Background

Amongst disorders of sex development (DSD) cases, conditions associated with under virilisation of the presumed XY boys are the largest group of children. Our international group (I-DSD.org) recently reported in Pediatrics that this group of people will increase as more affected infants are raised as boys. XY DSD boys often have low birth wt and are also often small for gestational age (SGA), as confirmed by Hughes et al, Cambridge using the ALSPAC cohort. Altered exposure to androgens has been linked with DSDs, intra-uterine growth restriction (IUGR) and placental problems, possibly all involving the IGF signalling pathway. For example, exposure to exognous androgens in sheep advances placental differentiation and increases placental differentiation but this early compensation to maintain placental efficienc cannot be mainted long term leading to placental inefficiency and IUGR. Furthermore, altered steroid exposure in fetal rats through exposure to MPA, a synthetic progestogen, reduced external genitalia masculinisation in males and increased it in females, and reduced bodyweight and placental weight in both males and females.

Aims

We hypothesise that:

(1) Boys with DSDs (namely hypospadias and/or cryptorchidism) are more at risk of being SGA, possibly due to altered placental development and/or funtion.

(2) The SGA phenotype associated with DSDs, such as hypospadias, is different to the SGA phenotype without hypospadias.

(3) Boys with hypospadias may have been denied sufficient androgen exposure prenatally and/or experience an ongoing lack of androgens, which may have a negative impact on their future health and well being.

We therefore propose to analyse the ALSPAC data for variables such as birth weight, gestational age at birth, placenta weight, congenital abnormalities at birth such as hypospadias, anogenital distance in the child, any fertility treatment prior to pregnancy, as well as moderately long-term outcome that relates to height, cardiometabolic and body composition including skeletal health.

We wish to compare the following groups - hypospadias and SGA, SGA and no hypospadias, average GA and hypospadias and AGA and no hypospadias. We may also be interested in the same analysis for individuals with cryptorchidism