Michael L. Eisenberg

Male Reproductive Disorders and Fertility Trends: Influences of Environment and Genetic Susceptibility.

It is predicted that Japan and European Union will soon experience appreciable decreases in their populations due to persistently low total fertility rates (TFR) below replacement level (2.1 child per woman). In the United States, where TFR has also declined, there are ethnic differences. Caucasians have rates below replacement, while TFRs among African-Americans and Hispanics are higher. We review possible links between TFR and trends in a range of male reproductive problems, including testicular cancer, disorders of sex development, cryptorchidism, hypospadias, low testosterone levels, poor semen quality, childlessness, changed sex ratio, and increasing demand for assisted reproductive techniques. We present evidence that several adult male reproductive problems arise in utero and are signs of testicular dysgenesis syndrome (TDS). Although TDS might result from genetic mutations, recent evidence suggests that it most often is related to environmental exposures of the fetal testis. However, environmental factors can also affect the adult endocrine system. Based on our review of genetic and environmental factors, we conclude that environmental exposures arising from modern lifestyle, rather than genetics, are the most important factors in the observed trends. These environmental factors might act either directly or via epigenetic mechanisms. In the latter case, the effects of exposures might have an impact for several generations post-exposure. In conclusion, there is an urgent need to prioritize research in reproductive physiology and pathophysiology, particularly in highly industrialized countries facing decreasing populations. We highlight a number of topics that need attention by researchers in human physiology, pathophysiology, environmental health sciences, and demography.

Multivariate Analysis of Risk Factors for Long-Term Urethroplasty Outcome

PURPOSE We studied the patient risk factors that promote urethroplasty failure. MATERIALS AND METHODS Records of patients who underwent urethroplasty at the University of California, San Francisco Medical Center between 1995 and 2004 were reviewed. Cox proportional hazards regression analysis was used to identify multivariate predictors of urethroplasty outcome. RESULTS Between 1995 and 2004, 443 patients of 495 who underwent urethroplasty had complete comorbidity data and were included in analysis. Median patient age was 41 years (range 18 to 90). Median followup was 5.8 years (range 1 month to 10 years). Stricture recurred in 93 patients (21%). Primary estimated stricture-free survival at 1, 3 and 5 years was 88%, 82% and 79%. After multivariate analysis smoking (HR 1.8, 95% CI 1.0-3.1, p = 0.05), prior direct vision internal urethrotomy (HR 1.7, 95% CI 1.0-3.0, p = 0.04) and prior urethroplasty (HR 1.8, 95% CI 1.1-3.1, p = 0.03) were predictive of treatment failure. On multivariate analysis diabetes mellitus showed a trend toward prediction of urethroplasty failure (HR 2.0, 95% CI 0.8-4.9, p = 0.14). CONCLUSIONS Length of urethral stricture (greater than 4 cm), prior urethroplasty and failed endoscopic therapy are predictive of failure after urethroplasty. Smoking and diabetes mellitus also may predict failure potentially secondary to microvascular damage.

The Relationship between Anogenital Distance, Fatherhood, and Fertility in Adult Men

Background Anogenital distance (AGD), a sexually dimorphic measure of genital development, is a marker for endocrine disruption in animal studies and may be shorter in infant males with genital anomalies. Given the correlation between anogenital distance and genital development, we sought to determine if anogenital distance varied in fertile compared to infertile adult men. Methods A cross sectional study of consecutive men being evaluated for infertility and men with proven fertility was recruited from an andrology clinic. Anogenital distance (the distance from the posterior aspect of the scrotum to the anal verge) and penile length (PL) were measured using digital calipers. ANOVA and linear regression were used to determine correlations between AGD, fatherhood status, and semen analysis parameters (sperm density, motility, and total motile sperm count). Findings A total of 117 infertile men (mean age: 35.3±17.4) and 56 fertile men (mean age: 44.8±9.7) were recruited. The infertile men possessed significantly shorter mean AGD and PL compared to the fertile controls (AGD: 31.8 vs 44.6 mm, PL: 107.1 vs 119.5 mm, p<0.01). The difference in AGD persisted even after accounting for ethnic and anthropomorphic differences. In addition to fatherhood, on both unadjusted and adjusted linear regression, AGD was significantly correlated with sperm density and total motile sperm count. After adjusting for demographic and reproductive variables, for each 1 cm increase in a mans AGD, the sperm density increases by 4.3 million sperm per mL (95% CI 0.53, 8.09, p = 0.03) and the total motile sperm count increases by 6.0 million sperm (95% CI 1.34, 10.58, p = 0.01). On adjusted analyses, no correlation was seen between penile length and semen parameters. Conclusion A longer anogenital distance is associated with fatherhood and may predict normal male reproductive potential. Thus, AGD may provide a novel metric to assess reproductive potential in men.

The relationship between male BMI and waist circumference on semen quality: data from the LIFE study

Michael L. Eisenberg1,*, Sungduk Kim2, Zhen Chen2, Rajeshwari Sundaram2, Enrique F. Schisterman2, and Germaine M. Buck Louis2 Departments of Urology, Obstetrics and Gynecology, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, CA 94305-5118, USA Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, 6100 Executive Blvd., Room 7B03, Rockville, MD 20852, USA

Increased Risk of High-Grade Prostate Cancer Among Infertile Men

It has been reported that fatherhood status may be a risk factor for prostate cancer. In the current study, the authors examined the subsequent occurrence of prostate cancer in a cohort of men evaluated for infertility to determine whether male infertility is a risk factor for prostate cancer.

The use of complementary and alternative fertility treatment in couples seeking fertility care: data from a prospective cohort in the United States

OBJECTIVE To determine the prevalence of complementary and alternative medicine (CAM) use among couples seeking fertility care and to identify the predictors of CAM use in this population. DESIGN Prospective cohort study. SETTING Eight community and academic infertility practices. PATIENT(S) A total of 428 couples presenting for an infertility evaluation. INTERVENTION(S) Interviews and questionnaires. MAIN OUTCOME MEASURE(S) Prevalence of complementary and alternative medicine therapy. RESULT(S) After 18 months of observation, 29% of the couples had utilized a CAM modality for treatment of infertility; 22% had tried acupuncture, 17% herbal therapy, 5% a form of body work, and 1% meditation. An annual household income of > or =

The Relationship Between Anogenital Distance and Reproductive Hormone Levels in Adult Men

200,000 (odds ratio 2.8, relative to couples earning <

Caucasian male infants and boys with hypospadias exhibit reduced anogenital distance

100,000), not achieving a pregnancy (odds ratio 2.3), and a positive attitude toward CAM use at baseline were independently associated with CAM use. CONCLUSION(S) A substantial minority of infertile couples use CAM treatments. CAM was chosen most commonly by wealthier couples, those not achieving a pregnancy, and those with a baseline belief in the effectiveness of CAM treatments.

Prognostic Implications of an Undetectable Ultrasensitive Prostate-Specific Antigen Level after Radical Prostatectomy

PURPOSE Anogenital distance is a marker for endocrine disruption in animal studies in which decreased distance has been associated with testicular dysfunction. In this study we investigated whether anogenital distance was associated with reproductive hormone levels in adult men. MATERIALS AND METHODS A total of 116 men (mean age 36.1 ± 8.0 years) were evaluated at an andrology clinic in Houston. Anogenital distance (the distance from the posterior aspect of the scrotum to the anal verge) and penile length were measured using digital calipers. Testis size was estimated by physical examination. Linear regression was used to determine correlations between genital measurements and hormone levels. RESULTS Anogenital distance (r = 0.20, p = 0.03) and penile length (r = 0.20, p = 0.03) were significantly associated with serum testosterone levels while total testis size was not (r = 0.17, p = 0.07). No relationship between genital length and luteinizing hormone, follicle-stimulating hormone or estradiol was identified. After adjusting for age the serum testosterone increased by 20.1 ng/dl (95% CI 1.8, 38.4; p = 0.03) for each 1 cm increase in anogenital distance. On multivariable models no statistically significant relationship existed between penile length and testosterone levels. Moreover men with hypogonadal testosterone levels (less than 300 ng/dl) had a significantly shorter anogenital distance compared to men with higher testosterone levels (31.6 vs 37.3 mm, p = 0.02). CONCLUSIONS Anogenital distance may provide a novel metric to assess testicular function in men. Assuming that anogenital distance at birth predicts adult anogenital distance, our findings suggest a fetal origin for adult testicular function.

Racial Differences in Vasectomy Utilization in the United States: Data From the National Survey of Family Growth

BACKGROUND Animal models of endocrine dysfunction have associated male genital defects with reduced anogenital distance (AGD). Human studies have correlated shorter AGD with exposure to putative endocrine disruptors in the environment but have not examined AGD in hypospadiac boys. We measured AGD in boys with hypospadias and those with normal genitals. METHODS Data were collected prospectively on boys undergoing urologic procedures at the University of California San Francisco and the Childrens Hospital of Oakland, CA, USA. Data included age, race, height, weight, BMI, urologic diagnoses and AGD. To minimize any potential effects of race on observed AGD, we examined only Caucasian boys. Differences between boys with hypospadias and those with normal genitals were examined through two-tailed Students t-tests. RESULTS One hundred and nineteen Caucasian boys ranging in age from 4 to 86 months underwent AGD measurement, of which 42 and 77 were boys with normal genitals and hypospadias, respectively. The mean (±SD) AGD of boys with hypospadias was 67 ± 1.2 versus 73 ± 1 mm for boys with normal genitals (P = 0.002). In these age-unmatched patient groups, there were also differences in age, height and weight (P = 0.0001, 0.0002 and 0.0004, respectively). After age matching (all <2 years of age), boys with hypospadias (n= 26) still featured a shorter AGD than boys with normal genitals (n= 26; 62 ± 2 versus 68 ± 2 mm respectively, P = 0.033) but the differences in age, height and weight were no longer significant. CONCLUSIONS In humans, hypospadias may indeed be associated with reduced AGD. Additional studies are needed to corroborate these preliminary findings and to determine their etiology.