Environmental endocrine modulators and human health: an assessment of the biological evidence, 1998
The possible relationship between in utero exposure to DES and male fertility was investigated through physical examination, seminal fluid analysis, and an in vitro sperm penetration assay (SPA) in zone-free hamster eggs in 17 men exposed in utero to DES, 12 non-DES-exposed men, and 11 fertile control men. Fourteen of 17 DES-exposed and 2 of 12 non-DES-exposed. men had SPA results compatible with infertility. All 11 fertile controls had SPA values in the fertile range. This study showed a significant difference between the mean sperm count in the DES-exposed group (66.4 million/ml) and the nonexposed group (101.7 million/ml). There were no differences between the exposed and nonexposed groups in either sperm morphology or motility. The likelihood of selection bias may be large because the men who participated in the study were aware that it was designed to evaluate effects of in utero DES exposure on male infertility. The high frequency of genital abnormalities (52%) such as epididymal cysts or abnormalities of the prostate, testicle, or penile meatus in this DES-exposed population compared with genital abnormalities (32 to 37%) reported in other studies suggests selection bias in this study.
In a subsequent and larger study using the same in vitro sperm penetration assay, there were no differences in sperm penetration between DES-exposed men (n = 51) and nonexposed men (n = 29) as well as no differences in sperm concentration, motility, or seminal leukocytes in DES-exposed and nonexposed men. Furthermore, although the frequency of genital abnormalities was related to in utero DES exposure (37% in DES-exposed men compared with 4% in nonexposed men), it was not related to reduced egg penetration. In contrast to the original study, 292 the principal aims of the follow-up study were not revealed to study participants.
In the largest fertility study of adult men exposed in utero to DES, there were three times more self-reported genital malformations in men with in utero exposure to DES (n = 253) than placebo-exposed controls (n = 241). However, despite the increased incidence of genital malformations, there was no significant difference in fertility between men exposed in utero to DES and unexposed men by any measure, including whether they had impregnated a woman, age at the birth of their first child, average number of children, medical diagnosis of a fertility problem, or length of time to conception. Furthermore, there were no differences between DES-exposed men and unexposed with respect to sexual function as measured by frequency of intercourse or reported episodes of decreased libido. The cohort of men in this study were exposed in utero during a randomized clinical trial of DES use during pregnancy at the University of Chicago in the early 1950s.
An earlier study of the same clinical trial cohort showed decreased sperm counts and abnormal sperm morphology in DES-exposed men (91 million/ml in 134 men) compared with nonexposed controls (115 million/ml in 87 men). Thus, it appears that high in utero total maternal doses of DES (11,500 to 12,600 mg) can lower sperm counts without affecting fertility. The failure of high maternal doses of DES administered over approximately 28 weeks to adversely affect the fertility of male offspring exposed in utero challenges the notion that in utero exposure to environmental estrogens (net exposure or body burdens), which are significantly less potent than DES, might impair male fertility.
- Environmental endocrine modulators and human health: an assessment of the biological evidence, Critical reviews in toxicology, NCBI PubMed, PMID: 9557209, 1998.
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