Society for Endocrinology UK Guidance on the Initial Evaluation of a Suspected Difference or Disorder of Sex Development (Revised 2021)

S. Faisal Ahmed; John Achermann; Julie Alderson; Naomi S. Crouch; Sue Elford; Ieuan A. Hughes; Nils Krone; Ruth McGowan; Talat Mushtaq; Stuart O'Toole; Leslie Perry; Martina E. Rodie; Mars Skae; Helen E. Turner

Disclosures

Clin Endocrinol. 2021;95(6):818-840. 

In This Article

XY DSD With low Testosterone and High Steroid Precursors

46, XY DSD with low testosterone and increased precursors can be caused by several variants of CAH, namely by 17α-hydroxylase (CYP17A1) deficiency, PORD and 3β-hydroxysteroid dehydrogenase type 2 (HSD3B2) deficiency, caused by inactivating gene variants in the corresponding genes CYP17A1, POR and HSD3B2, respectively. In addition, 46, XY DSD with low testosterone and increased precursors can typically be found in individuals affected by 17β-hydroxysteroid dehydrogenase type 3 (HSD17B3) deficiency, caused by HSD17B3 variants (Table 3).

Deficiency of CYP17A1 leads to CAH in about 1% of cases of 46, XY DSD. Characteristically, affected individuals present with external female genitalia and low DHEA, androstenedione and testosterone. There is an increase in mineralocorticoid synthesis and although there may be cortisol deficiency this is rarely manifested, as corticosterone can also bind and activate the glucocorticoid receptor. In PORD, sex steroids are characteristically low, sometimes low normal, whilst pregnenolone and progesterone and their metabolites accumulate, as expression of the combined block of CYP21A2 and CYP17A1 activities. Though there is often a relative preponderance of mineralocorticoid over glucocorticoid metabolites in affected cases, hypertension only manifests in adolescence or later. Although baseline glucocorticoid secretion is usually sufficient, in the majority of cases, the stress response to ACTH is significantly impaired, requiring at least stress dose hydrocortisone cover or permanent glucocorticoid replacement. 3β-HSD2 (also termed Δ4–Δ5 isomerase) deficiency invariably leads to glucocorticoid deficiency and as well as a variable degree of mineralocorticoid deficiency and its characteristic features are outlined in Table 4. 17β-HSD3 deficiency is responsible for the conversion of androstenedione to testosterone in the gonad and has no effect on adrenal steroidogenesis. Plasma steroids characteristically show increased androstenedione levels whilst testosterone levels are concurrently low, particularly after hCG stimulation. However, a low testosterone to androstenedione ratio may also occur in cases of gonadal dysgenesis and the reliability of a low ratio in identifying 17β-HSD3 deficiency is unclear. In urine, the typical finding is an increase in the androgen (and androstenedione) metabolites, androsterone and etiocholanolone, but this may only become apparent after puberty.

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