by John R. Lee, M.D.
Atherogenesis is the underlying cause of not only coronary artery disease
but of arterial disease throughout the body. It is seen as cholesterol plaque
within arteries, and we call it atherosclerosis. Female sex hormones exert
a protective effect against atherosclerosis. Women prior to menopause are at
a much lower risk (ratio 1:10) of cardiovascular disease than men of the same
age. After menopause, a woman's cardiovascular disease risk increases until
it becomes the main cause of death by about age 60. Total mortality from cardiovascular
disease in women eventually almost equals that of men. To understand how this
happens, it is important to understand atherogenesis.
The connection of serum cholesterol to atherosclerosis is a bit more complicated
than generally realized. The idea that cholesterol merely accumulates like
sludge in a river is a gross oversimplification. The fact that serum cholesterol
levels in postmenopausal women decrease when estrogen is given has led to the
assumption that estrogen protects against heart attacks. However, the Framingham
study finds that heart attack incidence in postmenopausal women on ERT is no
different than women not on ERT. Also, a randomized trial of estrogen plus
medroxyprogesterone acetate (Provera) found no prevention of coronary heart
disease in postmenopausal women compared to placebo 1 . Something is wrong
with the estrogen hypothesis concerning atherosclerosis. Progesterone has been
Atherogenesis begins in the middle layer of the arterial wall. It is here
that oxidized low-density lipoprotein (LDL-cholesterol) is ingested and recycled
by lysosomal hydrolysis in macrophages into cytoplasmic cholesteryl ester (CE).
Excessive accumulation of CE in macrophages yields the rounded, lipid-filled
foam cells that constitute a crucial early step of atherogenesis. Masses of
foam cells filling the middle layer of the arteries cause the intimal endothelial
lining cells to bulge up into the lumen. Inflammatory erosion of the intima
results in the serum cholesterol and fibrin that constitute the plaques seen
on the inner surface of atherosclerotic arteries.
A recent study 2 at the State University of New York at Stony Brook, NY, using
in vitro cell culture, finds that progesterone inhibits the change of cholesterol
into CE and decreases CE macrophage cellular levels, thus decreasing foam cell
creation. This inhibition of CE by progesterone was (1) reversed by removing
the progesterone, and (2) independent of progesterone receptors. Further, the
mechanism of action exhibited specific structural requirements, meaning that
synthetic progestins are not effective. Also, estradiol, in contrast to progesterone,
demonstrated no CE inhibition.
Progesterone's effect on glucocorticoid enhancement of CE accumulation in
human macrophages was also studied. Glucocorticoid enhancement of CE accumulation
occurs with either endogenous cortisol or synthetic glucocorticoids, such as
prednisolone and dexamethasone. Progesterone, added during glucocorticoid treatment,
blocked this increase of CE accumulation in macrophages. This effect of progesterone
was found to be due to prevention of glucocorticoid-induced increases in expression
and activity of the gene, acyl-CoA-cholesterol:acyl transferase (ACAT). Unlike
its inhibition of CE synthesis macrophages described above, progesterone's
inhibition of glucocorticoid enhancement of CE accumulation is nullified by
blocking its receptor. Here, again, progestins act to block the beneficial
effect of progesterone.
These findings help explain not only why chronic stress increases atherosclerosis
risk, but also how the proatherogenic action of glucocorticoids could be independent
of changes in plasma lipids and may not be prevented by controlling plasma
cholesterol. Antagonism by progesterone of glucocorticoid effects on macrophage
lipid synthesis is an important step in protecting against the risk of atherosclerosis
and, specifically, coronary disease.
- Coronary disease = atherosclerosis of coronary arteries = increased risk
of heart deaths.
- Macrophage lipid synthesis * increased foam cell accumulation * atherosclerosis.
- Progesterone inhibits macrophage lipid synthesis, thereby inhibiting
- Estrogen and progestins do not do this.
- Cortisol and synthetic glucocorticoids increase macrophage lipid synthesis.
- Therefore, endogenous and synthetic glucocorticoids increase the risk
of coronary heart disease.
- Progesterone inhibits this, and estrogen does not.
- Progestins may blockade progesterone receptors, thereby inhibiting progesterone's
beneficial effect of blocking glucocorticoid enhancement of macrophage
Studies by Hermsmeyer and colleagues at the Oregon Regional Primate Research
Center show that Premarin plus progesterone, but not Premarin plus medroxyprogesterone
acetate (Provera), protects against coronary artery spasm3.
Progesterone is not only antiatherogenic but also protects against coronary
Progesterone supplementation after menopause is far more effective in preventing
coronary heart disease and heart disease deaths than is estrogen alone or estrogen
1. Hulley S, Grady D, Bush T, Furberg C, et al. Randomized trial of estrogen
plus progestin for secondary prevention of coronary heart disease in postmenopausal
women. JAMA 1998; 280: 605-613.
2. Cheng W, Lau OD, & Abumrad NA. Two antiatherogeneic effects of progesterone
on human macrophages; inhibition of cholesteryl ester synthesis and block of
its enhancement by glucocorticoids. J Clin Endo and Metab 1999; 64: 265-271.
3. Miyagawa K, Rosch J, Stanczyk F, & Hermsmeyer K. Medroxyprogesterone
acetate interferes with ovarian steroid protection against coronary vasospasm.
Nature Medicine 1997; 3: 324-327.