When boys are born with cryptorchidism, the testicles have not dropped into the scrotum at birth. Although this may sound harmless, persistent cryptorchidism is associated with an increased risk of both testicular cancer and infertility. Researchers performed the largest registry study so far and once again showed that smoking during pregnancy is associated with an increased risk of cryptorchidism but a decreased risk of another rarer genital anomaly among boys, hypospadias.
Testicular cancer is the most frequent type of cancer among younger men and can strongly affect their ability to have children. About 1 in 20 cases of testicular cancer are believed to be directly linked to cryptorchidism, in which boys’ testicles do not descend into the scrotum on their own.
“We found the occurrence of cryptorchidism to be 18% higher among boys whose mothers smoked during pregnancy, and the risk increases with the number of cigarettes smoked. Conversely, we found a similar decrease in another genital anomaly, hypospadias. However, this is rarer and has a broad spectrum of severity. The mildest cases are primarily of cosmetic concern, but others are severe, and the boys need surgery and may have complications and other problems following this diagnosis. We do not yet understand why we found these associations, but previous research has shown that smoking affects an enzyme in the fetus that converts male sex hormones into female sex hormones. This may also be a random discovery, but others have also seen the same tendencies,” explains a main author, Daniel Lindbo, Department of Public Health, Research Unit for Epidemiology, Aarhus University.
No genetic association
The researchers included data for more than 800,000 live-born singleton boys. The researchers compared the number of genital anomalies with the self-reported numbers of cigarettes the women smoked during pregnancy and attempted to validate this association by adjusting for other confounding factors not considered in previous studies.
“Previous small studies show no association between maternal cigarette smoking during pregnancy and cryptorchidism and hypospadias, whereas a few larger epidemiological studies indicate a higher risk of cryptorchidism but a lower risk of hypospadias among boys born to mothers who smoked during pregnancy. The latter finding has been puzzling since maternal smoking during pregnancy is associated with an increased risk of most congenital anomalies,” says Daniel Lindbo.
Cryptorchidism is fairly common, affecting 2.5% of all boys, whereas hypospadias, in which the boy is born with the opening of the urethra on the underside of the penis instead of at the tip, affects only about 0.5% of boys. Less often, the opening is at the middle or the base of the penis. Rarely, the opening is in or beneath the scrotum.
“We carried out the largest study so far to demystify these puzzling results and more comprehensively understand whether the diverging risks are due to social, genetic and environmental factors,” explains Daniel Lindbo.
The researchers studied the association with smoking by comparing the risk between nearly 400,000 brothers.
“If the cause were genetic, we would expect to find a greater association of incidence among siblings, but we did not,” adds Daniel Lindbo.
Instead, this new and larger study confirmed the results that some of the previous major studies found.
“We found 18% more cryptorchidism cases but 16% fewer hypospadias cases among the boys born to mothers who smoked during pregnancy,” says Daniel Lindbo.
A possible reason
Boys with cryptorchidism can typically be treated with surgery, but it is still associated with two negative health outcomes: an increased risk of testicular cancer and subfertility at a young age. Boys with hypospadias can also be treated with surgery, sometimes multiple and not always with a satisfactory outcome.
“This is why detecting cryptorchidism early and ultimately avoiding it are important. There are many good reasons to quit smoking, and if our results confirm a real causal relationship, this will be another reason not to smoke,” explains Daniel Lindbo.
The study cannot directly answer why the risk of one genital anomaly is higher and another lower. However, the researchers found a possible reason explaining these apparently diverging results in the fetal state.
“Previous studies show that cigarette smoking inhibits the enzyme placental aromatase, which converts testosterone into estrogen. This decreases the fetal bioavailability of estrogen while increasing the bioavailability of testosterone, which may lower the risk of both anomalies. However, cigarette smoking also increases the risk of preterm delivery and induces fetal growth restriction, which are well-known risk factors for cryptorchidism,” says Daniel Lindbo.
Nevertheless, the percentage of boys with hypospadias may decrease because fetal growth restriction occurs so late in pregnancy that the urethral folds have already fused.
“Cigarette smoking may therefore protect against hypospadias by inhibiting placental aromatase, but this could also result from factors that our study and previous ones did not consider. Hopefully, future studies of anti-estrogenic effects can provide answers. The study indicates, like so many before, that smoking significantly affects fetal development,” concludes Daniel Lindbo.