Genetic and epigenetic effects on sexual brain organization mediated by sex hormones.

Alterations of sex hormone levels during pre- or perinatal sexual brain organization - responsible for long-term changes of gonadotropin secretion, sexual orientation, and gender role behavior - can be caused by: 1. Genetic effects, i.e. mutations or polymorphisms of a) 21-hydroxylase genes on chromosome 6, b) 3beta-hydroxysteroid dehydrogenase genes in chromosome 1 or c) X-chromosomal genes, and 2. Epigenetic effects, such as a) stressful situations - especially in combination with mutations - and b) endocrine disrupters, e.g. the pesticide DDT and its metabolites, which display estrogenic, antiandrogenic, and inhibitory effects on the enzyme 3beta-hydroxysteroid dehydrogenase leading to increased levels of dehydroepiandrosterone and its sulfate as precursors of endogenous androgens and estrogens. In connection with the introduction and extensive use of the pesticide DDT, the following findings were obtained in subjects born before as compared to those born during this period: 1. The prevalence of patients with polycystic ovaries (PCO), idiopatic oligospermia (IO), and transsexualism (TS) increased significantly (about 3-4 fold). 2. Partial 21-hydroxylase deficiencies were observed in most patients with PCO and TS and some patients with IO born before this period. 3. In contrast, most patients with PCO and TS and several patients with IO born during the period of massive use of DDT displayed clearly increased plasma levels of dehydroepiandrosterone sulfate (DHEA-S) and DHEA-S/cortisol ratios suggesting partial 3beta-hydroxsteroid dehydrogenase (3beta-HSD) deficiencies. Interestingly enough, geneticists could not find any mutations of 3beta-HSD genes in such subjects. However, o,p'-DDT and/or its metabolite o,p'-DDD are strong inhibitors of 3beta-HSD, indicating their possible co-responsibility for such life-long ontogenetic alterations. Finally, some data suggest that endocrine disrupters may also be able to affect the development of sexual orientation.