Progesterone therapy, endothelial function and cardiovascular risk factors: a 3-month randomized, placebo-controlled trial in healthy early postmenopausal women

Abstract

Background: Progesterone is effective treatment for hot flushes/night sweats. The cardiovascular effects of progesterone therapy are unknown but evidence suggests that premenopausal normal estradiol with also normal progesterone levels may provide later cardiovascular protection. We compared the effects of progesterone to placebo on endothelial function, weight, blood pressure, metabolism, lipids, inflammation and coagulation.

Methods and results: We conducted a randomized, double-blind, 3-month placebo-controlled trial of progesterone (300 mg daily) among 133 healthy postmenopausal women in Vancouver, Canada from 2003-2009. Endothelial function by venous occlusion plethysmography was a planned primary outcome. Enrolled women were 1-11 y since last menstruation, not using hormones (for >6 months), non-smoking, without diabetes, hypertension, heart disease or their medications. Randomized (1∶1) women (55 ± 4 years, body mass index 25 ± 3) initially had normal blood pressure, fasting lipid, glucose and electrocardiogram results. Endothelial function (% forearm blood flow above saline) was not changed with progesterone (487 ± 189%, n = 18) compared with placebo (408 ± 278%, n = 16) (95% CI diff [-74 to 232], P = 0.30). Progesterone (n = 65) and placebo (n = 47) groups had similar changes in systolic and diastolic blood pressure, resting heart rate, weight, body mass index, waist circumference, total cholesterol, low-density lipoprotein cholesterol and triglyceride levels. High-density lipoprotein was lower (-0.14 mmol/L, P = 0.001) on progesterone compared with placebo. Fasting glucose, hs-C-reactive protein, albumin and D-dimer changes were all comparable to placebo. Framingham General Cardiovascular Risk Profile scores were initially low and remained low with progesterone therapy and not statistically different from placebo.

Conclusions: Results indicate that progesterone has short-term cardiovascular safety. Endothelial function, weight, blood pressure, waist circumference, inflammation and coagulation were unchanged as were lipids except for HDL-C. The statistically significant decrease in HDL-C levels was not clinically important (based on lack of Cardiovascular Risk Profile change).

Trial registration: ClinicalTrials.gov NCT00152438.

Conflict of interest statement

Competing Interests: Initially Schering Canada and subsequently Besins Healthcare provided the oral micronized progesterone and identical placebo as an in-kind donation. There are no further patents, products in development, or marketed products to declare. This does not alter the authors' adherence to all the PLOS ONE policies on sharing data and materials.

Figures

Figure 1. Flow Diagram Of Healthy Early Postmenopausal Participants Through The Cardiovascular Assessment Portion Of The Progesterone For Hot Flushes Randomized Controlled Trial.

This shows those excluded before randomization for abnormal historical or physical examination results, those secondarily excluded because of laboratory abnormalities and those randomized to progesterone or placebo arms. Also indicated are those with analyzable venous occlusion plethysmography assessment of the endothelial function effects of progesterone or placebo, morphometric, blood pressure, lipid and inflammation data.

Figure 2. Endothelial Function on Progesterone or Placebo.

Forearm venous occlusion plethysmography was performed in 34 healthy early postmenopausal women in a randomized, placebo-controlled trial of oral micronized progesterone (300 mg, Progesterone) for hot flushes. This plot shows dose responses in forearm blood flow (FBF) to intra-brachial artery infusions of vasodilators: A. nitric oxide-releasing, endothelium-dependent (acetylcholine - ACh); B. endothelium-independent (sodium nitroprusside - SNP). Data are mean ± SE of percentage (%) increase in FBF above saline baseline for those randomized to Progesterone (n = 18) and Placebo (n = 16). The 15% increase in FBF at each dose of ACh during Progesterone therapy was not statistically significant.

Figure 3. Changes in Lipids on Progesterone or Placebo.

These graphs show dot plots of lipid changes in 108 healthy early postmenopausal women in a randomized controlled trial of oral micronized progesterone (Progesterone, 300 mg daily) for hot flushes between the 4-week run-in and the 12 weeks of experimental therapy. Women were randomized in a 1∶1 ratio to Progesterone (n = 63) or Placebo (n = 45). The median change is shown with a line of stars. A. Total Cholesterol changes—not different by therapy; B. High density lipoprotein cholesterol = HDC-C—the level during Progesterone therapy was significantly lower (−0.14 mmol/L, p = 0.001)( 95% CI of difference, −0.20, −0.07); C. Low density lipoprotein cholesterol = LDL-C—not different by therapy; D. Triglycerides—not different by therapy.

Figure 4. Changes in Framingham General Cardiovascular System Profile 10-y Risk Score.

These data are from 108 untreated healthy postmenopausal women (1–11 years since their last menstrual flow) in a randomized controlled trial of oral micronized progesterone (300 mg daily, Progesterone; n = 63) or identical placebo (Placebo, n = 45) for treatment of hot flushes/flashes and night sweats. This pair of dot-plots shows women's Framingham General CVS Profile during run-in by assignment to Progesterone or Placebo (left panel) and at the end of 12-weeks of experimental therapy (right panel). None of these differences were statistically significant.