Search

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.

Dehydroepiandrosterone (DHEA) is an endogenous androgenic steroid produced by the ovaries and adrenal glands. Research suggests that DHEA can be converted to testosterone in peripheral tissues. Classified as a nutritional supplement, this compound may be purchased without a prescription. The military and international sports organizations prohibit the use of exogenous androgenic/anabolic steroids. Steroid-screening results are considered "positive" when the urinary ratio of testosterone to epitestosterone (T/E), an inactive synthetic byproduct, exceeds 6:1. Human volunteers ingested the recommended daily dose of 50 mg each morning for 30 days to determine if DHEA causes an adverse effect on this ratio. Urinary samples were collected before ingestion and 2-3 h after ingestion. Urine samples were extracted using solid-phase columns and analyzed using a previously developed gas chromatography-mass spectrometry method. T/E results were compared to an average baseline generated from three urine samples obtained before the study. Mean baseline T/E ratios averaged 0.67 for the seven subjects (range 0.1-1.2). The mean T/E ratio after DHEA ingestion ranged from 0.03 to 2.11. Individual postdose T/E ratios ranged from 0.01 to 3.7. The results from these individuals indicate that the administration of DHEA at this dose, for this period of time, has a minimal effect on urine T/E ratios and would not be expected to result in a positive screen for testosterone abuse. One subject agreed to take a single dose of 250 mg. This acute, high dose caused his T/E ratio to increase by 40% relative to the predose value.