Effects of cigarette smoking on erectile dysfunction.

Cigarette smoking is a leading cause of preventable morbidity and mortality in the United States. Although public policies have resulted in a decreased number of new smokers, smoking rates remain stubbornly high in certain demographics with 20% of all American middle-aged men smoking. In addition to the well-established harmful effects of smoking (i.e. coronary artery disease and lung cancer), the past three decades have led to a compendium of evidence being compiled into the development of a relationship between cigarette smoking and erectile dysfunction. The main physiologic mechanism that appears to be affected includes the nitric oxide signal transduction pathway. This review details the recent literature linking cigarette smoking to erectile dysfunction, epidemiological associations, dose dependency and the effects of smoking cessation on improving erectile quality.

Men regret anabolic steroid use due to a lack of comprehension regarding the consequences on future fertility.

We examined whether men with anabolic-steroid-induced hypogonadism (ASIH) seeking testosterone supplementation therapy (TST) regretted their decision to use anabolic-androgenic steroids (AAS) and what their reasons were for this regret. An anonymous, prospective survey was distributed to 382 men seeking follow-up treatment for hypogonadism. Prior AAS use was confirmed by self-report, and men were categorised based upon whether they regretted (R) or did not regret (NR) their use of AAS. The average patient age was 40 ± 0.9 years (n = 79) and 15.2% expressed regret over AAS use. No demographic differences were identified between those who regretted AAS use (n = 12) and those who did not (n = 67). Regret was not related to ASIH diagnosis or to AAS-related side effects like increased aggression, mood disorders, erectile dysfunction, acne, fluid retention or dyslipidemia. Those who regretted AAS use were significantly more likely to have not comprehended the negative impact on future fertility (P < 0.030). Actual fertility issues were comparable in men who regretted AAS use (16.7%) and those who did not (13%). A total of 15.2% of men regretted using AAS. A lack of awareness regarding the negative long-term effects on fertility was the primary factor related to regret of AAS use in men with ASIH.

The male infertility office visit.

One in six couples are infertile, and in 50% of these couples, a male factor plays a role. Therefore, it is imperative that physicians become comfortable in the basic evaluation of the infertile male. By performing a thorough history and physical examination, physicians can usually establish a differential diagnosis and proceed to laboratory testing that will help to establish an etiology for infertility. The purpose of this review is to provide general guidelines for a physician seeking to evaluate a man's fertility status and to suggest the most common pathologies that might be found through a directed work-up.

Neuromorphology and neuropharmacology of the human penis: an in vitro study.

The neuromorphology and neuropharmacology of the human penis are only briefly described in literature. The present study was undertaken to define the adrenergic and cholinergic neuromorphology of the human corpus cavernosum (CC) and corpus spongiosum and to evaluate the in vitro response of the CC to pharmacologic stimulation. Human penile tissue was obtained from six transsexual patients undergoing penectomy. For morphologic study, the tissue was processed for (a) hematoxylin and eosin staining; (b) smooth muscle staining; (c) acetylcholinesterase localization; (d) glyoxylic acid histofluorescence; (e) electron microscopy; and (f) electron microscopy after glutaraldehyde dichromate fixation. In addition, strips of CC were placed in in vitro muscle chambers and tension changes recorded isometrically after stimulation with norepinephrine (NE) and acetylcholine. The CC contains abundant smooth muscle, numerous glyoxylic acidfluorescent (catecholaminergic) fibers and varicosities, and a scant distribution of acetylcholinesterase-positive fibers. Fewer of all these elements were present in the corpus spongiosum. No "polsters" were observed in the CC. Although glutaraldehyde-fixed controls exhibited no typical adrenergic vesicles (small, dense core, measuring 400-600 A in diameter), some small, strongly electron-dense vesicles were found in glutaraldehyde dichromate-fixed tissue and were thought to contain NE. A variety of other vesicles were also encountered. The addition of NE to the in vitro muscle chambers caused a dose-related contraction, which was blocked by pretreatment with phentolamine in all CC strips tested. Acetylcholine in high concentration produced minimal contraction in 2 of 24 strips. Our morphologic and pharmacologic data suggest that the sympathetic nervous system may affect erection by acting not only on the penile vasculature but also by direct action on the smooth muscle of the CC itself.

Rapid recovery of spermatogenesis after mitoxantrone, vincristine, vinblastine, and prednisone chemotherapy for Hodgkin's disease.

PURPOSE: Because the effects of mitoxantrone on human male fertility were unknown, we determined prospectively the effects of three courses of mitoxantrone (Novantrone), vincristine (Oncovin), vinblastine, prednisone (NOVP) chemotherapy on the potential for fertility of men with Hodgkin's disease (HD). PATIENTS AND METHODS: Semen analyses were performed on 58 patients with stages I-III HD before, during, and after chemotherapy and after the sperm count recovered from the effects of abdominal radiotherapy that was given after chemotherapy. RESULTS: Before the initiation of treatment, 84% of the patients were normospermic. Sperm counts declined significantly within 1 month after the start of NOVP chemotherapy. In the month after chemotherapy, 38% of patients were azoospermic, 52% had counts < 1 million/ mL, and 10% had counts between 1 and 3 million/mL. Between 2.6 and 4.5 months after the completion of chemotherapy, sperm counts recovered rapidly to normospermic levels in 63% of patients. In the remaining patients who were followed up for at least 1 year after standard upper abdominal radiotherapy, counts also recovered to normospermic levels. CONCLUSION: NOVP chemotherapy, like most other regimens, produced marked temporary effects or spermatogenesis. However, sperm production recovered very rapidly, within 3 to 4 months after the end of NOVP chemotherapy. This pattern was caused by killing differentiating spermatogenic cells, but there was little cytotoxicity or inhibition of stem cells from mitoxantrone or the other drugs. After the combination of NOVP plus abdominal radiotherapy, sperm counts and motility were restored in most patients to pretreatment levels, which were compatible with normal fertility.

Testosterone therapy and mortality risk.

Recent data suggest an increased risk of cardiovascular events and mortality in men on testosterone therapy (TT). To date, there are no long-term, prospective studies to determine safety. In such cases, retrospective observational studies can be helpful. We examined our patient database to determine whether TT altered the risk of all-cause mortality in men. We queried our hormone database for all men with a serum testosterone level and then examined charts to determine testosterone status. In all, 509 men had charts available for review. We linked our patient records to the National Death Index to determine mortality. Of the 509 men who met inclusion criteria, 284 were on TT and 225 did not use testosterone. Age (mean 54 years) and follow-up time (mean 10 years) were similar for both groups. In all, 19 men died--10 (4.4%) men not on TT and 9 (3.2%) men on TT. After adjusting for age and year of evaluation, there was no significant difference in the risk of death based on TT (hazard ratio 0.92, 95% confidence interval 0.36-2.35, P=1.0). There appears to be no change in mortality risk overall for men utilizing long-term testosterone therapy.

Microscopic visualization of intravasal spermatozoa is positively associated with patency after bilateral microsurgical vasovasostomy.

We evaluated pre-operative and intraoperative factors associated with successful patency following bilateral microsurgical vasovasostomy (VV). We retrospectively reviewed the charts of 1331 men who underwent bilateral VV by two surgeons between 2006 and 2013. Vasal fluid was examined intraoperatively for gross quality (i.e., clear or opaque and creamy/thick) and for the presence of spermatozoa on microscopy (i.e., whole spermatozoa, sperm fragments, or azoospermia). Post-operative patency was assessed by semen analysis or patient report of conception. Perioperative factors were explored using descriptive statistics and examined in logistic regression models for associations with post-operative patency. The median age at VV was 39 years [interquartile range (IQR): 35-44] and the median obstructive interval (OI) was 7 years (IQR: 4-11). Overall, 1307 patients achieved post-operative patency (98%) while 24 remained obstructed (2%). Among those who became patent, 410 reported conception. After adjustment for potential confounders, only microscopic examination of the intravasal fluid for the presence of spermatozoa (bilateral or unilateral whole spermatozoa vs. sperm parts/azoospermia) at the time of VV was significantly associated with post-operative patency with an odds ratio (OR) of 14.2 (95% CI: 5.8-34.9; p = <1 × 10(-8) ). Identification of bilateral or unilateral sperm fragments vs. azoospermia was also associated with increased odds of post-operative patency with an OR of 3.5 (95% CI: 0.9-13.6; p = 0.08). There was no statistically significant association between age at VV, OI, presence of granuloma, gross fluid quality, or surgeon and post-operative patency after controlling for potential confounders. Identification of whole spermatozoa in the vasal fluid at the time of VV was positively associated with post-operative patency. Our findings stress the need for intraoperative microscopy to aid in post-operative patient counseling.

Transferrin binds specifically to pachytene spermatocytes.

We have examined the secretion and binding of transferrin to rat testicular cells. The only testicular cells found to secrete transferrin were the Sertoli cells (control 549 +/- 6; FSH 1020 +/- 17 ng/day X 10(6) cells, mean +/- SEM). The Sertoli cells also contained specific binding sites for transferrin with a Kd of 2.0 X 10(-9)M. Of the other testicular cells examined only fractions rich in pachytene spermatocytes possessed specific transferrin-binding sites. Late pachytene spermatocytes (97% pure) bound [125I]iodotransferrin with a similar affinity as Sertoli cells (Kd 1.7 X 10(-9)M). Fractions of early and mid pachytene spermatocytes contained transferrin-binding sites with a higher affinity (Kd 0.3 X 10(-9)M). This is the first report of a protein that has specific binding sites on germ cells.

Characterization of human Sertoli cells in vitro.

The Sertoli cell is thought to play a significant role in the hormonal regulation of spermatogenesis within the rat testis. Little, however, is known about Sertoli cell function in man, largely because of the difficulties associated with the isolation of pure cell populations from human tissue. We have now developed a rapid and reproducible technique for establishing a human Sertoli cell monolayer culture. This has involved mechanical separation of the tissue, sequential trypsin and collagenase enzyme digestion, and final disruption of tubules by passage through a wire mesh grid. Using this technique, primary cultures can be maintained for up to 45 days. Ultrastructural studies of these cells have demonstrated the presence of the perinucleolar spheres, cell to cell junctional complexes, abundant lipid droplets, and smooth endoplasmic reticulum, all characteristic of Sertoli cells. Furthermore, biochemical markers of animal Sertoli cells, androgen-binding protein and gamma-glutamyl transpeptidase, have also been identified in these human cells. Concentrated media electrophoresed on nondenaturing gels containing 2 nM [3H]dihydrotestosterone produced a single peak of bound activity which coelectrophoresed with rat androgen-binding protein. This binding activity persisted despite media changes, thus ruling out contamination by serum binding proteins; fresh media lacked demonstrable binding activity. Using a colorimetric assay, these cells were also found to contain significant gamma-glutamyl transpeptidase activity compared to human foreskin fibroblasts and Leydig cells. Enzyme activity increased in a characteristic dose-response fashion in the presence of FSH (0.05-0.5 microgram/ml) and dibutyryl cAMP (0.1-1 microgram/ml), but not with LH or testosterone. These data offer the first demonstration of human Sertoli cells in monolayer culture and their production of a marker specifically regulated by FSH.

Regulation of transferrin secretion by human Sertoli cells cultured in the presence or absence of human peritubular cells.

Transferrin represents 1-4% of the total proteins secreted by human Sertoli cells, and the amount secreted by the cells was maximal after a 4- to 5-day period in culture, the time chosen for each medium change. During this first 4- to 5-day period, the addition of FSH, insulin, (Bu)2cAMP, and isobutylmethylxanthine had no effect on transferrin secretion; however, from days 4-5 to 8-10, each of the above compounds significantly stimulated transferrin secretion compared to control values. Testosterone (in the absence or presence of insulin) had no effect. Transferrin secretion increased for the first 5 days in culture, with a similar magnitude in the presence or absence of the above stimulators, and thereafter declined, more so in untreated cultures. These results suggest that these agents do not stimulate, but, rather, limit the decline in transferrin secretion. When human peritubular cells were cocultured with Sertoli cells, transferrin secretion was significantly elevated compared to that by Sertoli cells alone. Interestingly, in the cocultures (Bu)2cAMP stimulated transferrin secretion when added for the first 4- to 5-day culture period. Human fibroblasts or spent medium from the peritubular cell cultures did not mimic the effect found when peritubular and Sertoli cells were cocultured. These results provide evidence that peritubular cells play a critical role in regulating human Sertoli cell function.

Varicocele: a progressive or static lesion?

Varicoceles are associated with ipsilateral testicular atrophy in the adolescent. To determine if varicoceles are capable of causing progressive loss of fertility, we conducted a date-matched, retrospective study. We reviewed 2,989 patients evaluated for infertility at our institution from 1985 to 1990. A total of 285 (8.5%) patients were diagnosed with secondary infertility. A varicocele was identified as the cause of the patient's infertility in 177 (69%) men with secondary infertility. When matched by date to an identical number of men with primary infertility in whom 128 (50%) were infertile on the basis of a varicocele effect, the difference was significant (p < 0.0001). We conclude that a varicocele in some men is a progressive and not a static lesion resulting in the loss of previously established fertility. In addition, varicoceles are not only the leading cause of infertility in men with secondary infertility, but also occur with a greater frequency than in men with primary infertility.

Simplified gonadotropin-releasing hormone (GnRH) stimulation test.

Provocative gonadotropin-releasing hormone (GnRH) stimulation testing indirectly assesses testicular function with more sensitivity than determination of basal gonadotropin levels alone. Unfortunately, the drawbacks of multiple blood sampling and high cost have limited the clinical usefulness of this test. We herein present a simplified, two-point, thirty-minute GnRH stimulation test. Statistical analysis of data from 55 men with normal baseline gonadotropin levels, reveal that this simplified test is just as accurate as the traditional test (p less than 0.0001) without the latter's attendant difficulties. In addition, we found that normal basal gonadotropin levels had little correlation to the actual responses obtained from GnRH stimulation testing (r = 0.20 and r = 0.39 for luteinizing hormone and follicle-stimulating hormone, respectively).

Transrectal ultrasound and partial ejaculatory duct obstruction in male infertility.

Partial ejaculatory duct obstruction, due to either a congenital or an acquired cyst or ejaculatory duct stenosis secondary to calcification, chronic inflammation, can produce a wide spectrum of seminal fluid abnormalities. Sperm density may range from azoospermia to normospermia while ejaculate volume can be low to normal. Sperm motility is consistently diminished (less than 30%). We have treated 2 patients with ejaculatory duct stenosis whose diagnosis was accurately made with transrectal ultrasonography (TRUS). We now suggest that TRUS be used when there is a low semen volume (less than 1.0 cc), or low motility (less than 30%), or oligospermia (less than 20 million sperm/mL), and normal findings on physical examination with normal serum gonadotropin values in the absence of any other explanation.

Radioisotope angiography in diagnosis of varicocele.

A varicocele, the most common surgically correctable cause of subfertility in men, is a manifestation of abnormal retrograde venous blood flow through the internal spermatic vein into the peritesticular pampiniform plexus. Methods of diagnosing the varicocele, including careful physical examination using a Valsalva maneuver as well as a Doppler stethoscope, remain somewhat subjective. Venography, while a reliable and objective technique, is invasive and not without morbidity. In the present study, 16 patients with clinically detectable varicoceles of various sizes were studied using a testicular radioisotope angiogram developed in our laboratory. Following the injection of 15 mg. of stannous pyrophosphate which results in tagging of the circulating red cell pool, 20 mCi. of 99m-technetium were administered in an intravenous bolus injection. The isotope binds to the pyrophosphate thus tagging the red blood cells and creating a blood-pooling agent with a relatively short half-life (six hours). Perfusion studies as well as static views of the scrotal contents, both in the supine and erect position, with and without Valsalva maneuver, were obtained using a gamma camera. The activity in each hemiscrotum then was quantitated using a digital computer. It is proposed that quantitation of this differential blood pool will make the identification of even subclinical varicoceles a potentially objective determination.

Post-transplantation lymphocyst: use of ultrasound as adjunct in diagnosis.

Ultrasound examination has proved to be a useful diagnostic tool in the differentiation of lymphocyst from other causes of upper urinary tract obstruction in the renal transplant recipient.

Cryptorchidism in the subfertile male.

Certain conclusions may be drawn from the present review and presentation of new data concerning the unilaterally cryptorchid patient and possible subfertility: 1. The truly undescended testis--not the retractile testis of infancy--will not descend spontaneously after 1 year of age. 2. The seminal quality of the unilaterally cryptorchid patient is definitely impaired, although not rendered infertile, in a great majority of patients irrespective of the time of surgery. 3. The dystopic position of the maldescended testis appears to superimpose a second insult on what very likely may be an inherent abnormality in the cryptorchid testis, the latter accounting, perhaps, for its abnormal extrascrotal position. 4. Orchiopexy before the age of 5 seems advisable to ensure minimal histologic changes that may be secondary to the testis' increased exposure to elevated extrascrotal temperature. 5. The cryptorchid testis will be smaller in size irrespective of surgery, and usually correlates with significant testicular pathology. 6. Basal levels of gonadotropins, especially follicle-stimulating hormone, are likely to be elevated, but this does not necessarily imply overwhelming testicular damage. Androgen production should not be affected. 7. Surgical correction is advised when human chorionic gonadotropin stimulation fails to produce teticular descent, thereby defining the maldescended testis as not merely retractile but truly "crytorchid."

Deoxyribonucleic acid (DNA) flow cytometry: a new modality for quantitative analysis of testicular biopsies.

Methods currently in use for quantification of spermatogenesis are not widely accepted clinically because they are time-consuming and open to subjective interpretation. This study explores the use of flow cytometry as a rapid and objective modality for quantitative analysis of testis biopsies.

Stimulation of cyclic adenosine 3':5'-monophosphate accumulation in human testes in vitro by luteinizing hormone, follicle-stimulating hormone, and prostaglandins.

The gonadotropins luteinizing hormone (LH) and follicle-stimulating hormone (FSH) stimulate cyclic adenosine 3':5'-monophosphate (cyclic AMP) accumulation in human testicular incubates. The phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine acts synergistically with LH and FSH to enhance cyclic AMP accumulation. These studies indicate that cyclic AMP accumulation may be involved in the mechanism of action of LH and FSH in the human testes, as has been proposed for rat testes. The prostaglandins (PG PGE1, PGE2, PGA1, and PGF2alpha stimulate cyclic AMP levels at 10(-4) M in human testes. The E type prostaglandins are the most potent. They induce half-maximal stimulation of cyclic AMP at 7 x 10(-7) M.

PIP: Luteinizing hormone (LH) and follicle stimulating hormone (FSH) stimulated the accumulation of adenosine 3',5'-monophosphate (cAMP) within 30 minutes of addition to human testicular incubates. The phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine acted synergistically with FSH and to a lesser degree with LH to enhance cAMP accumulation. The findings indicate that cAMP accumulation may be involved in the mechanism of action of LH and FSH in the human testes, as has been proposed for rats. The prostaglandins (PG) PGE-1, PGE-2, PGA-1, and PGF-2-alpha stimulated cAMP levels at a concentration of 1/10,000 M in human testes. The E type prostaglandins were the most potent; they induced half-maximal stimulation of cAMP at 7/10,000,000 M.

Significant medical pathology uncovered by a comprehensive male infertility evaluation.

OBJECTIVE: To determine if there was a specific screening regimen that could identify all patients with significant medical pathology found during a comprehensive male infertility evaluation. DESIGN: A retrospective study. SETTING: Two university-based male infertility clinics. PATIENTS: Thirteen patients with male factor infertility identified with significant medical pathology. MAIN OUTCOME MEASURES: Initial presentation, history, physical examination, semen analysis, and hormone profile. RESULTS: The identification of significant medical pathology was uncovered in 13 of 1,236 patients (1.1%) presenting to a male infertility clinic. The pathology was identified with a thorough history in 4 of 13 patients (30.8%) and by a complete physical examination in 8 of 13 patients (61.5%). Semen analyses were available on 12 patients, and 1 patient was anejaculatory. Two patients were azoospermic. Of the patients with sperm present, the mean sperm concentration was 8.6 x 10(6)/mL (range, 0.8 to 27), and the mean sperm motility was 32.0% (range, 0% to 65%). In 5 patients, endocrine abnormalities were specifically related to the subsequent pathology identified. A tumor was identified in 10 patients (6 testicular tumors, 3 brain tumors, and 1 spinal cord tumor). Two patients had ejaculatory dysfunction as a result of mesonephric duct anomalies affecting the ejaculatory duct or bladder neck closure. One patient had Klinefelter's syndrome. CONCLUSIONS: There was no pathognomonic finding on history, physical examination, semen analysis, or hormone profile that identified all patients with significant medical pathology. The significant medical pathology identified was represented in all semen quality groupings, that is, azoospermia, severe oligospermia, mild oligospermia, and normospermia. We recommend a comprehensive urologic evaluation for all male partners of infertile couples with a male factor or unexplained infertility in an attempt to identify significant and potentially treatable medical pathology before engaging in a series of therapies with assisted reproductive techniques.

A quality control system for the optimized sperm penetration assay.

OBJECTIVE: To develop a quality control system for the optimized sperm penetration assay (SPA) and to use this system to monitor interassay variability and stability over time. DESIGN: Four semen donors were tested consecutively for a period of weeks (7 to 139 weeks) with the SPA. Their average semen analyses and SPA scores were evaluated to monitor natural biologic variation. Intra-assay variation was obtained by dividing 11 semen samples into three aliquots and testing each separately in the SPA. A single ejaculate from seven individuals was aliquoted and frozen to be used as a control. They were tested on different assay days in 1986 and subsequently in 1991 to evaluate the assay stability over time. MAIN OUTCOME MEASURES: Results were expressed as a sperm capacitation index (mean number of sperm penetrations per ovum). RESULTS: Consecutive weekly semen analyses and SPAs on donors exhibited coefficients of variation ranging from 20% to > 40%. In contrast, these variations were much greater than intra-assay variability. Analysis of frozen semen specimens tested in several SPAs also displayed a low coefficient of variation. When aliquots of these frozen samples were tested in the SPA 5 years later, there were no differences in the observed values, showing the remarkable stability of this assay over time. The lower limit of the normal fertile range did not change over a period of 2 years. CONCLUSIONS: Results show that using fresh semen samples as a positive control in the SPA is inadequate. This deficiency has been overcome with the use of frozen semen controls. With frozen semen for quality control, the optimized SPA developed in this laboratory is a highly reproducible assay that meets the strict criteria required for clinical laboratory certification.