Androgens in Health and Disease.pdf - E Library

Chapter 10/Androgens and Coronary Artery Disease 203
syndrome or menopause led to a decrease in HDL cholesterol (162–164). Castration or
suppression of endogenous testosterone with GnRH antagonists increased HDL cholesterol
by about 20% (81,165–172). The effect of GnRH antagonists can be prevented by
coadministration of testosterone (173). Taken together, these data indicate that testosterone
exerts consistent effects on HDL metabolism. These effects are most marked on the
large HDL subclass (i.e., HDL2) which is devoid of apolipoprotein A-II (81,128,146,167).
Substitution of testosterone in hypogonadal men or in elderly men led to minor or no
decrease in HDL cholesterol (see Table 3) (77,126–129,143,145,150–174). A recent metaanalysis
of 19 studies published between 1987 and 1999 (175) calculated that intramuscular
administration of an average dosage of 179 ± 13 mg testosterone ester every 16 ± 1 d
for 6 ± 1 mo was associated with an HDL cholesterol decrease of 2–5 mg/dL. This becomes
less prominent with increasing age of treated men and duration of treatment. Testosterone
substitution for up to 3 yr in men over the age of 50 yr did not produce any consistent
changes in circulating lipid levels (147,176). In a multicenter study of male contraception
in younger men, a significant decrease in HDL cholesterol was found in non-Chinese
subjects only (156). Transdermal application of T or dihydrotestosterone (DHT) also
exerted less effect on HDL cholesterol than intramuscular application (148,149,141,174).
Lowering of HDL cholesterol by T is considered to increase cardiovascular risks
because HDL cholesterol exerts several potentially antiatherogenic actions. However,
in transgenic animal models, only increases of HDL cholesterol induced by ApoA-I
overproduction but not by inhibition of HDL catabolism were consistently found to
prevent atherosclerosis (177). Therefore, using the mechanism of HDL modification and
by inference, changes in metabolism rather than circulating levels of HDL cholesterol
per se appear to determine the (anti-)atherogenicity of HDL (177,178). T upregulates the
scavenger receptor B1 (SR-B1) in the liver and stimulates selective cholesterol uptake.
Hepatic lipase (HL) hydrolyzes phospholipids on the surface of HDL, thereby facilitating the
selective uptake of HDL core lipids by SR-B1 (177,179). The activity of HL in postheparin
plasma is increased after the administration of exogenous T (128,143,146,152,180) and
slightly decreased by suppression of T after GnRH antagonist treatment (81). Increasing
both SR-B1 and HL activities are consistent with the HDL-lowering effect of T, which
reflects accelerated reverse cholesterol transport from the tissues to the liver. In accordance
with this, transgenic mice overexpressing HL showed a dramatic fall in circulating
HDL cholesterol levels, but atherosclerosis was inhibited rather than enhanced
(177,179,181). This highlights the pitfall of assuming that the HDL-lowering effect of
exogenous T will increase cardiovascular risk. Paradoxically, the mechanism by which
testosterone reduces circulating HDL cholesterol may actually confer protection from
rather than promotion of atherosclerosis.
LIPOPROTEIN(A)
Lipoprotein(a) [Lp(a)] has striking structural homology to plasminogen but no fibrinolytic
activity. Lp(a) levels higher than 30 mg/dL are an independent risk factor for coronary,
cerebrovascular, and peripheral atherosclerotic vessel diseases (182). Administration
of exogenous T to hypogonadal (183) or healthy men (138,155,157,167,184) decreased
serum Lp(a) significantly by 22–59%. Lp(a) increased by 40–60% in men when endogenous
T was suppressed by GnRH analogs (168,183,185). The Lp(a)-lowering effect of T
is independent of aromatization (184). How T regulates Lp(a) is unknown. Whether changes
in Lp(a) induced by T will affect cardiovascular risk is also unclear.