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.

Supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (Contracts #N01-HD-3-3355, N01-HD-3-3356 and N01-HD-3-3358). There are no competing interests.

BackgroundAnogenital 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.MethodsA 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).FindingsA 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 man's 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.ConclusionA 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.

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.

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Endocrine disruptors, such as environmental compounds with endocrine-altering properties, may cause hypospadias and cryptorchidism in several species, including humans. Anogenital distance is sexually dimorphic in many mammals, with males having longer anogenital distance on average than females. Animal models of proposed endocrine disruptors have associated prenatal exposure with hypospadias, cryptorchidism, and reduced anogenital distance. Human studies have correlated shorter anogenital distance to in utero exposure to putative endocrine disruptors. We review preliminary data suggesting that anogenital distance is reduced in boys with hypospadia and cryptorchidism. Hence, human hypospadias and cryptorchidism may be associated with reduced anogenital distance as a result of endocrine disruption.

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 Patients-428 couples presenting for an infertility evaluation Interventions-Interviews and questionnaires Main Outcome Measures-Prevalence of complementary and alternative medicine therapyResults-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% had utilized meditation. An annual household income ≥ $200,000 (OR 2.8, p=.04) relative to couples earning < $100,000, not achieving a pregnancy (OR 2.3, p=.01), and a positive attitude toward CAM use at baseline (p<.001) were independently associated with CAM use.Conclusions-A substantial minority of infertile couples utilize 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.

This study is supported in part by P01HD36289 from the Eunice Kennedy Shriver National Institute for Child Health and Human Development, National Institutes of Health (to D.J.L. and L.I.L.). The project was also partially supported by an NIH CTSA award number UL1 RR025744. None of the authors has any conflict of interest to declare.