Influence of sex hormones on catecholamine biosynthesis: the roles of progesterone and estrogen

Abstract

Catecholamines are hormones/neurotransmitters that play a key role in various physiological systems, including cardiovascular regulation and the stress response. Elevated levels of catecholamines have been linked to hypertension, with men typically having a higher prevalence of hypertension under the age of 50 compared to women. However, this trend reverses in post-menopausal women. Sex differences in hypertension and stress response are thought to be influenced, in part, by the sex hormones estrogen (E2) and progesterone (P). Despite this, the mechanisms by which P and E2 regulate catecholamine biosynthesis are poorly understood. While some research has focused on tyrosine hydroxylase (TH), limited studies are available on dopamine beta-hydroxylase (DBH) and phenylethanolamine-N-methyltransferase (PNMT). In women, E2 is thought to downregulate catecholamine production by altering biosynthetic enzyme activity and is therefore considered cardioprotective. Similarly, P has been shown to modulate catecholamine biosynthesis, though the exact mechanism remains unclear. This study examined the regulation of TH, DBH, and PNMT in PC12 cells treated with varying concentrations of P and E2. In addition, the potential role of P and E2 in modulating the neural (forskolin) and hormonal (dexamethasone) regulation of catecholamine bionsynthetic enzymes was examined. The overexpression of estrogen receptor (ER) subtypes alpha and beta via CRISPR activation (CRISPRa) was also investigated to further elucidate ER-mediated effects. Treatment with P and E2 hormones alone had no significant effect on TH, DBH, or PNMT mRNA expression. Dexamethasone treatment significantly increased mRNA expression of TH, DBH, and PNMT, and progesterone and estrogen potentiated the dexamethasone-induced increase in TH mRNA expression. Progesterone also attenuated DBH mRNA expression. These findings suggest that P and E2 modulate catecholamine biosynthesis and may contribute to the observed sex differences in hypertension prevalence.