Testosterone replacement in hypogonadal men alters the HDL proteome but not HDL cholesterol efflux capacity

Abstract

The effects of androgens on cardiovascular disease (CVD) risk in men remain unclear. To better characterize the relationship between androgens and HDL, we investigated the effects of testosterone replacement on HDL protein composition and serum HDL-mediated cholesterol efflux in hypogonadal men. Twenty-three older hypogonadal men (ages 51–83, baseline testosterone < 280 ng/dl) were administered replacement testosterone therapy (1% transdermal gel) with or without the 5α-reductase inhibitor dutasteride. At baseline and after three months of treatment, we determined fasting lipid concentrations, HDL protein composition, and the cholesterol efflux capacity of serum HDL. Testosterone replacement did not affect HDL cholesterol (HDL-C) concentrations but conferred significant increases in HDL-associated paraoxonase 1 (PON1) and fibrinogen α chain (FGA) (P = 0.022 and P = 0.023, respectively) and a decrease in apolipoprotein A-IV (apoA-IV) (P = 0.016). Exogenous testosterone did not affect the cholesterol efflux capacity of serum HDL. No differences were observed between men who received testosterone alone and those who also received dutasteride. Testosterone replacement in older hypogonadal men alters the protein composition of HDL but does not significantly change serum HDL-mediated cholesterol efflux. These effects appear independent of testosterone conversion to dihydrotestosterone. Further research is needed to determine how changes in HDL protein content affect CVD risk in men.

Musculoskeletal and prostate effects of combined testosterone and finasteride administration in older hypogonadal men: a randomized, controlled trial

“…Conversely, finasteride coadministration reduced LDL-cholesterol but did not alter triglycerides. The clinical ramifications of these blood lipid changes remains unknown (36). Additionally, several putative adverse events are associated with testosterone administration, including worsening of sleep apnea, edema, gynecomastia, increased incidence of cardiovascular events, acceleration of underlying prostate cancer, and liver-related side effects (6,7,25).…”

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

“…This activity was termed trypanosome lytic factor (TLF) ( 95,96 ). Immunoprecipitation studies increases in PON1 and fi brinogen ␣ -chain while lowering apoA-IV, but it had no effect on HDL-C levels or cholesterol effl ux functionality ( 79 ).…”

Testosterone, HDL and cardiovascular risk in men: the jury is still out

“…Moreover, the lipid-related effects of exogenous testosterone appear highly contingent on whether parenteral or oral routes of administration are employed. Oral testosterone administration significantly reduced HDL-C levels in young, healthy men [6], whereas when older, hypogonadal men were treated with transdermal testosterone, we found no significant changes in HDL-C after 3 months of therapy [5]. These disparate effects may be a consequence, in part, of first-pass hepatic metabolism that occurs with oral but not parenteral administration.…”

“…This effect has been achieved consistently with the administration of supraphysiologic doses of oral androgens to young men [2], but has been far less consistent when testosterone therapy has been used at physiologic doses to restore eugonadal serum levels, particularly in older men [4,5]. Moreover, the lipid-related effects of exogenous testosterone appear highly contingent on whether parenteral or oral routes of administration are employed.…”

“…Ongoing research efforts are similarly exploring alternative strategies for assessing the relationship between HDL and CVD, including measurement of HDL particle number and size, determination of HDL protein cargo and assays of other HDL functions [5,15]. For example, our research has generated the novel finding that testosterone replacement in older, hypogonadal men confers changes in the protein composition of HDL particles in the absence of changes in HDL-C [5].…”