Incidence of Bilateral Cryptorchidism is Increased and the Fertility Potential is Reduced in Sons Born to Mothers who Have Smoked During Pregnancy.

S/T = number of spermatogonia and gonocytes per tubule

Recent reports have shown a decline in human male reproductive health—a high prevalence of cryptorchidism and hypospadias, low and probably decreasing semen quality, an increasing incidence of testicular cancer and a growing demand for assisted reproduction. These changes seem to be interrelated and may be symptoms of a common underlying entity with foundations in fetal life due to adverse environmental influences. Chemicals have been found to possess either weak estrogenic, anti-androgenic or other hormonal activities, which are often referred to as endocrine disrupters. Wildlife experience and animal studies have provided evidence that fetal or perinatal exposure to endocrine disrupters results in disturbed sexual differentiation, urogenital malformations and decreased reproductive health in adult life. However, no existing evidence for a connection between exposure to endocrine disrupters in fetal life and childhood and adult reproductive health in humans has clearly been observed, and, therefore, other exogenous factors may have greater influence on human reproductive health.

Biggs et al found that maternal and pregnancy characteristics associated with cryptorchidism included maternal smoking during pregnancy and placental abnormality. McBride et al also found a significant higher proportion of smokers among the mothers of 244 boys with cryptorchidism compared to the mothers of 488 controls. However, others have found no effect on testicular cancer or cryptorchidism in relation to prenatal factors such as maternal smoking habits.

An increasing incidence of cryptorchidism in British boys born in 1952 (1.4%) compared to those born in 1977 (2.9%) has been published, and a similar trend was seen in Denmark. However, current data reveal a recent downward trend. Toledano et al found that orchiopexy rates for boys 0 to 14 years old decreased by 33% between 1992 and 1998 in England. In Denmark data demonstrated a 17% decrease from 1990 to 2000. The updated information of the latter study was obtained using the same method as described in the study by Thorup and Cortes. In the same period smoking rates among women decreased from 45% to 33%. Thus, at least in Denmark the orchiopexy rate may be related to the smoking rate among women.

The incidence of cryptorchidism and hypospadias, decreasing semen quality and increase in testicular cancer has been specifically shown to be comparatively greater in Denmark, our country of origin, where testicular cancer occurs in approximately 1% of males. The aim of the present study was to investigate the influence of maternal smoking during pregnancy on offspring fertility potential related to cryptorchidism.

DISCUSSION

A close relationship between maternal smoking and adverse trends in offspring reproductive health in relation to cryptorchidism was observed. The absolute and age related number of spermatogonia and gonocytes per tubule cross-section was significantly decreased in the testes of boys whose mothers had smoked heavily compared to the same parameters in boys whose mothers were nonsmokers. It has been suggested that components in tobacco smoke may impair fetal Sertoli cells, which foster the germ cells.

The observed frequency of heavy smoking of 13% (21 of 157) among pregnant women related to cryptorchidism may possibly not be higher than expected for Danish pregnant women in general (11% to 14% in the last decade). In a review of 2,150 orchiopexies in 7 studies 23% of the boys were operated on because of bilateral cryptorchidism.7 Noteworthy in the present study is the significantly increased risk of bilateral cryptorchidism in boys whose mothers smoked heavily during pregnancy, which may indicate that heavy maternal smoking affects the pathogenesis of cryptorchidism.

Altered hormone levels in smokers may have a causal role in cryptorchidism. Human chorionic gonadotropin and epidermal growth factor are found at decreased levels in smokers compared to nonsmokers. Furthermore, it is noteworthy that there was no increased risk of intra-abdominal testes among boys whose mothers smoked heavily during pregnancy. Consequently, heavy smoking during pregnancy induced bilateral cryptorchidism with undescended testes located distal from the abdominal cavity. The current model for testicular descent involves 2 independent steps, the transabdominal phase and the inguinoscrotal phase. It is generally accepted that the inguinoscrotal phase is at least partly dependent on fetal testicular testosterone secretion, which in turn is initiated and maintained by human chorionic gonadotropin produced by the placenta.

The absence of germ cells and impaired fertility potential in our study group strongly supports the findings of Storgaard et al, who reported that sons of mothers who smoked more than 10 cigarettes daily during pregnancy had reduced sperm density, total sperm count and inhibin B, and increased follicle-stimulating hormone. Others have reproduced their results, also observing smaller testis size among men exposed to smoking in utero. Similar to the studies by Storgaard and Jensen et al, the weakness of our study is the gap of time between index pregnancy and inquiry about smoking habits (median 3 years in our study only). However, we find it hard to believe that any woman would admit to smoking at least 10 cigarettes every day throughout the pregnancy if she had not. Accidentally including some mothers neglecting tobacco consumption during the first month of pregnancy in the nonsmoking group would possibly only underestimate the significant difference between the 2 groups, so this possible recall bias would not invalidate our conclusion.

The present study revealed reduced birth weights in the group of patients whose mothers smoked heavily. Low offspring birth weight is well known to be associated with maternal smoking during pregnancy and may be related to impaired placental function. In an analysis by Biggs et al adjustment for birth weight did not affect the odds ratio associated with smoking, suggesting that smoking may be related to cryptorchidism independent of its well documented association with low birth weight. Our study sample is too small for a similar correction.

Testicular descent is at least partly dependent on fetal testicular testosterone, which in turn is initiated and maintained by human chorionic gonadotropin produced by the placenta. Heavy smoking results in impaired placental function, and cryptorchidism may be associated with impaired placental function. Recently, a similar relation between maternal smoking and hypospadias in offspring has been described. Roelofs et al found that the rate of smoking mothers in 604 boys with hypospadias was 23.1% compared to 13.8% in 261 controls. Furthermore, a decreased incidence of testicular cancer has been demonstrated in Danish men born during World War II, where the consumption of tobacco was dramatically reduced. Finally, the greater risk of malignancy in cryptorchid testes is well established.

In conclusion, if the postulated decline in human male reproductive health—ie high prevalence of cryptorchidism and hypospadias, low and probably decreasing semen quality, increasing incidence of testicular cancer—is associated with a common underlying entity with foundations in fetal life, we suggest, based on the literature and our results, that maternal smoking may have an additional major role in the adverse trends in human male reproductive health.