Our data suggest a pathophysiologic link between placental hCG production and cryptorchidism. Relative hCG insufficiency could contribute to cryptorchidism, as hCG is known to stimulate fetal testicular androgen production with peak hCG levels at weeks 8-11 of gestation, after which hCG levels decline to 10–15% of peak concentrations from week 20 of gestation [
4]. Of note, fetal circulating hCG is known to follow a similar pattern as maternal hCG, with circulating values approximately one third to one ninth of maternal values, fetal hCG being a more important ligand than luteinizing hormone (LH) for stimulating steroidogenesis up to 20 weeks of gestation [
4]. The lower hCG values observed in mothers of boys with cryptorchidism could, therefore, lead to lower fetal testosterone production, thus contributing to the defect in testis migration. The association between placental hCG and minor genital anomalies has already been raised in a few studies [
11‐
13]. No difference [
11,
13], or, at most, a trend toward a difference [
12] was seen between affected boys and controls. However, these studies were associated with some limitations. Boys with cryptorchidism were mixed with subjects with hypospadias, the cohorts of cases and controls were small, serum samples were old stored samples, and the matching of subjects and controls was not precise, even for gestational age at time of hCG measurement (important considering that maternal hCG levels can change by up to 20% from one week to the next at this time of gestation) [
14]. Finally, gestational age was not determined by early ultrasound scan in these studies, whereas ultrasound estimation of gestational age has been shown to significantly reduce the variance of the markers [
15]. We therefore believe that a very precise matching for gestational age is likely to be critical, and this could explain the lack of power to differentiate hCG levels between the groups in these previous studies. In the present study, we excluded preterm birth as well as complicated pregnancy, and AFP levels were similar between cases and controls: we believe that the normal AFP levels indicated a normal fetoplacental unit, thus suggesting that the lower hCG values were not due to a dysfunctioning placenta. In one study, high AFP levels and low birth weight were both associated with cryptorchidism [
16]. The authors suggested that this may reflect placental dysfunction, some aspect of which could contribute to cryptorchidism [
16]. In this previous study, hCG was not measured : whether low hCG values due to a dysfunctioning placenta could have also contributed to cryptorchidism is therefore unknown.
Experimental evidences in rats have identified a programming window for reproductive male masculinization [
7], and have shown that critical androgen action and physiological change in androgen levels did not need to occur at the same time. From the timing in rats, the corresponding programming window in humans would be 8–14 weeks of gestation whereas blood samples here were taken between gestational week 12 and 16, corresponding to the end of this window. Although it is likely that the altered hCG levels shown here could be present earlier in gestation, our study was not designed to ascertain this point nor directly measure androgen levels or action.