men.

Endocrine studies were performed on fertile and infertile obese men and compared with fertile and infertile nonobese men in order to determine the independent and codependent effects of obesity and fertility status on the male hypothalamic-pituitary gonadal axis. The obese infertile group exhibited significant endocrinologic changes as compared with fertile nonobese control group which was not observed in any of the other three groups. Serum testosterone was significantly lower. The testosterone/estradiol ratio was significantly lower despite a lack of significant change in serum estradiol levels. Serum steroid hormone binding globulin (SHBG) was significantly lower which correlated with elevated bioavailability of both testosterone and estradiol in the obese infertile group. Serum luteinizing hormone levels were no different, suggesting that free testosterone levels were unchanged. Obese infertile men exhibit endocrinologic changes that are not observed in men with either obesity or infertility alone. Reduction of serum SHBG, total testosterone, and testosterone/estradiol ratio appear to be a marker of infertility among obese men.

The effect of varicoceles on testicular blood flow in man.

OBJECTIVES: To assess the effect of varicoceles on testicular blood flow in man. METHODS: Testicular blood flow was measured in 248 consecutive men attending an infertility clinic and 34 fertile volunteers using color duplex ultrasonography. RESULTS: The testicular blood flow of men with either clinical and/or subclinical varicoceles was not significantly different from controls without varicoceles. CONCLUSIONS: Varicoceles do not significantly alter testicular blood flow in man.

Effect of level of anastomosis and quality of intraepididymal sperm on the outcome of end-to-side epididymovasostomy.

OBJECTIVES: Epididymovasostomy is commonly performed at the most distal site of the epididymis where whole sperm are present within the lumen, regardless of their motility status. Although more fresh and motile sperm can be found more proximally within the epididymis, it is believed that the outcome of epididymovasostomy is better more distally. Because the current results of epididymovasostomy are far from perfect, it would be ideal to be able to harvest motile sperm for cryopreservation at the time of surgery in case the patient remains azoospermic postoperatively. The objective of this study was to determine the effect of the level of epididymal anastomosis and quality of sperm on the outcome of surgery. METHODS: An end-to-side epididymovasostomy was performed on 131 azoospermic men with a mean age of 39 years and a mean obstructive interval of 18 years. The etiology of obstruction was vasectomy in 48%, infectious in 19%, congenital in 20%, and unknown in 13%. The average duration of follow-up was 32 months. The overall patency rate was 67% and pregnancy rate was 27%. Subgroups of patients with an anastomosis to the same level of the epididymis on all functional sides were identified as follows: caput (56), corpus (28), and cauda (13). These groups were compared in regard to the presence of motile sperm within the epididymal lumen at the time of surgery, patency rates, postoperative semen quality, and pregnancy rates. RESULTS: Motile sperm were present more often in both the caput (54%) and corpus (61%) than in the cauda epididymis (25%) (P < 0.05). The patency rates for the three subgroups were not significantly different. The postoperative total motile sperm count and pregnancy rate for the corpus epididymis (13 x 10(6) and 45%) was significantly (P < 0.05) better than for the caput (4.4 x 10(6) and 22%) but no different than that of the cauda (10 x 10(6) and 23%). The patency and pregnancy rates for anastomoses performed at levels demonstrating motile sperm were not significantly better than at sites with nonmotile sperm, but the postoperative total motile sperm count was better (P < 0.05). CONCLUSIONS: The results of this study suggest that the outcomes of epididymovasostomy to the corpus and cauda epididymis are roughly equivalent and superior to the caput. Therefore, it may be reasonable to move more proximally from the cauda to corpus in the search for motile sperm for cryopreservation during an end-to-side epididymovasostomy. In contrast, moving from the corpus to the caput epididymis has a significant adverse effect upon outcome; it is, therefore, not worthwhile to search for viable sperm for cryopreservation in this clinical setting.

Physiologic variations of serum testosterone within the normal range do not affect serum prostate-specific antigen.

OBJECTIVES: To determine the relationship between endogenous total serum testosterone levels and serum prostate-specific antigen (PSA) concentrations. If a correlation exists between these two parameters, then use of testosterone-specific reference ranges may enhance the utility of PSA as a marker for prostate cancer. METHODS: Data were obtained from 150 men without previous history of prostate cancer. PSA was measured by the Abbott IMX microparticle enzyme immunoassay and total testosterone determined by the Coat-A-Count radioimmunoassay. RESULTS: No correlation was found between testosterone and PSA, even when corrected for age and weight. CONCLUSIONS: The data suggest that determination of the total serum testosterone level does not improve the sensitivity or specificity of PSA as a tumor marker.

Relationship between antisperm antibodies and testicular histologic changes in humans after vasectomy.

OBJECTIVE: To determine whether or not there is an association between testicular histologic changes and antisperm antibodies in vasectomized men. METHODS: Morphometry was performed on testicular biopsy specimens obtained from 19 vasectomized men and 21 fertile control subjects. Antisperm antibody status was determined on the serum of each patient and control subject using the indirect immunobead assay. RESULTS: Significant increases in seminiferous tubule wall thickness (p < 0.001), focal interstitial fibrosis (p < 0.001), and percent composition of interstitium (p < 0.01) were observed in vasectomized men as compared with control subjects. Serum antisperm activity was present in 74 percent of the vasectomized men but none in the control subjects (p < 0.001). There was no association between testicular histologic changes and immune status. CONCLUSIONS: Vasectomized men exhibit significant testicular histologic changes and increased autoimmune activity as compared with fertile control subjects. These histologic changes are not directly associated with antisperm antibody status, suggesting that some other pathophysiologic process must be responsible.

Transrectal ultrasonography of infertile men.

OBJECTIVE: To determine normal transrectal ultrasonographic anatomy in young men and the frequency of abnormalities in the infertile population. DESIGN: Transrectal ultrasonography was performed upon 30 fertile volunteers and 150 consecutive men referred for male factor infertility. SETTING: A male fertility center. RESULTS: Transrectal ultrasonography was normal in 60% of controls and 53% of infertile group. The frequency of hyperechoic lesions within the prostate was similar in controls (40%) and infertile men (39%). Müllerian duct cysts were present in 11% of the infertile men and none of the volunteers. Rectal exam was normal in all of the men. CONCLUSIONS: Transrectal ultrasonography is more sensitive at detecting abnormalities of the seminal vesicles and prostate than rectal exam. Hyperechoic lesions within the prostate is frequently a normal finding. Müllerian duct cysts are more frequently observed in infertile men and may be a cause of ejaculatory duct obstruction.

Diagnosis of vasal obstruction with seminal vesiculography: an alternative to vasography in select patients.

OBJECTIVES: To determine whether the pelvic and inguinal portion of the vas deferens can be visualized during seminal vesiculography. DESIGN: Retrospective review of the seminal vesiculograms performed in six patients to determine the frequency of visualization of the vas deferens. A prospective evaluation to determine the amount of contrast necessary to visualize the vas deferens was performed in three patients. RESULTS: The vas deferens was visualized down to the level of the scrotum in four of the six initial studies examined retrospectively. The vas deferens was visualized adequately after the infusion of > or = 10 mL of contrast in all three studies performed prospectively. CONCLUSION: Seminal vesiculography is a minimally invasive diagnostic alternative to vasography that can be used to document the patency of the pelvic and inguinal portions of the vas deferens in select patients.

Ultrasonographic diagnosis of varicoceles.

OBJECTIVE: To assess the ability of color duplex scrotal ultrasonography to detect subclinical varicoceles and confirm the diagnosis of clinical varicoceles. DESIGN: Physical examination, color duplex scrotal ultrasonography and internal spermatic venography was performed on 64 testicular units in 33 men. SETTING: Male fertility center. PATIENTS: Two hundred sixty-two consecutive men being evaluated for male factor infertility of whom 33 agreed to undergo venography. MAIN OUTCOME MEASURES: Ultrasonographic measurement of scrotal vein diameter of patients in the supine and upright position, before and during valsalva maneuver, and scrotal vein blood flow reversal with valsalva maneuver was compared with the findings of varicocele by physical examination and venography. RESULTS: The best predictor of a varicocele was internal spermatic vein diameter, and the best overall performance of ultrasonography was achieved with the patient at rest in the supine position. The best cutoff point for venous diameter for a clinical varicocele was 3.6 mm and 2.7 mm for a subclinical varicocele, but the overall accuracy was only 63%. CONCLUSIONS: Confirmatory studies are needed to support the ultrasonographic diagnosis of varicoceles before considering surgical repair.

Life-threatening conditions associated with male infertility.

Most urologists' clinical experience is that infertility is a rare presenting sign of life-threatening medical disorders in men. Considering the current practice of infertile couples presenting to the gynecologist for initial evaluation and the popularity of assisted reproductive technology, many men are evaluated with a semen analysis alone and treatment instituted without urologic consultation. This may cause a delay in the diagnosis of a significant medical illness or misdiagnosis of a potentially treatable cause of male factor infertility. We reviewed the records of 1236 new male infertility patients presenting to Bowman Gray School of Medicine and Baylor Medical College in an attempt to determine the frequency of significant medical disease in men presenting with infertility and whether any pattern of semen analysis findings was predictive of these disorders. Thirteen men, or 1.1% of the total population, were found to have a significant medical illness upon full urologic evaluation (Table 5). Testicular tumors were found in six, spinal cord tumor in one, brain tumors in three, genitourinary malformation in two, and a chromosomal abnormality in one. Interestingly, one of these patients was a physician with bilateral testicular cancer who had an abnormal semen analysis and had undergone multiple cycles of intrauterine insemination before referral. We could not identify a pathognomonic pattern on semen analysis that would allow us to predict the presence of medical illnesses in these 13 patients. Sperm counts ranged from azoospermic to almost normal semen parameters.(ABSTRACT TRUNCATED AT 250 WORDS)