Steroid Sulfatase Deficiency and Androgen Activation Before and After Puberty

Abstract

Context: Steroid sulfatase (STS) cleaves the sulfate moiety off steroid sulfates, including dehydroepiandrosterone (DHEA) sulfate (DHEAS), the inactive sulfate ester of the adrenal androgen precursor DHEA. Deficient DHEA sulfation, the opposite enzymatic reaction to that catalyzed by STS, results in androgen excess by increased conversion of DHEA to active androgens. STS deficiency (STSD) due to deletions or inactivating mutations in the X-linked STS gene manifests with ichthyosis, but androgen synthesis and metabolism in STSD have not been studied in detail yet.

Patients and methods: We carried out a cross-sectional study in 30 males with STSD (age 6-27 y; 13 prepubertal, 5 peripubertal, and 12 postpubertal) and 38 age-, sex-, and Tanner stage-matched healthy controls. Serum and 24-hour urine steroid metabolome analysis was performed by mass spectrometry and genetic analysis of the STS gene by multiplex ligation-dependent probe amplification and Sanger sequencing.

Results: Genetic analysis showed STS mutations in all patients, comprising 27 complete gene deletions, 1 intragenic deletion and 2 missense mutations. STSD patients had apparently normal pubertal development. Serum and 24-hour urinary DHEAS were increased in STSD, whereas serum DHEA and testosterone were decreased. However, total 24-hour urinary androgen excretion was similar to controls, with evidence of increased 5α-reductase activity in STSD. Prepubertal healthy controls showed a marked increase in the serum DHEA to DHEAS ratio that was absent in postpubertal controls and in STSD patients of any pubertal stage.

Conclusions: In STSD patients, an increased 5α-reductase activity appears to compensate for a reduced rate of androgen generation by enhancing peripheral androgen activation in affected patients. In healthy controls, we discovered a prepubertal surge in the serum DHEA to DHEAS ratio that was absent in STSD, indicative of physiologically up-regulated STS activity before puberty. This may represent a fine tuning mechanism for tissue-specific androgen activation preparing for the major changes in androgen production during puberty.

Figure 1.

Androgen activation pathway from dehydroepiandrosterone (DHEA), which is either inactivated to DHEA sulphate (DHEAS) or activated via androstenedione and testosterone to the most powerful androgen, 5a-dihydro-testosterone. HSD3B, 3beta-hydroxysteroid dehydrogenase; HSD17B, 17beta-hydroxysteroid dehydrogenase; SRD5A, 5alpha-reductase; SULT2A1, DHEA sulfotransferase; STS, steroid sulfatase.

Figure 2.

Serum and urinary DHEA and DHEAS in patients with STSD and healthy sex- and age-matched controls. A and B, Levels of serum DHEA and DHEAS, their ratio, reflective of STS activity, as well as the 24-hour urinary excretion of DHEAS. A, Data from the prepubertal subgroup (STSD, n = 13; controls, n = 15). B, Data from the postpubertal subgroup (STSD, n = 12; controls, n = 19). C, Ratio of serum DHEA/DHEAS, reflective of STS activity, is visualized as a function over age (top) (STSD patients; n = 30; gray circles; and healthy controls; n = 38; open circles).

Figure 3.

Active androgens and their metabolism of patients with STSD (n = 30) compared with healthy male controls (n = 38). Box and whisker plots depicting median, interquartile range, and 10th–90th percentile are used to visualize serum testosterone (left), the sum of 24-hour urinary excretion of the active androgen metabolites androsterone and etiocholanolone (middle), and the ratio of urinary 5αTHF to THF reflective of net 5α-reductase activity (right). A, Data for the prepubertal subjects (STSD, n = 13; controls, n = 15). B, Results in the postpubertal subgroup (STSD, n = 12; controls, n = 19).