Research: Progesterone & Cardiovascular Health

Overview

There is already significant evidence that progesterone, unlike synthetic progestins, has no adverse effects on cardiovascular risk factors. No change in any of the thrombotic or inflammatory markers studied was observed, despite significant symptomatic improvement compared to placebo, in 30 women receiving 20 mg/day progesterone cream for 4 weeks (Stephenson et al. 2004). When bioidentical progesterone (an oral micronized preparation) was used in one group in the PEPI study in place of medroxyprogesterone acetate (MPA), this group had a significantly higher HDL cholesterol levels than the MPA group, indicating a different pharmacological effect than the synthetic progestin with a more favorable effect on blood lipids (Writing Group for the PEPI Trial, 1995).

Not only is there a lack of adverse effects of bioidentical progesterone on the cardiovascular system, but there is evidence of beneficial effects also. A progesterone vaginal gel produced an increase in exercise tolerance in postmenopausal women with coronary artery disease or previous myocardial infarction who were being treated with estradiol, while MPA did not, compared with estradiol alone (Rosano et al. 2000), suggesting an advantage for progesterone in women at risk for cardiovascular disease. Progesterone’s long term hemostatic role is suggested by its ability to reduce coronary hyperreactivity even in the presence of atherosclerosis in oophorectomized rhesus monkeys (Hermsmeyer et al. 2004). Koh et al. (2004) reported that progesterone together with lower dose conjugated equine estrogens (CEE) had comparable beneficial effects to conventional high dose CEE on flow mediated dilation, high density lipoproteins, and triglycerides, which may suggest that peripheral vascular function in postmenopausal women is markedly improved by direct actions on the vascular wall.

The reduction of the risk of heart attacks, angina pectoris, stroke, and other major heart and vascular disease by restoring hormone balance could delay the decline in cardiovascular function in women for decades.

Research

Stephenson K, Price C, Kurdowska A, Neuenschwander P, Stephenson J, Pinson B, Stephenson D, Alfred D, Krupa A, Mahoney D, Zava D, Bevan M. Topical progesterone cream does not increase thrombotic and inflammatory factors in postmenopausal women. Presented at the 46th Annual Meeting of the American Society of Hematology, San Diego, December 4-7, 2004. Blood 2004; 104(11): Abstract 5318.

No change in any of the thrombotic or inflammatory markers studied (total factor VII:C, factor VIIa, factor V, fibrinogen, antithrombin, PAI-1, CRP, TNFα, and IL-6) was observed, despite significant symptomatic improvement compared to placebo, in 30 women receiving 20 mg/day progesterone cream for 4 weeks. This finding indicates a lack of potential adverse effects of progesterone on the cardiovascular system, particularly with respect to risk of coronary artery disease and stroke.
Menopause. 2004 May-Jun;11(3):255-63. Chronic treatment with progesterone but not medroxyprogesterone acetate restores the endothelial control of vascular tone in the mesenteric artery of ovariectomized rats. Chataigneau T, Zerr M, Chataigneau M, Hudlett F, Hirn C, Pernot F, Schini-Kerth VB.

This study helps explain the more beneficial effects on the cardiovascular system of progesterone compared with MPA because of its enhancement of the protective effects of endothelial cells on the arterial walls.
Hermsmeyer RK, Mishra RG, Pavcnik D, Uchida B, Axthelm MK, Stanczyk FZ, Burry KA, Illingworth DR, Kaski JC, Nordt FJ. Prevention of coronary hyperreactivity in pre-atherogenic menopausal rhesus monkeys by transdermal progesterone. Arterioscler Thromb Vasc Biol . 2004 May;24(5):955-61.

Previous studies by Hermsmeyer, et al demonstrated a reduction of coronary reactivity in response to sub-physiological levels of progesterone in non-atherogenic monkeys. In this study, the authors sought to determine if transdermal progesterone cream conferred coronary vascular protection in surgically menopausal pre-atherosclerotic rhesus monkeys. Compared with monkeys receiving placebo cream (n= 5), treated monkeys (n= 7) experienced reduced Lipoprotein (a) levels, and an attenuation of coronary vasoconstriction, which was artificially stimulated by intracoronary serotonin plus U46619. Coronary hyperreactivity is a component of coronary artery disease and was demonstrated in this study to be prevented in pre-atherosclerotic primates by progesterone cream treatment.
Koh KK, Shin M-S, Sakuma I, Ahn JY, Jin DK, Kim HS, Kim DS, Han SH, Chung W-J, Shin EK (2004). Effects of conventional or lower doses of hormone replacement therapy in postmenopausal women. Arterioscler Thromb Vasc Biol. 2004; 24:1516-1521.

Progesterone together with lower dose conjugated equine estrogens (CEE) had comparable beneficial effects to conventional high dose CEE on flow mediated dilation, high density lipoproteins, and triglycerides, which may suggest that peripheral vascular function in postmenopausal women is markedly improved by direct actions on the vascular wall.
Bagis T, Gokcel A, Zeyneloglu HB, Tarim E, Kilicdag EB, Haydardedeoglu B. The effects of short-term medroxyprogesterone acetate and micronized progesterone on glucose metabolism and lipid profiles in patients with polycystic ovary syndrome: a prospective randomized study. J Clin Endocrinol Metab 2002 Oct;87(10):4536-40.

This randomized prospective study evaluated and compared the effects of ten days treatment with oral and vaginal micronized progesterone (MP) and medroxyprogesterone acetate (MPA) on glucose metabolism, lipid profiles, and hormonal parameters in 28 patients with polycystic ovary syndrome (PCOS). Oral MPA and oral MP decreased luteinizing hormone (P = 0.028, P = 0.009, respectively) and total testosterone (P = 0.013, P = 0.037, respectively) levels. There was no change in hormonal parameters with vaginal MP. Basal insulin decreased (P = 0.021) and insulin sensitivity increased significantly in the oral MPA group. Low density lipoprotein cholesterol (LDL) and lipoprotein (a) levels decreased only in the MPA group. This study concluded that MPA and oral MP may reduce insulin sensitivity in patients with PCOS. Vaginal MP had no effect on glucose metabolism and lipid profiles.
Mather KJ, Norman EG, Prior JC, Elliott TG. Preserved forearm endothelial responses with acute exposure to progesterone: A randomized cross-over trial of 17-beta estradiol, progesterone, and 17-beta estradiol with progesterone in healthy menopausal women. J Clin Endocrinol Metab 2000 Dec;85(12):4644-9.

Regularly menstruating women enjoy relative protection from cardiovascular disease. Until recently, this has been attributed to the function of estrogen, despite the fact that progesterone is also present. This study evaluated the differing acute effects of 17-beta estradiol with and without progesterone with progesterone alone on endothelial function in a randomized crossover trial. Endothelial function was evaluated via endothelium dependent and independent forearm blood flow (FBF) using venous occlusion plethysmography. Flow responses were measured during brachial artery infusions achieving physiological levels of E2, E2 + P4, or P4 respectively along with either acetylcholine (an endothelium-dependent vasodilator), or sodium nitroprusside (an endothelium-independent vasodilator) in 27 healthy menopausal women with no cardiovascular disease risk factors. Small, statistically non-significant increases in endothelium-dependent flow responses were seen with all treatments. No impairment in response was seen with P4 alone or in combination with E2. The authors concluded that progesterone does not have detrimental vascular effects in humans.
Rosano GM, Webb CM, Chierchia S, Morgani GL, Gabraele M, Sarrel PM, de Ziegler D, Collins P. Natural progesterone, but not medroxyprogesterone acetate, enhances the beneficial effect of estrogen on exercise-induced myocardial ischemia in postmenopausal women. J Am Coll Cardiol 2000 Dec;36(7):2154-9.

This randomized crossover study compared the effects of estradiol (E2) (2mg/day), estradiol + progesterone (P4) vaginal gel (2 mg/day + 90 mg on alternate days), and estradiol + medroxyprogesterone acetate (MPA) (2 mg/day + 10 mg/day) on exercise-induced myocardial ischemia in eighteen postmenopausal women with coronary artery disease (CAD) or previous myocardial infarction (MI). Utilizing treadmill testing, patients were evaluated for exercise tolerance after each estradiol phase and at day 10 of each progestogen phase. The results demonstrated an increase in exercise tolerance with both E2 alone and E2 + progesterone, but not by E2 + MPA as compared to baseline. Furthermore, E2 + P4 demonstrated a significant increase in exercise tolerance when compared to MPA. The results suggest that progesterone may be preferred to progestins for hormone replacement therapy in women at risk for cardiovascular disease.
Sitruk-Ware R. Progestins and cardiovascular risk markers. Steroids 2000 Oct-Nov;65(10-11):651-8.

This article reviews the effects of various synthetic progestins and progesterone on cardiovascular health. Many synthetic progestins, especially 19-nortestosterone and some 17-hyroxyprogesterones, have negative effects on cardiovascular risk factors, whereas natural progesterone does not. Further studies utilizing natural and other steroids should be considered.
Minshall RD, Stanczyk FZ, Miyagawa K, Uchida B, Axthelm M, Novy M, Hermsmeyer K (1998). Ovarian steroid protection against coronary artery hyperreactivity in rhesus monkeys. J Clin Endocrinol Metab 1998; 83(2):649-59.

Medroxyprogesterone acetate, but not natural progesterone, negated the protective effects of estradiol against coronary artery hyperreactivity.
Miyagawa K, Rosch J, Stanczyk F, Hermsmeyer K. Medroxyprogesterone interferes with ovarian steroid protection against coronary vasospasm. Nature Medicine 1997;3(3): 324-327.

Ovariectomized rhesus monkeys were treated with physiological levels of 17-beta estradiol in combination with either medroxyprogesterone or progesterone (oral micronized) for four weeks. Following pathophysiological stimulation without injury to induce coronary vasospasm, it was shown that progesterone plus estradiol was protective against vasospasm, whereas estradiol plus medroxyprogesterone allowed vasospasm, concluding that medroxyprogesterone increases risk of coronary vasospasm, while progesterone does not.
Writing Group for the PEPI Trial. Effects of estrogen or estrogen/progestin regimens on heart disease risk factors in postmenopausal women. The postmenopausal estrogen/progestin interventions (PEPI) trial. JAMA 1995; 273(3):199-208.

Bioidentical progesterone (an oral micronized preparation) was used in one group in the PEPI study in place of MPA. Results showed that the progesterone group had significantly higher HDL cholesterol levels than the MPA group, indicating a different pharmacological effect than the synthetic progestin with a more favorable effect on blood lipids.
Ottosson UB, Johansson BG, et al. Subfractions of high-density lipoprotein cholesterol during estrogen replacement therapy: A comparison between progestogens and natural progesterone. American Journal of Obstetrics and Gynecology 1993 Mar;151(6): 746-50.

Fifty-eight postmenopausal women were followed with respect to subfractions of high-density lipoprotein during 3 cycles of unopposed estrogen. The women received either levonorgestrel, medroxyprogesterone acetate, or natural progesterone during the last ten days of the treatment period. Both progestogens significantly lowered HDL cholesterol, whereas natural progesterone had no effect on HDL levels.
Bolaji II, Grimes H, Mortimer G, Tallon DF, Fottrell PF, O’Dwyer EM. Low-dose progesterone therapy in oestrogenised postmenopausal women: effects on plasma lipids, lipoproteins and liver function parameters. Eur J Obstet Gynecol Reprod Biol 1993 Jan;48(1):61-8.

This 12 month prospective, open, non-comparative study measured the effects progesterone (oral micronized 100mg/day) paired with 0.625 mg conjugated equine estrogens (CEE) and found progesterone had no adverse effects on the lipid profile when combined with CEE. This lack of effect differs from other studies that noted adverse effects on lipid profiles when synthetic progestins were utilized with CEE.
Saarikoski S, Yliskoski M, Penttila I. Sequential use of norethisterone and natural progesterone in pre-menopausal bleeding disorders. Maturitas 1990 Jun;12(2):89-97.

This randomized controlled study evaluated the effects of norethisterone (NET) and micronized progesterone (MP) on bleeding disorders in pre-menopausal women. 80 patients were randomized to the trial and all were found via endometrial morphology to need progestogen therapy. They were subsequently treated with NET or MP. In both treatment groups, hyperplastic changes disappeared during the first three cycles, with the duration of treatment being 6 months. NET decreased follicle-stimulating hormone, luteinizing hormone, estradiol and sex-hormone-binding globulin levels (P < 0.001) whereas no changes were seen during MP treatment. High-density-lipoprotein cholesterol and triglyceride levels were also lowered by NET (P< 0.001-0.02) slightly decreased phospholipids. MP treatment had no effect on lipid profiles suggesting it may be a preferred progestogen for the treatment of bleeding disorders.
Hargrove JT, Maxson WS, Wentz AC, Burnett LS. Menopausal hormone replacement therapy with continuous daily oral micronized estradiol and progesterone. Obstetrics & Gynecology April 1989; 73( 4): 606-12.

Fifteen menopausal subjects were studied to determine the efficacy and safety of hormone replacement therapy with micronized estradiol (E2) and progesterone. Ten subjects were given 0.7-E2 (1.05 mg daily) and progesterone (200-300 mg daily) and evaluated over one year at month 0, 1, 3, 6 and 12. Five subjects were administered conjugated estrogens (0.625mg daily) and medroxyprogesterone acetate (10 mg daily) and evaluated at the same intervals. Results showed all 10 women on E2 and progesterone had a decrease in total cholesterol with an increase in HDLs and sustained amenorrhea with no endometrial hyperplasia or withdrawal bleeding after six months of observation. Four of five women in the conjugated estrogen group continued to have withdrawal bleeding without endometrial hyperplasia. HDLs also increased in this group but no significant change in total cholesterol was found.
Rylance PB, Brincat M, Lafferty K, De Trafford JC, Brincat S, Parsons V, Studd JW. Natural progesterone and antihypertensive action. Br Med J (Clin Res Ed) 1985 Jan 5;290(6461):13-4.
In a placebo controlled, double blind crossover study, increasing doses of natural progesterone was given orally to six men and four postmenopausal women with mild to moderate hypertension who were not receiving any other antihypertensive drugs. Compared to before treatment values and to placebo, progesterone caused a significant reduction in blood pressure, suggesting that progesterone has an antihypertensive action rather than a hypertensive one as has been previously thought. The authors suggest this protective effect of progesterone should be investigated further.