MANAGEMENT OF ENDOCRINE DISEASE: Gonadal dysfunction in congenital adrenal hyperplasia

Abstract

Gonadal dysfunction is an adverse outcome in patients with congenital adrenal hyperplasia (CAH), which may become apparent already during puberty. Clinical consequences of gonadal dysfunction include menstrual disturbances in females and hypogonadism and impaired fertility in males and females. In males, gonadal dysfunction can be caused by primary gonadal failure due to testicular adrenal rest tumours (TART), and by secondary gonadal failure due to poor hormonal control. In females, gonadal dysfunction can result from an overproduction of adrenal androgens including 11-oxygenated C-19 androgens and progestins, and rarely from ovarian adrenal rest tumours. In all patients with CAH, optimal hormonal control is the key for adequate gonadal function. Therefore, regular measurements of adrenal steroids and/or their metabolites should be performed. In addition, markers of the hypothalamus-pituitary-gonadal axis need to be assessed. In females, the regularity of the menstrual cycle should be evaluated. In males, regular evaluation for TART using ultrasonography is recommended from the start of puberty or even earlier when poor hormonal control is present. When TART is present, counselling on cryopreservation of semen should be offered.

Production of 11-Oxygenated Androgens by Testicular Adrenal Rest Tumors

“…Reduced fertility in 21OHD men with TART is considered to be associated with mechanical obstruction of the seminiferous tubules ( 31 ). In addition to the mechanical effects, adrenal-derived androgens likely contribute to the suppression of the hypothalamic-pituitary-gonadal axis, as suggested by the suppressed gonadotropins in men with poorly controlled 21OHD, and by the inverse correlation of 11KT with T in reproductive age men (as opposed to the direct correlation of these 2 steroids in females and pre-pubertal boys) ( 9 , 14 ).…”

“…In addition to the mechanical effects, adrenal-derived androgens likely contribute to the suppression of the hypothalamic-pituitary-gonadal axis, as suggested by the suppressed gonadotropins in men with poorly controlled 21OHD, and by the inverse correlation of 11KT with T in reproductive age men (as opposed to the direct correlation of these 2 steroids in females and pre-pubertal boys) ( 9 , 14 ). Hypothetically, the local (adrenal-like) steroid production by TART might have paracrine effects on healthy testicular tissue, impairing the normal gonadal function ( 31 ).…”

Characteristics of In2G Variant in Congenital Adrenal Hyperplasia Due to 21-Hydroxylase Deficiency

“…Fertility is also compromised in males with CAH, mostly due to testicular adrenal rest tumor (TART) or sometimes hypogonadotropic hypogonadism ( 78 ). However, the remaining testicular tissue is larger, and the amount and quality of semen are better in patients with the In2G variant, although not reaching statistical difference ( 79 ), with male SW CAH having an increased number of adopted children ( 80 ).…”

Disorders of Sex Development of Adrenal Origin

“…In childhood, pseudoprecocious and central precocious puberty, advanced bone age and impaired final height -are common features of the disease as a consequence of periods of hyperandrogenism and long-term glucocorticoid treatment ( 15 ). Later in life, common long-term complications in female adolescents and young adults with CAH include pubertal dysfunction, menstrual abnormalities, and fertility issues ( 19 , 20 ). Pathophysiology of these complications includes an excess of C19 steroids of classic adrenal steroidogenesis and of the more recently explored alternative or “backdoor” pathway involving 11-oxo-steroids ( 21 , 22 ).…”

“…Potential causes of reduced fertility include anatomical issues due to hyperandrogenism, unfavorable cervical mucus for sperm migration, and endometrial thickening impairing embryo implantation and psychosocial factors ( 24 ). Ovarian adrenal rest tumors (OART) are rare in females with CAH, in contrast to the higher prevalence of testicular adrenal rest tumors (TART) present in males and are usually secondary to longstanding poor hormonal control ( 20 ).…”