CARDIOVASCULAR RISK WITH SYNTHETIC PROGESTINS VERSUS PROGESTERONE
The WHI study demonstrated that the addition of MPA to Premarin® (a CEE) resulted in a substantial increase in the risk of heart attack and stroke. This outcome with MPA is not surprising because synthetic progestins produce negative cardiovascular effects and negate the cardioprotective effects of estrogen. Progesterone, in contrast, has the opposite effect because it maintains and augments the cardioprotective effects of estrogen, thus decreasing the risk for heart attack and stroke.
One mechanism contributing to these opposing effects for cardiovascular risk is the differing effects on lipids. Medroxyprogesterone acetate and other synthetic progestins generally negate the positive lipid effects of estrogen and show a consistent reduction in HDL,148,153–159,163 the most important readily measured determinant of cardioprotection, while progesterone either maintains or augments estrogen’s positive lipid and HDL effects.
For instance, the PEPI trial, a long-term randomized trial of HRT, compared a variety of cardiovascular effects including lipid effects of both MPA and progesterone in combination with CEE. While all regimens were associated with clinically significant improvements in lipoprotein levels, many of estrogen’s beneficial effects on HDL-C were negated with the addition of MPA. The addition of progesterone to CEE, however, was associated with significantly higher HDL-C levels than with MPA and CEE (a notable sparing of estrogen’s beneficial effects).
Fahraeus et al compared the lipid effects of synthetic progestins with progesterone in 26 postmenopausal women who had been receiving cutaneous estradiol for 3 to 6 months. Women received either 120 ⎧g of l-norgestrel or 300 mg of progesterone sequentially for another 6 months. Compared with the use of progesterone, l-norgestrel resulted in significant reductions in HDL and HDL-2.
Ottosson et al compared the lipid effects of estrogen when combined with either of 2 synthetic progestins, or bioidentical progesterone. Menopausal women were initially treated with 2 mg estradiol valerate (cyclical) for 3 cycles, and then were randomized to receive MPA, levonorgestrel, or progesterone. Serum lipids and lipoproteins were analyzed during the last days of the third, fourth, and sixth cycles. Those receiving estrogen combined with levonorgestrel had a significant reduction in HDL and HDL sub-fraction 2 (18% and 28%, respectively), as did those receiving MPA (8% and 17%, respectively). Conversely, there were no significant changes seen in the HDL and HDL sub-fraction levels with the use of progesterone.
Furthermore, a randomized trial by Saarikoski et al which compared the lipid effects in women using the synthetic progestin norethisterone and progesterone, those on synthetic progestin had a significant decrease in HDL, whereas those using progesterone had no decrease in HDL.
A number of studies have shown that coronary artery spasm, which increases the risk for heart attack and stroke, is reduced with the use of estrogen and/or progesterone.149–151-,174,179,180 However, the addition of MPA to estrogen has the opposite effect, resulting in vasoconstriction,149–151,174 thus increasing the risk for ischemic heart disease.
Minshall et al compared coronary hyperreactivity by infusing a thromboxane A2 mimetic in primates, which were administered estradiol along with MPA or progesterone. When estradiol was given with progesterone, the coronary arteries were protected against induced spasm. However, the protective effect was lost when MPA was used instead of progesterone.
Miyagawa et al also compared the reactivity of coronary arteries in primates pretreated with estradiol combined with either progesterone or MPA. None of the animals treated with bioidentical progesterone experienced vasospasm, while all of those treated with MPA showed significant vasospasm.
Mishra et al1 also found that progesterone protected against coronary hyperreactivity, while MPA had the opposite effect and induced coronary constriction.
In a blinded, randomized, crossover study, the effects of estrogen and progesterone were compared with estrogen and MPA on exercise-induced myocardial ischemia in postmenopausal women with coronary artery disease. Women were treated with estradiol for 4 weeks and then randomized to receive either progesterone or MPA along with estradiol. After 10 days on the combined treatment, the patients underwent a treadmill test. Patients were then crossed over to the opposite treatment, and the treadmill exercise was repeated.
Exercise time to myocardial ischemia was significantly increased in the progesterone group compared with the MPA group.
Adams et al1examined the cardioprotective effects of CEE and progesterone versus CEE and MPA in primates fed atherogenic diets for 30 months. The CEE and progesterone combination resulted in a 50% reduction in atherosclerotic plaques in the coronary arteries. This result was independent of changes in lipid concentrations. However, when MPA was combined with the CEE, almost all the cardioprotective effect (atherosclerotic plaque reduction) was reversed.
Other studies have shown that progesterone by itself or in combination with estrogen inhibits atherosclerotic plaque formation. Synthetic progestins, in contrast, have a completely opposite effect: they promote atherosclerotic plaque formation and prevent the plaque-inhibiting and lipid-lowering actions of estrogen.
Transdermal estradiol, when given with or without oral progesterone, has no detrimental effects on coagulation and no observed increased risk for venous thromboembolism (VTE). This result is in contrast to an increased risk for VTE with CEE, with or without synthetic progestin, which significantly increases the risk for VTE, whether both are given orally (eg, oral estrogen and oral synthetic progestin) as transdermal estrogen and oral synthetic progestin, or both estrogen and synthetic progestin given transdermally.
Medroxyprogesterone acetate also has undesirable intrinsic glucocorticoid activity, whereas progesterone does not have such negative effects and is a competitive inhibitor of aldosterone, which is generally a desirable effect.
No changes in blood pressure are observed with progesterone in normotensive postmenopausal women, but a slight reduction in blood pressure is shown in hypertensive women.
Synthetic progestins can significantly increase insulin resistance, when compared with estrogen and progesterone.
The expression of vascular cell adhesion molecule-1 (VCAM-1) is one of the earliest events in the atherogenic process. Otsuki et al compared the effects of progesterone and MPA on VCAM-1 expression and found that progesterone inhibited VCAM-1. No such effect was observed with MPA.
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