Fact Sheets - Male Reproductive Tract Abnormalities

Issue: In utero Exposure to hormonally active chemicals is contributing to the observed increase in the incidence of male reproductive tract abnormalities.

Background: Increases in the incidence of cryptorchidism (failure of the testis to descend into the scrotum) and hypospadias (urethral opening along the shaft of the penis) have been reported. Normal development of the male reproductive tract is dependent on the expression and action of Müllerian inhibiting substance and androgens (testosterone and dihydrotestosterone) during fetal development. Since development of the male reproductive tract is under sex hormone control, changes in the incidence of hypospadias and cryptorchidism could therefore be considered as likely markers of endocrine disturbance.

Trends in hypospadias and cryptorchidism: Data from two birth defects surveillance systems in the USA have shown that the prevalence of hypospadias at birth has increased between the 1970s and 1990s. Similarly, analysis of the secular trends in the prevalence of cryptorchidism also indicates an increase over time. In a prospective study carried out by the John Radcliffe Hospital Cryptorchidism Study Group, 7441 boys from Oxford were examined for cryptorchidism at birth and then again at three months of age during 1984 - 1988. The cryptorchidism rate at birth was found to have increased by 35.1%, and at three months of age by 92.7% compared with the rates reported in an earlier study for the mid-1950s in 3612 male infants in London. While direct comparison between these two studies is hampered by different inclusion criteria, it would seem that the prevalence of cryptorchidism has increased in Great Britain.

Consistency of the data: Considerable variation in the incidence of hypospadias has been reported for different malformation surveillance systems. Analysis of the birth prevalence rates for hypospadias and cryptorchidism collected through the International Clearing House for Birth Defects Monitoring System has revealed a wide inter-country variation in rates of hypospadias and cryptorchidism around the world. A factor of 3 or more could be observed between the highest rates (in USA and Israel for hypospadias, USA and Canada for cryptorchidism) and the lowest rates (Finland, Japan, China and South America for hypospadias; South America for cryptorchidism). Differences in methodologies and other factors make the comparison difficult. The secular evolution within various registries suggest an increase in hypospadias rates during the seventies and the eighties in USA, Scandinavia and Japan. No change was observed in Canada, a country geographically very close to the USA. For both pathologies a tendency towards a decline of rates has been found after 1985.

Experimental evidence: A number of epidemiological studies have suggested that exposure to pesticides may be linked to male reproductive tract abnormalities in Granada, Spain, Norway, Colombia, and the United States. In Denmark, analysis of the data from all live male infants discharged from Danish hospitals with a diagnosis of cryptorchidism or hypospadias between 1983 and 1992 demonstrated a significantly increased risk of cryptorchidism but not hypospadias in sons of women working in gardening (OR 1.7, 95% CI 1.1-2.4).

In animal experiments, cryptorchidism has been induced with gestational exposure to suspected estrogenic and anti-androgenic chemicals, such as mono-n-butyl phthalate in rats and flutamide in pigs. Mid-gestational exposure to TCDD has produced cryptorchidism, reduced germ cell numbers and epididymal abnormalities in pigs, accompanied by reduced estrogen receptor-a mRNA expression in the gubernaculum and epididymis and increased estrogen receptor-a protein levels in the testis.

Biological Plausibility: Animal studies demonstrate that exposure to estrogens during development can result in cryptorchidism and hyospadias. In humans, the induction of reproductive tract abnormalities (epididymal cysts, cryptorchdism and other genital abnormalities) in sons of DES-exposed mothers has been well documented. However, meta-analysis of 14 human studies on the influence of either oral contraceptives (less potent than DES) or progestagens has not produced any convincing evidence of an effect of prenatal exposure. The possible role of exogenous estrogens in the maternal diet in hypospadias has recently been investigated. Mothers who were vegetarian during pregnancy had an increased risk of giving birth to a boy with hypospadias compared with omnivores who did not supplement their diet with iron. (OR 4.99, 95% CI 2.10-11.88). Omnivores who supplemented their diet with iron in the first half of pregnancy also had a raised risk (OR 2.07, 95% CI 1.00-4.32). It was suggested that vegetarians would have a greater exposure to phytoestrogens than omnivores and this might explain the raised risk in that group.

Known risk factors associated with cryptorchidism include ethnicity, a family history of cryptorchidism, low birth weight, use of analgesics during pregnancy, birth order, maternal obesity, Caesarean delivery, pre-term birth and congenital malformations. Several of these are also risk factors for hypospadias. Evidence of a seasonal effect with peaks for cryptorchidism occurring at different times of the year in various studies has also been reported, although the significance of this finding has yet to be determined.

Conclusions: The data on secular trends in the incidence of hypospadias and cryptorchidism should be interpreted with considerable caution, given the lack of longitudinal studies and the consequent difficulties in comparing data from separate studies.

Key Papers on this issue:

N.E. Skakkebaek et al., Testicular dysgenesis syndrome: an increasingly common developmental disorder with environmental aspects. Human Reproduction (5):972-978, Jul 2001Get summary.