Will estradiol/progesterone capsules for oral use become the best choice for menopausal hormone therapy?

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During October 2018, the US Food and Drug Administration approved capsules containing 1 mg estradiol and 100 mg progesterone as continuous combined menopausal hormone therapy (MHT) for the treatment of vasomotor symptoms in postmenopausal women with a uterus. This was the first fixed combination of oral estradiol plus micronized progesterone. The approval was based particularly on the REPLENISH trial, a phase-3, randomized, double-blind, placebo-controlled, multicenter study investigating the safety and efficacy of four daily doses of estradiol/progesterone combinations. The primary efficacy and safety endpoints were changes from baseline to weeks 4 and 12 in the frequency and severity of moderate to severe vasomotor symptoms, and the incidence of endometrial hyperplasia at 12 months. The positive results with respect to the two primary endpoints of the trial have already been reported¹. The REPLENISH trial also investigated additional efficacy endpoints, such as quality of life² using the Menopause-Specific Quality of Life questionnaire, a validated questionnaire assessing four domains (vasomotor, psychosocial, physical, sexual), which showed improvement within the first 3 treatment months. As additional safety endpoints, cardiometabolic parameters were also assessed, as published in this present issue of Climacteric³.

A total of 1835 participants received the medication (safety population); 1684 postmenopausal women were treated with one of the four oral estradiol/progesterone (E2/P4) doses (1/100 mg [n = 415], 0.5/100 mg [n = 424], 0.5/50 mg [n = 421], 0.25/50 mg [n = 424]) and 151 women received placebo. Across treatment groups, demographics and baseline characteristics were comparable. Women were generally healthy, with a mean Framingham 10-year risk of coronary heart disease score of about 2.5%. In total, 1.275 (69.5%) completed the study at 52 weeks. The discontinuation rate of 30% is a limitation of this study. However, it should be considered that, to ensure study investigators and participants are blinded to treatment, a double-dummy blinding technique has to be used – that is, all women took two capsules daily –which may have reduced the compliance. Only five women discontinued the study due to adverse events, due to changes in lipids or coagulation factors.

The authors concluded from their results that there were ‘no clinically meaningful effects on lipids, glucose or coagulation factors compared to placebo’³. It seems remarkable that they did not make conclusions about clinical cardiovascular outcomes. Indeed, they reported about four ‘vascular adverse events’: these were three cases of coronary heart disease and one case of deep vein thrombosis (DVT) in the 0.5 mg E2/50 mg P4 group, possibly related to treatment, although this participant had a family history of DVT. As the authors discussed, these rates are as expected for a menopausal population.

The cardiometabolic parameters assessed in the REPLENISH study are laboratory parameters commonly used for screening purposes in internal medicine and thus it can be concluded that E2/P4 combinations, used orally in postmenopausal women in good cardiovascular health, are neutral with respect to lipid and glucose metabolism and within the coagulation system. This has also been reported in studies using estradiol transdermally combined with orally applied micronized progesterone^4,5. In contrast, a variety of studies using oral estrogens combined with synthetic progestogens showed negative changes, such as a decrease of high-density lipoprotein cholesterol (especially when using androgenic progestogens), an increase of triglycerides, and, in some studies using higher dosages of synthetic progestogens, also disturbances in glucose metabolism^4,6.

Negative metabolic changes have also been seen in other well-designed studies; for example, in the Postmenopausal Estrogen/Progestin Intervention (PEPI) study, where significant increases in triglycerides with conjugated equine estrogens alone or combined with medroxyprogesterone acetate or micronized progesterone have been observed⁷. In the REPLENISH study, coagulation factors remained largely in the normal ranges, whereas studies using oral estrogens combined with synthetic progestogens often showed hypercoagulability or coagulation activation⁴.

Since clinical outcome studies using estradiol transdermally (as a patch, gel, or spray) combined with oral micronized progesterone have been published showing no risk of DVT and stroke in contrast to oral MHT preparations, this combination has been suggested to be the best option for reducing cardiovascular risks and may reduce also the risk of gallbladder diseases, some forms of diabetes mellitus and metabolic syndrome, and risk of hypertension^4,8,9. However, to compare the different risk profiles, we need clinical endpoint studies with the new oral E2/P4 formulations. However, from the pathophysiological and pharmacological view, we would not expect that future clinical endpoint studies using oral E2/P4 combinations will lead to better clinical outcome results compared to studies already performed using oral estrogens. In particular, one might expect an increased risk of DVT due to the first-pass liver effect on the hemostatic system. Possible dose-dependent actions on inflammatory markers might also result in adverse effects, such as destabilization of arterial plaques with the risk of ischemic stroke, although these effects may be ameliorated by the use of micronized progesterone rather than synthetic progestins^4,9.

For many postmenopausal women, the choice between oral and transdermal estrogen may not be particularly significant in terms of health outcomes. However, many may benefit from the use of progesterone instead of synthetic progestogens. The neutral vascular effect can be important in patients with pre-existing hypertension and other vascular risks, and many climacteric patients appreciate the sedative properties, even quite often using only oral micronized progesterone without any estrogen combination. Of paramount importance would be further studies to confirm that the breast cancer risk can be decreased, as suggested from observational studies^10,11. From our own in vitro and animal studies, we have concluded that, in comparison with certain synthetic progestogens, use of micronized progesterone may help to avoid the development of those breast cancer types which are associated with the expression of special membrane-bound receptors^12,13 which, when detected in blood or serum of breast cancer patients, are associated with a worse prognosis^14,15.

Perhaps the most important result of REPLENISH is the demonstration of endometrial safety using progesterone as the progestogen component¹. This has been the subject of controversial discussion for years. One systematic review even concluded that progesterone increases the risk of endometrial cancer regardless of the regimen¹⁶, but the conclusion was made only on the basis of two studies, where the dosage and duration of the progestogen phase were not really clear (Etude Epidémiologique de femmes de la Mutuelle Générale de l'Education Nationale [E3N] and European Prospective Investigation into Cancer and Nutrition [EPIC]). On the basis of the REPLENISH data, this statement is wrong! Another review suggested that progesterone should preferably be used vaginally to achieve higher endometrial levels¹⁷. In the REPLENISH trial, no endometrial cancer and only a low incidence of endometrial proliferation (2.9% or less) were seen. Thus, the REPLENISH trial is the first large, sufficient statistically powered study to demonstrate no hyperplasia using progesterone continuously combined with different estradiol dosages.

Presently, it is not clear whether transdermally applied progesterone would have any relevant advantages. The only option to use progestogens transdermally is combi-patches containing a synthetic progestin (norethisterone acetate or levonorgestrel as the progestogen component), with very few data on clinical outcomes. Unfortunately, we have concluded from the existing literature that the various tested preparations of transdermal progesterone have not adequately proved efficacy and especially not endometrial safety¹⁸. Reviewing all data using transdermal estradiol plus an additional oral progestogen¹⁹, we recommend, especially in high-risk patients, the use of 200 mg progesterone for 12 days monthly within a sequential design or 100 mg daily within a continuous combined regimen if transdermal estradiol in dosages of 50–60 µg/day are applied (i.e. 50 µg patches, about two puffs/two pumps of gel or spray). This approximately corresponds with the dosage of the new US Food and Drug Administration-approved oral 1 mg E2/100 mg P4 formulation. However, based on our own experience in our department in Beijing with more than 500 outpatients daily, we have experienced slightly more bleeding problems using progesterone instead of synthetic progestogens. For bleeding problems also in younger patients (type AUB-O) or for treatment of endometrial hyperplasia, we use synthetic progestogens (e.g. dydrogesterone) instead of micronized progesterone. For MHT, we individualize the dosages of estradiol and/or progesterone according to bleeding patterns and findings on vaginal sonography. We also use outpatient hysteroscopy if we cannot maintain regular withdrawal bleedings during the sequential design or amenorrhea during the continuous combined design¹⁸. We remain cautious because endometrial effects may vary, perhaps due to different individual hepatic metabolisms of progesterone. In cases of persistent irregular bleeding where no ultrasonic or histologic abnormalities exist, we increase the progesterone dosage as first-line treatment because it is very well tolerated. We also sometimes use a strong synthetic progestin once or twice per year to induce a ‘hormonal curettage’, which mostly will stop irregular bleedings, especially during the continuous combined regimen.

The new fixed E2/P4 formulation may increase compliance, because most women prefer oral application of both estrogen and progestogen in one formulation. Indeed, if future clinical practice confirms what we can expect from existing data, the new formulation, which combines the ‘body identical’ hormones (wanted by women) in standardized dosages in contrast to compounded hormonal products, could become an important choice for patients needing MHT. However, it will not replace transdermal estradiol (patches, gel, spray) plus oral micronized progesterone as, in our view, this remains the best choice for reducing risks like DVT, stroke, and gallbladder diseases²⁰.

Potential conflict of interest

The authors report no conflict of interest.

Source of funding

Nil.