PubMed · 4351566
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J A Mahoudeau, H Bricaire. 1973-02-21. [Current data on plasmatic androgens].. https://pubmed.ncbi.nlm.nih.gov/4351566/
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Dysregulated nitric oxide (NO) signaling contributes to the pathogenesis of hypertension, a prevalent and often sex-specific risk factor for cardiovascular disease. We previously reported that mice deficient in the α1-subunit of the NO receptor soluble guanylate cyclase (sGCα1 (-/-) mice) display sex- and strain-specific hypertension: male but not female sGCα1 (-/-) mice are hypertensive on an 129S6 (S6) but not a C57BL6/J (B6) background. We aimed to uncover the genetic and molecular basis of the observed sex- and strain-specific blood pressure phenotype. Via linkage analysis, we identified a suggestive quantitative trait locus associated with elevated blood pressure in male sGCα1 (-/-)S6 mice. This locus encompasses Cyp4a12a, encoding the predominant murine synthase of the vasoconstrictor 20-hydroxy-5,8,11,14-eicosatetraenoic acid (20-HETE). Renal expression of Cyp4a12a in mice was associated with genetic background, sex, and testosterone levels. In addition, 20-HETE levels were higher in renal preglomerular microvessels of male sGCα1 (-/-)S6 than of male sGCα1 (-/-)B6 mice. Furthermore, treating male sGCα1 (-/-)S6 mice with the 20-HETE antagonist 20-hydroxyeicosa-6(Z),15(Z)-dienoic acid (20-HEDE) lowered blood pressure. Finally, 20-HEDE rescued the genetic background- and testosterone-dependent impairment of acetylcholine-induced relaxation in renal interlobar arteries associated with sGCα1 deficiency. Elevated Cyp4a12a expression and 20-HETE levels render mice susceptible to hypertension and vascular dysfunction in a setting of sGCα1 deficiency. Our data identify Cyp4a12a as a candidate sex-specific blood pressure-modifying gene in the context of deficient NO-sGC signaling.
On catalytic hydrogenation of Delta(9)-steroids (e.g. 3beta-hydroxy-5-methyl-19-nor-5beta-androst-9-en-17-one), four isomers were formed: 9alpha,10alpha-, 9alpha,10beta-, 9beta,10alpha- and 9beta,10beta-adducts. The product distribution was affected by the nature of the C-3 substituent. A chair conformation of A, B, and C rings was found in all of the products with the exception of the 9alpha,10alpha-adduct whose B ring adopts a twist boat conformation. The products were utilized for the synthesis of dihydrotestosterone analogues.
Ovarian theca cells are the predominant source of gonadotropin-stimulated androgen biosynthesis in vivo. Troglitazone (TG), a synthetic agonist of the peroxisome proliferator-activated receptor gamma (PPARgamma) and a thiazolidinedione used to treat insulin resistance, decreases serum androgen concentrations in women with hyperthecosis and/or polycystic ovary syndrome. Using reverse transcription-polymerase chain reaction (RT-PCR), we demonstrated the presence of PPARgamma mRNA in the porcine ovary. Since activation of ovarian PPARgamma may alter hormone-stimulated steroidogenesis in vitro, we cultured porcine theca cells for 48 h in the presence of two different PPARgamma ligands, TG and 15-deoxy-Delta(12,14)-prostaglandin J2 (15d-PGJ2). Putative TG-mediated activation of PPARgamma resulted in a 53%-69% decrease in LH- and/or insulin-stimulated androstenedione and testosterone accumulation. Although TG reduced 3-isobutylmethylxanthine-enhanced LH-stimulated cAMP accumulation by 74%-78%, it did not alter basal cAMP concentrations. Exposure to 8Br-cAMP did not overcome the TG-induced inhibition of androgen accumulation. In contrast, TG administration amplified basal and hormone-stimulated progesterone accumulation, particularly in the presence of insulin, without altering levels of 17alpha-hydroxyprogesterone. The putative natural PPARgamma ligand, 15d-PGJ2, inhibited androgen biosynthesis and stimulated progesterone production. RT-PCR-based amplification of cytochrome P450 cholesterol side-chain cleavage (CYP11A) and cytochrome P450 17alpha-hydroxylase/C-17,20-lyase (CYP17) transcripts indicated that TG moderately enhanced expression of these genes. However, TG did not affect CYP17 protein expression. We conclude that putative ligand-mediated activation of PPARgamma decreases LH- and/or insulin-driven theca cell androgen production by impairing the ability of CYP17 to synthesize androstenedione from available progestins. The corresponding augmentation of progesterone production could suggest that PPARgamma activation induces theca cell differentiation toward a progestin-synthesizing phenotype.