Environmental endocrine modulators and human health: an assessment of the biological evidence, 1998
Animal DES Data
The biological plausibility of a relationship between in utero exposure to exogenous estrogen and cryptorchidism is supported by animal studies. In the mouse model, following maternal DES doses of 0.1, 1.0, 2.5, 5, 10, and 100 mg/kg/d on days 9 to 16 of gestation, only the highest dose (100 mg/kg/d) produced observable reproductive tract effects, including cryptorchidism, on male offspring. The lack of effects on the male mouse reproductive tract following in utero exposure to doses of DES of less than 100 µg/kg/d may have implications for humans exposed in utero to compounds identified as environmental estrogens that have significantly less estrogenic activity than DES. If a testosterone surge is the triggering event in testicular descent, elevated estrogen levels during this critical time period may be required to offset it.
Human DES Data
There are a number of studies of sons exposed in utero, primarily to DES, in which the subsequent incidence rates of cryptorchidism have been increased compared with unexposed infants. Cryptorchidism incidence rates were assessed in 308 males whose mothers had participated 25 years earlier in a randomized double-blind study of the usefulness of DES on reducing miscarriage.The initial clinical trial had been conducted at the University of Chicago, where the DES dosing protocol was 5 mg/d starting at the seventh week of gestation, and increasing by 5 mg/d every second week, up to a maximum daily dose of 150 mg at 34 weeks. Women were enrolled in this treatment protocol no later than the 20th week of pregnancy; 95% of the women in the treatment group received total DES doses between 11,500 mg and 12,600 mg. Thus, males were exposed in utero to substantial maternal DES doses during a critical time of reproductive tract development. In the DES-exposed males, 17 of 308 reported cryptorchidism compared with one in the unexposed group. As the unexposed and DES-exposed groups were approximately the same size, the single case of cryptorchidism reported in the unexposed group may be too low, exaggerating the association with cryptorchidism in the exposed group. If, as noted above, the prevalence of cryptorchidism in the U.S. at birth is 0.8%,suggesting that approximately 2 to 3 cases of cryptorchism in the unexposed group would be expected. Even if this is correct, in utero exposure to DES still resulted in an increased incidence of cryptorchidism in male offspring.
In a large retrospective study conducted in a population drawn from the Mayo Clinic, the incidence rate of cryptorchidism at birth was 0.78% in over 14,000 male births from 1943 to 1973. Multivariate analysis provided no evidence to suggest that in utero estrogen exposure was associated with an increased incidence of cryptorchidism in male offspring. The retrospective nature of this study poses some problems due to the uncertainty surrounding patient compliance (e.g., DES doses) and the validity of diagnosis. In particular, noncompliance would tend to reduce the strength of any observed association. While acknowledging that animal studies demonstrate a cause and effect relationship between prenatal exposure to DES and cryptorchidism, Beard et al. note that, “…evidence that estrogen and/or progestin exposure causes cryptorchidism in humans is less impressive.” The studies of the Mayo Clinic cohorts are important because maternal median doses ranging from 720 to 1675 mg (with mean exposure durations of about 121 d) were extremely low, relative to total maternal doses used elsewhere (e.g., over 11,000 mg at the University of Chicago).
Other studies have investigated cryptorchidism in offspring exposed to DES in utero, but most of these fail to provide sufficient information concerning total maternal DES doses. In a study of men exposed in utero to DES in the San Francisco area, there were no differences between exposed and unexposed in any testicular parameter. The approximate total maternal DES dose was 3000 mg with an average fetal exposure duration of 23 weeks. There were three cases of cryptorchidism (in addition to other genitourinary abnormalities) in 225 men exposed in utero to DES in the Los Angeles area and one case in 111 unexposed men.
While the number of subjects in this study was small making incidence rates unstable, it is of interest that the median total maternal DES dose of 4575 mg was relatively high (mean duration of exposure of 112 d); 67% of subjects began taking DES during the first trimester.
The results of the Mayo Clinic studies, showing no increased risk of cryptorchidism among DES-exposed males, suggest that the relatively lower maternal doses used there are unlikely to cause this condition. The existence of an apparent maternal DES no effect dose for cryptorchidism challenges the biological plausibility that in utero exposure to much weaker compounds identified as environmental estrogens may be associated with cryptorchidism following in utero exposure. Because individual environmental estrogens tested to date are significantly less potent than DES, it will be important to determine whether net estrogenic activity (i.e., after accounting for total estrogenic and antiestrogenic activity) of environmental estrogens (either as dietary intake or as body burdens) would be present at sufficient concentrations to cause in utero estrogenic effects (e.g., cryptorchidism) on developing offspring similar to DES. In particular, studies comparing animal and human DES effect and no effect maternal dose levels with typical mixtures of environmental estrogens exposure levels will be critical. Because a DES dose of 100 µg/kg was the only effective maternal dose in producing cryptorchid testes in experiments with mice, it will be necessary to determine whether mixtures of typically encountered environmental estrogens have a comparable net estrogenic potency. Perhaps more importantly, because a human maternal total DES median dose of 720 mg appears to have been ineffective in producing cryptorchidism in offspring exposed in utero, it will also be necessary to determine net estrogenic potency of typically encountered mixtures of environmental estrogens.
- 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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