Ovarian hyperandrogynism as a result of congenital adrenal virilizing disorders: evidence for perinatal masculinization of neuroendocrine function in women.

Abstract

Women with congenital adrenal hyperplasia due to 21-hydroxylase deficiency often have a polycystic ovary-like syndrome, consisting of hyperandrogynism, infertility, menstrual irregularities, and elevated LH levels. This is generally considered secondary to poor control of the congenital adrenal hyperplasia. However, our experience led us to suspect that ovarian hyperandrogenism occurs even when congenital adrenal hyperplasia is well controlled on glucocorticoid therapy. Therefore, we tested the hypothesis that congenital adrenal virilizing disorders result in ovarian hyperandrogenism. We studied eight women with congenital adrenal virilizing disorders, seven with well controlled classic 21-hydroxylase deficiency and one with congenital virilizing adrenal carcinoma removed at 1.7 yr of age. We also studied six women with late-onset 21-hydroxylase deficiency, without signs of congenital virilization. An ovarian source of androgens was assessed after suppressing adrenal function with dexamethasone and then testing pituitary-ovarian function by a GnRH agonist (nafarelin) test. Five women with congenital adrenal virilizing disorders (four with classic 21-hydroxylase deficiency and one with congenital virilizing adrenal carcinoma) and one women with late-onset 21-hydroxylase deficiency had ovarian hyperandrogenism as determined by subnormal suppression of free testosterone after dexamethasone and/or by increased 17-hydroxyprogesterone response to nafarelin while on dexamethasone. All women with congenital adrenal virilization and ovarian hyperandrogenism had elevated LH levels after dexamethasone or elevated early LH response to nafarelin, which suggests that LH excess is the cause of their ovarian hyperandrogenism. This was not the case for the late-onset 21-hydroxylase-deficient woman. Our data are compatible with the hypothesis that congenital adrenal virilization programs the hypothalamic-pituitary axis for hypersecretion of LH at puberty. This is postulated to frequently cause ovarian hyperandrogenism even when adrenal androgen excess is subsequently controlled by glucocorticoid therapy.

Polycystic ovary syndrome in adolescents

“…The most likely answer is that the source of excess androgen is the foetal ovary although the adrenal may also play a role. Barnes and colleagues 20 noted clinical and biochemical manifestations of PCOS (including excess ovarian androgen production) in young adults with non-classical congenital adrenal hyperplasia due to 21-hydroxylase deficiency.…”

Long-Term Gynecological Outcomes in Women with Congenital Adrenal Hyperplasia due to 21-Hydroxylase Deficiency

“…Given the degree of hirsutism and delayed menarche, the patients most likely have been exposed to longer periods of hyperandrogenaemia, which may either be of adrenal or ovarian origin [19]. Ovarian hyperandrogenism in classic CAH is reported to result from perinatal masculinization of the hypothalamic-pituitary-ovarian axis [20]. With a BMI within the range of overweight [21], obesity in the CAH patients, and especially the higher risk of obesity in CAH children as compared to the background population [22], may further aggravate a hyperandrogenic condition.…”

Polycystic Ovary Syndrome in Adolescence

“…Recently, evidence has accrued for a developmental basis for the syndrome. Either prenatal androgen excess or perinatal insults that cause intrauterine growth retardation may predispose to obesity, insulin resistance, and androgen excess in later life [17,[54][55][56].…”

“…This accounts for less than 5% of cases [13]. Polycystic ovaries occur in about one-third of these, however [80], and the adrenal rests of the ovaries that can occur in this condition may be difficult to distinguish from PCOS [55]. Androgen-secreting tumors of the ovaries or adrenal glands occur in only about 0.2% of cases [81], but many are malignant.…”

“…In atypical cases, CT scan may be indicated to rule out an adrenal tumor. It is not clear whether ultrasound will distinguish the rare ovarian adrenal rests of nonclassic congenital adrenal hyperplasia from polycystic ovaries [55]. Most importantly, while the remaining disorders are rare, well under 1%, patients must be followed to be sure that they respond to therapy as expected.…”