Skip to content


The REPLENISH trial was a phase 3, randomized, double-blind, placebo-controlled, multicenter study, in postmenopausal women with a uterus, evaluating a new form of menopausal hormone therapy (MHT). Capsules containing estradiol plus progesterone (E2/P4) with four different dosages (1 mg/100 mg, 0.5 mg/100 mg, 0.5 mg/50 mg, and 0.25 mg/50 mg) were tested. The primary endpoints were the efficacy to treat vasomotor symptoms within a three months substudy and the proof of endometrial safety after 12 months treatment. The positive results of these two primary trial endpoints have already been reported [1]. The REPLENISH trial also tested the changes in cardiometabolic parameters during treatment with these oral E2/P4 formulations in comparison to placebo, as recently published in “Climacteric”, the official journal of the International Menopause Society [2]. One thousand six hundred eighty-four postmenopausal women received one of the four E2/P4 doses (1 mg/100mg [n=415], 0.5 mg/100mg [n=424], 0.5 mg/50mg [n=421], 0.25 mg/ 50mg [n=424]), and 151 women received placebo. Participants’ mean age was 54.6 years (range: 40–66 years) and mean body mass index was 26.7 kg/m2 (range:14.0–34.5 kg/m2); most were white (65.4%) or African American (32.1%). Changes in lipid and coagulation parameters and blood glucose from baseline at 6, 9, and 12 months were assessed. Minimal increases of potential clinical importance were observed in total cholesterol, triglycerides, and glucose at month 12 with E2/P4 (1–4%, 6–11%, and 1%, respectively) and placebo (3%, 7%, and 2%, respectively). Overall no clinically significant changes in lipid parameters, coagulation factors or glucose were seen between the treatment groups.


From the evaluation of the cardiometabolic parameters in the REPLENISH study, it can be concluded that oral E2/P4 combinations are neutral on lipid and glucose metabolism and on the coagulation system. This is the result of a study using the prospective, placebo-controlled “golden standard design”. Total cholesterol, HDL, LDL, triglycerides were assessed, as well as glucose; these parameters are  widely used in clinical practice to screen for cardiovascular risks. Measured coagulation factors included prothrombin time, activated partial thromboplastin time (aPTT), fibrinogen, protein C (factor XIV), protein S, antithrombin III, and factor V Leiden. These parameters are also widely assessed in other studies investigating changes in hemostatis under MHT. Changes in fasting lipids and glucose levels were not significant and these parameters remained within normal ranges. In contrast, negative changes in lipid and glucose metabolism have been seen in a variety of studies using oral estrogens combined with synthetic progestogens; oral formulations have often induced hypercoagulability and other negative vascular (e.g. vasoconstrictory) effects [3-6]. Only five women discontinued the study because of changes in lipids or coagulation factors, reported as adverse events [2].

As in the REPLENISH study using oral E2/P4, many studies have shown the neutral effect of transdermal E2 (patch, gel or spray) combined with oral micronized progesterone on cardiometabolic markers. Since with this combination clinical outcome studies have been published showing no risk of deep vein thrombosis and stroke, in contrast to oral MHT, transdermal estradiol plus micronized progesterone has been suggested to be the best option for reducing cardiovascular risks [7,8]. In the REPLENISH study the authors reported about four “vascular adverse events”, three cases of coronary heart disease (CHD) and one case of deep vein thrombosis (DVT) [2]. However, the study did not have the statistical power to allow any conclusions about these clinical outcomes.

Cardiovascular risks like DVT, stroke and CHD can be expected whenever estrogens are used orally. So this new option for MHT perhaps may not replace transdermal estradiol use to reduce these risks. On the basis of our recent systematic review, we still recommend transdermal estradiol plus free additional combination of progesterone, especially for at-risk patients [9]. Unfortunately, we had to conclude, on the basis of another review that, to date, it is not possible to achieve FDA-approved endometrial safety using transdermal progesterone, so women have to use two different routes of administration, which can reduce compliance [10].

Estradiol combined with progesterone, moreover, may reduce the risk of breast cancer, independently from the route of administration, compared with combinations using synthetic progestogens, as suggested from observational studies [11,12]. This is especially true if certain membrane-bound receptors, predictive of a worse breast cancer prognosis [13,14], are expressed, as suggested from our recent in-vitro and animal studies [15,16].

In October 2018, the FDA approved the 1 mg E2/100 mg P4 dose for the treatment of vasomotor symptoms in postmenopausal women with a uterus as the very first fixed continuous combined E2 plus P4 [17]. This new option of MHT must be considered an alternative to compounded hormonal products, which millions of women are using after WHI [18]. This product has well defined “bioidentical components” (desired by women), and it is certainly effective for the treatment of vasomotor symptoms, has beneficial sedative effects, improves quality of life [19] and, most important, provides FDA-approved endometrial safety [1].


  • Alfred O. Mueck Department of Women’s Health, University of Tuebingen, Germany and Beijing Obstetrics and Gynecology Hospital, Capital Medical University Beijing, China


International Menopause Society

Install International Menopause Society - DEV

Install this application on your home screen for quick and easy access when you’re on the go.

Just tap then “Add to Home Screen”