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Progesterone & Heart Health
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- Carmody BJ, Arora S, Wakefield MC, Weber M, Fox CJ, Sidawy AN. Progesterone inhibits human infragenicular arterial smooth muscle cell proliferation induced by high glucose and insulin concentrations. J Vasc Surg 2002 Oct;36(4):833-8.
In vitro, progesterone was shown to have antiproliferative effects on vascular smooth muscle after proliferation was induced by models simulating hyperinsulinemia and hyperglycemia. Progesterone may, therefore, have a protective role against the atherosclerotic changes seen with diabetes (type II).
- Cheng W, Lau OD, Abumrad NA. Two antiatherogenic effects of progesterone on human macrophages; inhibition of cholesteryl ester synthesis and block of its enhancement by glucocorticoids. J Clin Endocrinol Metab 1999 Jan;84(1):265-71.
This study evaluated the effects of estradiol and progesterone on cholesteryl ester(CE) formation. Progesterone blocked CE formation, while estradiol had no effect. In comparison, cortisol and prednisolone (a widely prescribed glucocorticoid) both increased CE formation from 2-fold to 5-fold. This study demonstrated a role for progesterone in the decrease of cardiovascular risk factors that was not mediated by the progesterone receptor.
- Hermsmeyer RK, Mishra RG, Pavcnik D, Uchida B, Axthelm MK, Stanczyk FZ, Burry KA, Illingworth DR, Juan C, Nordt FJ. Prevention of coronary hyperreactivity in preatherogenic 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 subphysiological 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 preatherosclerotic rhesus monkeys. Compared with monkeys receiving placebo cream (n= 5), treated monkeys (n= 7) experienced reduced Lp (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 preatherosclerotic primates by progesterone cream treatment.
- Lee WS, Harder JA, Yoshizumi M, Lee ME, Haber E. Progesterone inhibits arterial smooth muscle cell proliferation. Nat Med 1997 Sep;3(9):1005-8.
Premenopausal women have a lower mortality from atherosclerotic cardiovascular disease than age-matched men. Progesterone receptors have been found in human and rat aortic smooth muscle cells in vivo and in vitro. This study examined the effect of progesterone on the proliferation of vascular smooth muscle cells. At physiologic levels, progesterone dose-dependently inhibited DNA synthesis and proliferation. RU486, a progesterone antagonist, blocked inhibition. This inhibition of arterial smooth muscle suggests a protective effect of progesterone against atherosclerosis.
- Molinari C, Battaglia A, Grossini E, Mary DA, Surico N, Vacca G. Effect of progesterone on peripheral blood flow in prepubertal female anesthetized pigs. J Vasc Res 2001 Nov-Dec;38(6):569-77.
To determine the effects of progesterone on the peripheral circulation, prepubertal female pigs were anesthetized with sodium pentobarbitone and changes in the superior mesenteric, left renal and left external iliac flow caused by intravenous infusion of progesterone were assessed using electromagnetic flow meters. Increased blood flows in the mesenteric, renal, and iliac arteries were demonstrated in all 20 subjects. In 4 additional subjects, a dose dependent effect was noted. This effect was blocked by the injection of N(omega)-nitro-L-arginine methyl ester.Results demonstrated a vasodilatory effect of progesterone, with the mechanism being that of nitric oxide release.
- Otsuki M, Saito H, Xu X, Sumitani S, Kouhara H, Kishimoto T, Kasayama S. Progesterone, but not medroxyprogesterone, inhibits vascular cell adhesion molecule-1 expression in human vascular endothelial cells. Arterioscler Thromb Vasc Biol 2001 Feb;21(2):243-8.
This study utilizing human umbilical vein endothelial cells (HUVEC’s) demonstrated that progesterone, but not medroxyprogesterone acetate (MPA) inhibited expression of vascular cell adhesion molecule-1 (VCAM-1), demonstrating a role for progesterone in the prevention of atherosclerosis. The differing effects of progesterone and MPA are clinically important, as MPA is widely used in hormone replacement therapy, when, as this research suggests, progesterone might be a more appropriate option.
- 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, p atients 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 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 the progestogen of choice for hormone replacement therapy for women at risk for cardiovascular disease.
- 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.
- Tsuda K, Kinoshita Y, Nishio I. Synergistic role of progesterone and nitric oxide in the regulation of membrane fluidity of erythrocytes in humans: an electron paramagnetic resonance investigation. Am J Hypertens 2002 Aug;15(8):702-8
Progesterone increased red blood cell membrane fluidity in this in vitro study, in part by a nitric oxide-dependent mechanism. It has been demonstrated that progesterone may play various roles in the regulation of blood pressure and other cardiovascular activities. The findings of this study suggest a positive role for progesterone in the improvement of microcirculation in humans.
- 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 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 LH (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.
- 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.
- 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.
- 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.
- 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.
- 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
Eighteen postmenopausal women were randomized to receive 17-beta estradiol with a synthetic progestin (medroxyprogesterone acetate) or a progesterone vaginal gel for 4 weeks, then crossed over to the alternate treatment. Researchers found through treadmill testing that estrogen plus progesterone significantly increased exercise time before myocardial ischemia, when compared to estradiol plus synthetic progestin. In addition, 2 patients on the synthetic progestin arm had to discontinue due to unstable angina. This research suggests that women at risk for cardiovascular disease need to consider progesterone as a safer alternative to synthetic progestins as a part of their hormone replacement therapy regime.
- 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. 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.
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