Date Published: April 15, 2019
Publisher: Public Library of Science
Author(s): Heidi Kucera, Birgit Puschner, Alan Conley, Trish Berger, Hubert Vaudry.
Production of steroid hormones is complex and dependent upon steroidogenic enzymes, cofactors, receptors, and transporters expressed within a tissue. Collectively, these factors create an environment for tissue-specific steroid hormone profiles and potentially tissue-specific responses to drug administration. Our objective was to assess steroid production, including sulfated steroid metabolites in the boar testis, prostate, and liver following inhibition of aromatase, the enzyme that converts androgen precursors to estrogens. Boars were treated with the aromatase inhibitor, letrozole from 11 to 16 weeks of age and littermate boars received the canola oil vehicle. Steroid profiles were evaluated in testes, prostate, and livers of 16, 20, and 40 week old boars using liquid chromatography/mass spectrometry. Testis, prostate, and liver had unique steroid profiles in vehicle-treated animals. Only C18 steroid hormones were altered by treatment with the aromatase inhibitor, letrozole; no significant differences were detected in any of the C19 or C21 steroids evaluated. Testis was the only tissue with significantly decreased free estrogens following treatment with the aromatase inhibitor; estrone and estradiol concentrations were lower (p < 0.05) in testes from 16, 20, and 40 week letrozole-treated boars. However, concentrations of the sulfated conjugates, estrone-sulfate and estradiol-sulfate, were significantly decreased (p<0.05) in 16 and 20 week boar testes, prostates, and livers from letrozole-treated boars. Hence, the distribution of estrogens between the free and conjugated forms was altered in a tissue-specific manner following inhibition of aromatase. The results suggest sulfated testicular estrogens are important estrogen precursors for the prostate, potentially enabling peripheral target tissues to synthesize free estrogens in the male pig.
To fully understand steroid hormone synthesis, regulation, and the mechanisms involved is challenging. Interplay and regulation of enzymes, cofactors, receptors, steroid hormones, and protein hormones within a single tissue are complex [1–10]. Recently, the role of steroid sulfates and the expression of sulfotransferase and sulfatase have been recognized as critical players in the regulation of steroid hormone production in a tissue [7, 11]. Quantitatively, the most important steroid hormone in the human circulation is dehydroepiandrostenedione-sulfate (DHEA-sulfate) with concentrations 100–10,000 times higher than circulating androgens and estrogens . The classical theory was that sulfate conjugation was strictly for enhanced clearance of steroid hormones due to increased water solubility and inability to bind to steroid receptors . More recently, increased biological half-life of sulfo-conjugates and desulfation as a path to free steroids are recognized as potential alternative roles [1, 2, 7, 14].
To our knowledge, this study provides the most comprehensive assessment of steroid tissue concentrations in the boar to date. Although the steroids evaluated were extensive, the pheromone androstenone was not included in the panel. Testicular concentrations detected in this study were consistent with the testicular origin indicated for previously described steroid sulfates . In contrast to a previous suggestion that dihydrotestosterone increased from puberty to maturity , our data do not suggest an increase in dihydrotestosterone in either the testis or the prostate although our data did not include comparisons with prepuberal timepoints. Apparent age-related decreases in testicular steroids among vehicle-treated boars may reflect increased testicular mass, due at least in part to increased spermatogenesis. Our multi-tissue approach in combination with a broad steroid profile provide critical information on the role of each of these tissues in steroidogenesis, steroid intracrinology, and steroid sulfate metabolism.
A multi-tissue approach in combination with aromatase inhibition and investigation of a broad array of steroids, revealed complexity and unique roles for individual organs in steroid hormone synthesis. Results from animals treated with letrozole displayed the primary role of the testis in synthesis of estrogens and estrogen sulfates, and suggested the dependence of the prostate on sulfated testis-derived steroid hormone precursors. Furthermore, individual organs may maintain tissue-specific profiles of active steroid hormones independent of systemic influences. Our research sheds light on the critical regulatory role of steroid sulfates in a tissue and suggests future research on the interplay of free and sulfo-conjugated steroid hormones within a tissue.