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Other Endocrine Disorders Causing Anovulation: Congenital Adrenal Hyperplasia
Introduction
The congenital adrenal hyperplasias (CAH) are a group of relatively rare autosomal recessive disorders that result from mutations (in homozygosity or double heterozygosity) in the genes encoding several enzymes or proteins involved in the synthesis of adrenal steroids. They share a common pathophysi-ologic mechanism that consists of a deficiency in the synthesis and secretion of cortisol, the main glucocorticoid in humans. Although certain mechanisms are not completely understood, cortisol deficiency results in compensatory stimulation of the hypothalamic–pituitary axis, hypersecretion of corticotropin-releasing hormone (CRH) and corticotropin (ACTH), and hyperplasia of the dysfunctional adrenal glands (1).
The clinical presentation and consequences of CAHs depend on the gene mutated and on the degree of protein or enzymatic deficiency resulting from these mutations. Deficiency of 21α-hydroxylase accounts for approximately 90% of cases of CAH with 11β-hydroxylase deficiencies being second in frequency in most populations and 17α-hydroxylase, 3β-hydroxysteroid dehydrogenase, and steroidogenic acute response protein/20-22 desmolase deficiencies being much rarer (1). In general, the most severe forms are termed “classic CAH” and are present at birth whereas milder forms are termed “nonclassic CAH” and are diagnosed after 6 years of age. However, the genotype/phenotype concordance is not always perfect in these disorders.
All CAHs influence reproduction, either as the consequence of adrenal androgen excess (21α-hydroxylase and 11β-hydroxylase deficiencies) or as the result of a severe deficiency in the synthesis and secretion of gonadal steroids (3β-hydroxysteroid dehydrogenase, 17α-hydroxylase, and steroidogenic acute response protein/20-22 desmolase deficiencies) (LOE 2a) (1).
Patients with 3β-hydroxysteroid dehydrogenase, 17α-hydroxylase, and steroidogenic acute response protein/20-22 desmolase deficiencies present with female hypogonadism or male pseudohermaphroditism, and most patients are infertile (with the very rare exception of a few cases characterized by mild enzymatic deficiencies of 3β-hydroxysteroid dehydrogenase or 17α-hydroxylase (2,3)) (LOE 3). Hence, this chapter focuses on 21α-hydroxylase and 11β-hydroxylase deficiencies, in which adrenal androgen excess may exert a negative impact on fertility, requiring ovulation induction and/or assisted reproductive technology (4). Moreover, the presentation of nonclassic 21α-hydroxylase and 11β-hydroxylase deficiencies may be indistinguishable from functional forms of female hyperandrogenism, such as polycystic ovary syndrome or idiopathic hyperandrogenism (LOE 2a). These CAHs must be excluded before a diagnosis of functional androgen excess is made (5) at least in patients of certain ethnicity in which asymptomatic carriers of these genetic adrenal disorders are more frequent (Grade B).
Classic 21α-Hydroxylase and 11β-Hydroxylase Deficiencies
The classic form of 21α-hydroxylase deficiency is present at birth and diagnosed by neonatal screening or by clinical findings soon after birth or in early infancy, depending on the severity of the deficiency. The most severe form associates cortisol and aldosterone deficiency with severe androgen excess and is termed “salt-wasting” 21α-hydroxylase deficiency. “Simple-virilizing” 21α-hydroxylase deficiency is a milder form in which aldosterone deficiency is not clinically apparent, and androgen excess causes the symptoms. Accordingly, virilization of external genitalia at birth dominates the picture in girls whereas in boys with salt-wasting CAH, failure to thrive, dehydration, hyponatremia, and hyperkalemia typically appear within the first 2 weeks of postnatal life (6). In boys with simple-virilizing CAH that was not detected by neonatal screening, early virilization appears usually before 4 years of age (6).
In classic 11β-hydroxylase deficiency, different grades of virilization of external genitalia in girls and penile enlargement in boys are present at birth and may be followed by early sexual maturation in infancy, but instead of mineralocorticoid deficiency, these patients present with hypertension because of the increased secretion of 11-deoxycorticosterone, which is a potent mineralocorticoid (7).
Infertility is common in classic 21α-hydroxylase and 11β-hydroxylase deficiencies, and its severity parallels that of the enzymatic deficiency (LOE 2a). Sexual functioning may be impaired by anatomic distortion of external genitalia even after reconstructive surgery, delayed gender assignment, and altered psychosexual development. As a result, many female patients with classic CAH never try to conceive (4,8) (LOE 2a). Also, increased androgen concentrations leading to anovulation and increased non-cycling progesterone levels decreasing endometrium receptivity in women and inhibition of gonadotro-pin secretion and testicular adrenal rest tumors that may obstruct seminiferous tubules in men (4,8) may contribute to infertility (LOE 2b).
Patients with classic CAH seeking fertility usually require intensification of their adrenal steroid replacement therapy (with glucocorticoids and in salt-wasting forms with gluco- and mineralocorti-coids) with the aim of suppressing androgen and progesterone excess (to below 2 nmol/l), and reducing testicular rest tumors in men (4,8,9) (Grade B). The latter might require surgery, but the results toward restoration of fertility are uncertain (8). Intensification of replacement therapy in women with classic CAH results in pregnancy rates comparable to that of the normal population, yet the fertility rates are much lower (9) (LOE 2b). However, a significant number of women with classic CAH require ovulation induction or assisted reproductive technology to conceive (4) (LOE 2a). As in other causes of adrenal insufficiency, women with classic CAH may need stress glucocorticoid regimens during delivery of surgery.
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