Acute sex steroid withdrawal increases cholesterol efflux capacity and HDL-associated clusterin in men

Abstract

Exogenous androgens can lower HDL-cholesterol (HDL-C) concentrations, yet men with low serum testosterone have elevated rates of cardiovascular disease (CVD). HDL function may better predict CVD risk than absolute HDL-C quantity. We evaluated the acute effects of medical castration in men on HDL-C, cholesterol efflux capacity and HDL protein composition. Twenty-one healthy men, ages 18–55, received the GnRH antagonist acyline and one of the following for 28 days: Group 1: placebo, Group 2: transdermal testosterone gel and placebo, Group 3: transdermal testosterone gel and an aromatase inhibitor. Sex steroids, fasting lipids, and cholesterol efflux to apoB-depleted serum were measured in all subjects. The HDL proteome was assessed in Group 1 subjects only. In Group 1, serum testosterone concentrations were reduced by >95%, and HDL-C and cholesterol efflux capacity increased (p=0.02 and p=0.04 vs. baseline, respectively). HDL-associated clusterin increased significantly with sex steroid withdrawal (p=0.007 vs. baseline). Testosterone withdrawal in young, healthy men increases HDL-C and cholesterol efflux capacity. Moreover, sex steroid deprivation changes HDL protein composition. Further investigation of the effects of sex steroids on HDL composition and function may help resolve the apparently conflicting data regarding testosterone, HDL-C, and CVD risk.

Long‐term testosterone therapy in hypogonadal men ameliorates elements of the metabolic syndrome: an observational, long‐term registry study

“…T therapy has been shown to reduce HDL3-C subfraction and LpA-I:A-II particles but not the more anti-atherogenic HDL2-c and LpA-I particles (66). Rubinow et al showed that androgen deprivation increased cholesterol efflux from macrophages and demonstrated that sex steroid manipulation modified the HDL proteome (67). Furthermore, T therapy in older hypogonadal men altered HDL protein and lipid composition but did not significantly change serum HDL-mediated cholesterol efflux (68).…”

Clusterin/apolipoprotein J binds to aggregated LDL in human plasma and plays a protective role against LDL aggregation

“…These authors reported that apoJ preserves the anti‐inflammatory, antioxidant, and antiatherogenic properties of HDLs (39, 40). Several studies have found that the content of apoJ in HDLs is decreased in subjects with diabetes, obesity, or metabolic syndrome and in patients with active coronary disease (11, 12, 43). In the latter, the antiapoptotic activity of HDLs is compromised in part by its reduced apoJ content (12).…”

“…It is noteworthy that the concentration of apoJ used in our experiments is within the physiologic range. Several studies report that the concentration of apoJ in blood ranges from 50 to 150 mg/ml (41)(42)(43)(44)(45), and the usual concentration of apoB in normolipemic subjects ranges from 0.8 to 1.0 mg/ml. The ratio of apoJ/apoB in blood is therefore around 1/10.…”

Proteomic diversity of high density lipoproteins: our emerging understanding of its importance in lipid transport and beyond

“…Sex steroid withdrawal in men was shown to increase HDL-associated levels of clusterin (apoJ) while increasing the capacity of HDL to promote cholesterol effl ux from macrophages ( 78 ). A follow-up study showed that testosterone replacement in hypogonadal men promoted signifi cant and clot propagating/inhibiting proteases, although much more work is needed to understand the precise roles they play.…”