Sex Hormones and Blood PCSK9 Levels

Proprotein convertase subtilisin kexin 9 (PCSK9) is a secreted glycoprotein that was first demonstrated to play a role in lipoprotein metabolism in 2003 when several gain-of-function single nucleotide polymorphisms (SNPs) in PCSK9 were shown to associate with autosomal dominant hypercholesterolemia (ADH). Soon after, loss-of-function nonsense and missense SNPs in PCSK9 were shown to associate with hypocholesterolemia. Much is still not known about PCSK9's mechanism of action, its substrate(s), its regulation, and factors affecting its function, but we do know that PCSK9 decreases LDL clearance through degradation of LDL receptors. We examined plasma PCSK9 and serum lipids in182 normolipidemic subjects (98 men, 84 women) and found with Spearman analysis a significant correlation between plasma PCSK9 and total cholesterol (TC), LDL-C, and TC/HDL-C in men but not in women, suggesting a gender difference in PCSK9 regulation and/or function.

Following on our unexpected but novel and exciting observation, we hypothesize: that serum levels of testosterone and estradiol would be significantly correlated with plasma PCSK9 levels, that testosterone and 17-B estradiol replacement therapies in men and women respectively would result in changes in the levels of plasma PCSK9, that testosterone and estradiol modify the effect of PCSK9 on serum lipids in different ways, explaining at least in part, the gender dichotomy in PCSK9 function, and that a significant percentage of the effect of hormone replacement therapy on lipids is mediated through PCSK9 function.

Cohort #1 will be 60 hypogonadal men and cohort #2 will be 60 postmenopausal (hypoestrogenic) women before and after testosterone and estrogen replacement therapy respectively. They will undergo measurements of plasma PCSK9, serum testosterone in men or estradiol in women and TC, triglycerides, HDL-C and LDL-C before and 3 months after starting on replacement therapy. These panel studies will allow us to evaluate whether (a) hormone replacement therapy has an effect on PCSK9, and (b) whether resulting changes in PCSK9 are then associated with lipid response.