In this issue of epidemiology, Jensen and colleagues1 present fresh evidence on maternal cigarette smoking and the risk of cryptorchidism in offspring. These new data tip the balance in the direction of a true association. The authors report a positive association that joins at least 7 previous studies with similar, although less compelling, findings.2–8 Beyond adding to the tally of positive findings, the Jensen study shows trends of increasing risks with 2 measures of maternal smoking during pregnancy—increasing average number of cigarettes smoked per day and increasing average nicotine content. Further, these trends are based on prospectively collected exposure information from more than 11,000 pregnancies, with 16 to 19 years of follow-up for evidence of cryptorchidism.
How does cigarette smoking fit into a causal picture of cryptorchidism? Premature delivery and small-for-gestational age are both risk factors in that the testes normally descend relatively late in pregnancy, during the third trimester. This raises the possibility that smoking produces cryptorchidism through the developmental delay of male fetuses. However, the investigators were able to rule out this causal pathway by showing that the maternal smoking trend remained after restricting the study sample to term births with normal or heavy birth weights.
Endocrine disruption is a possible risk factor, since the testicular descent appears to be controlled by hormones. Intra-abdominal cryptorchidism, which occurs in approximately 5–10% of cases,9 represents failure of the testes to migrate to the groin in early pregnancy. Based on studies in mice, this step of testicular development is, at least in part, under control of an insulin-like factor (Insl-3), produced by Leydig cells and inhibited by estrogens. However, most undescended testes are in an inguinal position, resulting from the failure of the more complex and less understood migration into the scrotal sac. This second phase of descent is thought to be influenced by androgens.
Following the first descriptions of these 2 steps in testicular development, exogenous endocrine disruptors have been strongly suspected to be in the causal pathway of cryptorchidism.10 While there is some supporting evidence from both animals and humans, epidemiologic studies have not provided strong support.9,10 Studies of direct exposure to xenoestrogens, such as pesticides, have been hampered by the small numbers exposed. Findings on estrogen and progesterone use in pregnancy are also inconclusive, perhaps due to the timing of exposure, since most use is during early pregnancy before inguinal descent of testes occurs. Other possible markers of high estrogen levels such as nausea and vomiting in pregnancy, primiparity, and obesity, have been examined, also with mixed results.10
Does cigarette smoke fit with the endocrine disruptor theory? Environmental epidemiologists don’t typically include cigarette smoke on their lists of endocrine disruptors, although lead, cadmium, arsenic, phenols, and benzo(a)pyrene (all components of cigarette smoke) are thought to have hormonal effects. Further, altered hormone levels have been well documented in smoking women. Shorter menstrual cycle lengths and younger age at menopause are associated with cigarette smoking, raising suspicion that exposure is antiestrogenic. More specific support for endocrine disruption by cigarette smoking comes from a study by Windham and colleagues,11 who measured daily estradiol, progesterone, and follicle stimulating hormone levels across menstrual cycles and found differences between smokers and nonsmokers in all 3 hormones.
While it appears safe to say that cigarette smoking is an endocrine disruptor, we don’t know whether it has antiandrogenic effects in the fetus late in gestation, thereby inhibiting inguinal testicular descent. Certainly the toxic constituents of cigarette smoke have other adverse effects, such as oxidative stress, mutagenicity, and vasoconstriction, that might affect testicular development in the fetus.
Regardless, the findings of Jensen and colleagues should drive further research on the epidemiology and pathogenesis of cryptorchidism. Several questions are raised from their findings. First, why would the effect of father’s smoking be of similar magnitude to that of mother’s smoking? The authors raise the possibility that mothers might underreport their own smoking when their partners also smoke. This would be difficult to tease out with reported smoking levels, and should be addressed with more biologic measures of exposure.
Second, does the effect of cigarette smoking on cryptorchidism vary according to phenotype? Jensen et al1 found slightly lower risk estimates for boys who required surgical intervention, which is a more homogeneous subgroup than cryptorchidism as a whole (which can include boys with retractile, spontaneously descending, or absent testes or acquired cryptorchidism). One might expect the converse—a greater risk for the more narrowly defined subgroup—because misclassification is reduced. However, the effect of risk factors, including cigarette smoking, may well vary by phenotype.
Third, are hormone levels in the third trimester different according to maternal smoking status and presence of cryptorchidism at birth? Fetal (not maternal) hormone levels are most relevant, and would have to be measured during late gestation well before parturition. While the answer to this question would help elucidate the mechanism of undescended testes, and perhaps lead to identification of other risk factors, obtaining these data presents significant challenges and may be impossible.
Fourth, what genetic influences might be involved in an association between cigarette smoking and cryptorchidism? Clearly, if this association is real, it is not complete: most smoking-exposed male fetuses are born with normally descended testes. Genetically determined metabolic factors are reasonable candidates, such as polymorphisms of cytochrome P450 enzymes that are involved in both metabolizing the products of cigarette smoke and in the synthesis and breakdown of endogenous hormones.
Finally, does in utero smoking exposure play a role in the associations between cryptorchidism and increased risks of infertility and testicular cancer?12,13 If the answer is yes, the public health impact of smoking in pregnancy would be vastly extended.
The prevalence of cigarette smoking in most developed countries has decreased over the past few decades, following public health warnings. This includes decreases among women of childbearing age and pregnant women.14 Cigarette packages in the United States warn smokers of “fetal injury, premature birth and low birth weight,” and these labels, along with targeted public health efforts, have convinced approximately 40% of women who enter pregnancy as smokers to quit.14 The 10–15% of women who continue to smoke throughout pregnancy might be influenced by language about the risk of birth defects (not currently among the health warnings). Cigarette smoking already appears to increase the risk of several congenital anomalies including oral clefts and gastroschisis. If the association with cryptorchidism can be replicated in studies with biologic measures of smoking exposure, then yet another birth defect could be added to this list. Cryptorchidism is linked to decreased testicular size and sperm counts, infertility, and testicular cancer.15–17 Detailed warnings about these adverse outcomes in the unborn baby’s future might have an additional impact on both mother and father’s smoking habits during the gestation of their offspring.
ABOUT THE AUTHOR
MARTHA WERLER is Senior Epidemiologist in the Slone Epidemiology Center at Boston University and Associate Professor of Epidemiology at Boston University School of Public Health. She is a reproductive epidemiologist and has been conducting studies of maternal risk factors, such as medications, vitamins, and cigarette smoking, in relation to risks of birth defects for over 20 years.
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