Clomiphene and hypospadias on a detailed level: Signal or chance?

BACKGROUND: Clomiphene, a drug used to induce ovulation, is chemically related to diethylstilbestrol (DES). DES is associated with vaginal cancer and infertility among daughters and with hypospadias among second-generation male offspring. Because clomiphene has a long half-life and metabolites have been found in feces up to 6 weeks after administration, fetal exposure is possible if the mother took this drug prior to becoming pregnant. METHODS: Case-control analyses were performed to investigate the association between clomiphene exposure and hypospadias. Cases were all male subjects registered in the European Concerted Action on Congenital Anomalies and Twins (EUROCAT) Northern Netherlands registry for congenital anomalies with nonsyndromal hypospadias. Controls were all male children born without hypospadias, including those with chromosomal and monogenic defects. Logistic regression analyses were performed to calculate odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: Of 392 cases, 7 (1.8%) were exposed to clomiphene compared with 64 of 4538 controls (1.4%). For penoscrotal hypospadias, we found that the OR was significantly increased (6.08; 95% CI, 1.40-26.33); for the mild and moderate forms of hypospadias, the ORs were not increased. CONCLUSIONS: Because penoscrotal hypospadias is rare, the effect is diluted when all forms of hypospadias are studied as a group. Therefore, our study stresses the importance of studying birth defects on as detailed a level as possible. Other studies should be conducted to confirm our findings.     

Changing Male Reproductive Health: A Review of the Clinical Evidence?

Several lines of circumstantial evidence suggest that we may be seeing adverse changes in male reproductive health. A possible decline in semen quality has attracted most attention, but there are stronger indications of a rising incidence of testicular cancer, with increases observed in both Europe and the USA. There are striking geographic variations in both the incidence of testis cancer and in the observed rate of increase, and it is noteworthy that testis cancer is much more common in Denmark, where low sperm counts have been reported, than in Finland, where semen quality seems to be better. Another cause for concern is the rising incidence of congenital malformations of the male genital tract — cryptorchidism and hypospadias. In the UK, for example, rates of cryptorchidism have increased by as much as 65 to 77%. The data are harder to interpret on semen quality. In a meta-analysis, Carlsen et al. (1992) identified significant decreases over time in sperm concentration, corresponding to a fall of almost 50% between 1940 and 1990. Several groups have since examined secular trends in semen quality, with some reporting a downward trend and others no change. However, evidence has emerged of striking regional differences in semen quality, whether due to ethnic, genetic, environmental, or lifestyle factors remains to be determined.