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Boys born with a classic form of congenital adrenal hyperplasia due to severe 21-hydroxylase deficiency (21-OHD) present with adrenal insufficiency and have a high risk of infertility in adulthood. Infertility in these men is explained by three mechanisms, which may be interrelated: 1) deficiency of the pituitary gonadotropins LH and FSH, which are inhibited by the anti-gonadotropic effect of elevated steroid precursors such as progesterone, 17-hydroxyprogesterone, and androgen precursors via their extra-adrenal conversion to testosterone and estradiol; 2) obstructions to the testicular excretory tracts (rete testis); and 3) destruction of normal testicular parenchyma, and hence seminiferous tubules, secondary to both testicular ischemia induced by compression of hilar vessels and tumor invasion. The latter two mechanisms are linked to the appearance of bilateral testicular tumors of adrenal origin. These tumors, known as testicular adrenal rest tumors (TARTs), are prevalent in adolescence and adulthood, but can occur as early as childhood. They should be systematically detected by testicular palpation and ultrasound. Their presence is detrimental to fertility, and must therefore be managed early and actively by experts in the field. The high prevalence of infertility in men born with severe 21-OHD raises the question of fertility preservation (FP). FP is systematically proposed in expert centers as soon as a sperm analysis has been performed. A sperm analysis with preservation of frozen spermatozoa should be proposed from puberty onwards, especially if intra-testicular adrenal inclusions have been detected. Awareness of the major risk of infertility in men born with severe 21-OHD, among pediatric and adult endocrinologists as well as urologists/andrologists and reproductive physicians, is essential for improving management in adulthood and preventing infertility.