Disorders of Sex Development of Adrenal Origin

Abstract

Disorders of Sex Development (DSD) are anomalies occurring in the process of fetal sexual differentiation that result in a discordance between the chromosomal sex and the sex of the gonads and/or the internal and/or external genitalia. Congenital disorders affecting adrenal function may be associated with DSD in both 46,XX and 46,XY individuals, but the pathogenic mechanisms differ. While in 46,XX cases, the adrenal steroidogenic disorder is responsible for the genital anomalies, in 46,XY patients DSD results from the associated testicular dysfunction. Primary adrenal insufficiency, characterized by a reduction in cortisol secretion and overproduction of ACTH, is the rule. In addition, patients may exhibit aldosterone deficiency leading to salt-wasting crises that may be life-threatening. The trophic effect of ACTH provokes congenital adrenal hyperplasia (CAH). Adrenal steroidogenic defects leading to 46,XX DSD are 21-hydroxylase deficiency, by far the most prevalent, and 11β-hydroxylase deficiency. Lipoid Congenital Adrenal Hyperplasia due to StAR defects, and cytochrome P450scc and P450c17 deficiencies cause DSD in 46,XY newborns. Mutations in SF1 may also result in combined adrenal and testicular failure leading to DSD in 46,XY individuals. Finally, impaired activities of 3βHSD2 or POR may lead to DSD in both 46,XX and 46,XY individuals. The pathophysiology, clinical presentation and management of the above-mentioned disorders are critically reviewed, with a special focus on the latest biomarkers and therapeutic development.

Keywords: DSD; adrenal insufficiency; aldosterone; congenital adrenal hyperplasia; cortisol; glucocorticoid; lipoid; mineralocorticoid.

Figure 1

Chromosomal, gonadal and genital sex. Chromosomal sex is determined at fertilization, according to the X or Y chromosome carried by the spermatozoon. Gonadal sex differentiation occurs during the 7^th week of gestation: testes secrete androgens and anti-Müllerian hormone (AMH). The ovaries do not produce androgens and AMH in the first trimester of gestation. Genital differentiation is driven by testicular hormones: androgens produced by Leydig cells bind to the androgen receptor (AR) and induce the differentiation of the Wolffian ducts into the epididymides, the vasa deferentia and the seminal vesicles as well as the virilization of the urogenital sinus and of the external genitalia. In the absence of androgen action, the Wolffian ducts regress, and the urogenital sinus and the external genitalia undergo female differentiation. AMH, secreted by Sertoli cells, binds to the AMH receptor (AMHR) and provokes Müllerian duct regression; in the absence of AMH action, Müllerian ducts form the Fallopian tubes, the uterus and the upper vagina. Reproduced with permission from: Freire AV, Ropelato MG, Rey RA. Ovaries and Testes. In: Kovacs CS, Deal CL, editors. Maternal-Fetal and Neonatal Endocrinology: Physiology, Pathophysiology, and Clinical Management. Elsevier, 2020, pp 625-641. Copyright ^© 2000 Elsevier Inc (3).

Figure 2

Genital virilization in 46,XX individuals. (A) Pathophysiology of virilization: virilization of external genitalia may occur in 46,XX patients with ovaries and hyperandrogenism of adrenal (congenital adrenal hyperplasia) or extra-adrenal (aromatase deficiency, androgenic tumors or drugs) origin; alternatively, virilization of external genitalia with partial regression of Müllerian ducts may occur in 46,XX patients with testicular or ovotesticular DSD. (B, C) External genitalia of 46,XX patients with congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency: Prader stage III (B) and stage V (C). (D) Schematic of Prader staging for patients with CAH. Reprinted with permission from Rey RA, Josso N. Diagnosis and treatment of Disorders of Sexual Development. In: Jameson JL, De Groot LC, de Kretser DM, Giudice LC, Grossman A, Melmed S, Potts JT, Weir GC, eds. Endocrinology: Adult and Pediatric, 7th edition. Philadelphia: Elsevier Saunders; 2016:2086-2118. Copyright ^© 2016 Elsevier Inc (7). (B, C) kindly provided by Dr. M. Podestá, Buenos Aires, Argentina.

Figure 3

Adrenal and gonadal steroidogenesis. The initial steroidogenic steps (in green) are identical in the adrenals and the gonads. The steps in brown are specific of the adrenal cortex, and the steps in blue or red are specific of the gonads. Steroidogenic Acute Regulatory (StAR) protein enables cholesterol influx into the mitochondria. Cytochrome P450 side chain cleavage (P450scc) enzyme removes the cholesterol side chain yielding the first C21, Δ5-steroid pregnenolone. All Δ5-steroids are converted to Δ4-steroids by 3β-hydroxysteroid dehydrogenase type 2 (3βHSD2). In the zona glomerulosa of the adrenal cortex, the first Δ4-steroid progesterone, is converted to deoxycorticosterone (DOC) by the 21-hydroxylase (21OH) activity of cytochrome P450c21; subsequently, the 11β-hydroxylase (11βOH) activity of P450c11β (encoded by CYP11B1) or of the aldosterone synthase (P450c11AS, encoded by CYP11B2) catalyzes DOC conversion to corticosterone, and finally P450c11AS, through its 18-hydroxylase (18OH) and 18-methyl oxidase (18-oxidase) activities respectively yields 18-hydroxycorticosterone (18OH-corticosterone) and aldosterone. In the zona fasciculata, cytochrome P450c17 converts pregnenolone and progesterone to 17-hydroxypregnenolone (17OH-Pregnenolone) and 17-hydroxyprogesterone (17OH-Progesterone), which is subsequently converted to 11-deoxycortisol by 21OH and to cortisol by 11βOH. In the zona reticularis of the adrenal cortex and in the gonads, the 17,20-lyase activity of P450c17 is facilitated by cytochrome b5 (CYP5A) yielding dehydroepiandrosterone (DHEA) and only secondarily androstenedione. DHEA may be sulphated to DHEA-S by sulfotransferase 2A1 (SULT2A1) in the adrenal. Gonadal 17β-hydroxysteroid dehydrogenase (17βHSD) type 3 converts DHEA to androstenediol and androstenedione to testosterone; in the adrenal these steps are minorly catalyzed by 17βHSD type 5 (encoded by AKR1C3). In the ovary, cytochrome P450 aromatase (P450aro) converts androstenedione to estrone and testosterone to estradiol. The activity of many of these enzymes is induced by steroidogenic factor 1 (SF1, also known as AD4BP, encoded by NR5A1) or by the cytochrome P450 oxidoreductase (POR). Reproduced with modifications from: Rey RA, Grinspon RP. Normal male sexual differentiation and aetiology of disorders of sex development. Best Practice & Research Clinical Endocrinology & Metabolism (2011) 25:221-238. doi: 10.1016/j.beem.2010.08.013. Copyright ^© 2010 Elsevier Ltd (6).

Figure 4

The alternative or “backdoor” pathway of androgen synthesis and the 11-oxygentaed androgens. In the “backdoor” pathway, progesterone is converted to 5α-dihydroprogesterone (DHP) by 5α-reductase type 1 (5α-Red 1) and subsequently reduced to allopregnanolone by 3α-hydroxysteroid dehydrogenase (3α-HSD) encoded by either AKR1C2 or AKR1C4. Similarly, 17-hysroxyprogetserone (17OH-progesterone) is converted to 5α-17-hydroxy DHP and to 17hydroxy-allopregnanolone (17OH Allopregnanolone). Cytochrome P450c17, though its 17,20 lyase activity, catalyzes 17OH Allopregnanolone conversion to androsterone. Subsequently, androsterone can be metabolized by adrenal 17β-hydroxysteroid dehydrogenase type 5 (17βHSD5) to yield androstanediol, which is oxidized by 3α-HSD encoded by AKR1C2 and finally transformed to dihydrotestosterone (DHT) by 17βHSD type 6 (also known as retinol dehydrogenase or RoDH), without involving testosterone. Blockage of cortisol synthesis resulting in the accumulation of 17-hydroxyprogesterone and androstenedione leads to the synthesis of 11-oxygenated androgens: the 11β-hydroxylase activity of cytochrome P450c11β catalyzes the conversion of androstenedione and testosterone to 11-hydroxyandrostenedione (11OH-androstenedione) and 11-hydroxytestosterone (11OH-testosterone), respectively. Subsequently, 11β-hydroxysteroid dehydrogenase type 2 (11βHSD2) converts them to 11keto-androstenedione and 11keto-testosterone. Finally, 5α-Red 1 leads to the synthesis of 11-hydroxy-DHT and 11-keto-DHT.