Fertility in Tall Men and Women Treated with High-Dose Sex Steroids during Adolescence and Genetic Determinants of Tall Stature

This doctoral thesis describes in a large group of constitutional tall men and women the long-term effects of high-dose sex steroid treatment to reduce final height and the genetic determinants of tall stature. In part 1 we evaluated fertility and gonadal function in later life of two independent cohorts of tall women and one cohort of tall men who did or did not receive high-dose sex steroid treatment in adolescence. We found that estrogen treated women experienced more difficulties conceiving and more often received medical treatment for infertility compared with untreated women. Treated women had a decreased chance of achieving at least one live birth. We report a dose-response relationship between fertility in later life and the estrogen dose used, as women treated with 200 µg of EE significantly more often experienced fertility problems than women treated with 100 µg. Finally, we showed that treated women were at increased risk of being diagnosed with imminent ovarian failure. They exhibit signs of accelerated ovarian aging with concomitant follicle pool depletion, which may be the basis of the observed infertility. In men we found no long-term impact of this treatment on fatherhood or semen quality. Testosterone production, however, is reduced in androgen treated men. In part 2 we have shown in a candidate gene analysis that several common polymorphisms in the IGF-1, IGFBP-3 and HMGA2 genes are associated with extremely tall stature in a Dutch cohort. Next we have performed a genome-wide association study using extreme tall phenotype as trait. We discovered a new genome-wide significant SNP in the gene for RBM39, which is involved in sex steroid mediated transcription.

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