Influence of 17-Hydroxyprogesterone, Progesterone and Sex Steroids on Mineralocorticoid Receptor Transactivation in Congenital Adrenal Hyperplasia

Abstract

Background: Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency leads to accumulation of steroid precursors and adrenal androgens. These steroids may have a biological effect on the steroid receptor with clinical consequences on diagnostics and treatment in CAH patients. Therefore, we analysed the effect of accumulated steroids [17-hydroxyprogesterone (17OHP), progesterone, androstenedione and testosterone] on aldosterone-mediated transactivation of the human mineralocorticoid receptor (hMR). Methods: A transactivation assay using transiently transfected COS7 cells was employed. Cells were co-transfected with hMR-cDNA, MMTV-luciferase and renilla-luciferase expression vectors. Transfected cells were incubated with six different steroid concentrations in addition to aldosterone (10^-10<smlcap>M</smlcap>). Luciferase and renilla activities were measured to quantify hMR transactivation. Results: Linear regression analysis showed statistically significant linear inhibition of transactivation of the hMR by 10^-10<smlcap>M</smlcap> aldosterone in the presence of increasing 17OHP [F(1,5) = 11.34, p = 0.019] and progesterone [F(1,5) = 11.08, p = 0.021] concentrations. In contrast, neither androstenedione nor testosterone affected hMR transactivation by aldosterone at a concentration of 10^-10<smlcap>M</smlcap>. Conclusion: Our study shows for the first time that neither androstenedione nor testosterone has a biological effect on aldosterone-mediated transactivation of the hMR. 17OHP and progesterone have an anti-mineralocorticoid effect in vitro that may clinically lead to an increased requirement of mineralocorticoids in poorly controlled CAH patients.

Clinical outcomes and characteristics of P30L mutations in congenital adrenal hyperplasia due to 21-hydroxylase deficiency

“…It is due to accumulation of some steroid precursors which can cause, especially in poorly controlled patients, aldosterone mediated transactivation of the human mineralocorticoid receptor. [107][108][109]. Adding mineralocorticoids in SV patients may provide decreased renin activity and may enable decrease of glucocorticoid dose.…”

The role of gonadotropins in testicular and adrenal androgen biosynthesis pathways—Insights from males with congenital hypogonadotropic hypogonadism on hCG/rFSH and on testosterone replacement

“…17‐OHP is recognized to have anti‐mineralocorticoid 15 and glucocorticoid potency, 16,17 without direct androgenic properties. Since cross‐reactivity among steroids is a recognized phenomenon, due to the high degree of homology at the DNA‐binding domains of nuclear receptors within the steroid hormone receptor superfamily, 18 the measured differences in serum 17‐OHP concentrations may have clinical implications.…”

Congenital Adrenal Hyperplasia

“…19 The elevated 17-OHP and progesterone concentrations exacerbate the mineralocorticoid deficiency because both hormones have anti-mineralocorticoid effects and, in vitro, interfere with aldosterone-mediated mineralocorticoid receptor transactivation. 20 In addition, the lack of prenatal cortisol exposure interferes with adrenomedullary development and can be associated with epinephrine deficiency and hypoglycemia. 21 …”