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This paper [1] is a collaboration between the Early vs Late Interventions Trial (ELITE) [2] investigators, and the manufacturers of a commercially available, FDA approved, oral estradiol and progesterone combination preparation (Bijuva®; TherapeuticsMD; Boca Raton, FL). In this post-hoc analysis, the investigators reanalyzed coagulation factors assessed in the REPLENISH clinical trial. The REPLENISH trial [3] was a phase 3, randomized, double-blinded, placebo-controlled, multicenter trial designed to determine the efficacy of four different doses of estradiol with progesterone for reduction of VMS and on endometrial safety ( as NCT01942668). The REPLENISH study had several characteristics optimal for the investigation reported here. These include:

1) adequate sample size (n=1845),
2) random assignment to one of five estradiol (E2) and progesterone (P4) intervention groups,
3) a range of varying daily E2/P4 doses (1 mg/100 mg, 0.5 mg/100 mg, 0.5 mg/50 mg, 0.25 mg/50 mg),
4) a matching placebo group,
5) adequate duration (as long as 12 months) to investigate coagulation effects (biomarkers not events), and
6) a prospective study design.

Of those enrolled, 1215 women were classified as early menopausal (<6 years since menopause), and 297 were in the late menopausal group (>10 years since menopause) for the purpose of this post-hoc analysis. This “age/time” since menopause classification was comparable to the analysis in ELITE [1].

As complications of the prothrombotic impact of oral estrogens are the subject of multiple reviews, they will not be recounted here [4, 5]. Suffice it to say, in large, randomized clinical trials, like the Women’s Health Initiative (WHI), thrombotic complications represented the principle source of serious adverse effects [6]. The REPLENISH dataset analyzed here, like the results reported by Curb et al [7] in WHI, offers insights into potential differences in coagulation effects between oral estradiol and progesterone vs conjugated equine estrogens + medroxyprogesterone acetate [8, 9], and the impact of time since menopause (early: less than 6 years postmenopausal vs late: more than 10 years following the last menstrual period) on thrombosis risk. The authors hypothesize that oral estradiol (E2) has a differential effect on coagulation factors, as a marker of thrombosis risk, according to time since menopause, in other words, a gap or timing hypothesis [10], but specifically for thrombosis.

In this post-hoc analysis, higher E2 doses and serum E2 concentrations were associated with statistically significant reductions in several coagulation and anti-coagulation measures compared to baseline. These included the prothrombin time, the activated partial thromboplastin time, antithrombin, fibrinogen, protein C, and protein S over the 12-month intervention and follow-up period. The associations of the E2 dose and serum E2 levels with coagulation and anti-coagulation measures were statistically of greater magnitude in late versus early postmenopausal women.

The serum P4 concentration did not have a statistically significant effect on coagulation or anti-coagulation measures and did not confound the association between the E2 dose and serum E2 level with any coagulation or anti-coagulation measures, a finding consistent with previous reports, and unlike contraceptive progestogens including medroxyprogesterone acetate commonly used in menopausal hormone therapy [11].


Oral hormone therapy has long been assumed to increase pro-coagulation risk whether by increasing procoagulant factors or decreasing anticoagulant factors or some combination of both. By implication, these biochemical changes are assumed to be the underlying cause for the thrombotic and thromboembolic events in those hormone therapy investigations. However, those data have commonly been confounded by combining early and late postmenopausal women, or by including conjugated equine estrogens with its higher thrombotic risk compared with estradiol [8, 9]. If the results presented here by Sriprasert and colleagues can be replicated in healthy early postmenopausal women less than 6 years since their final menses, the benefit/risk ratio of oral estradiol and natural progesterone can be shifted toward benefit. These results also suggest a gap or timing hypothesis for venous thrombotic or thromboembolic risk, as has been the controversial explanation for many of the cardiovascular outcomes in clinical trials over the last 20 years [2, 10].

James A. Simon, MD
Clinical Professor, George Washington University
Medical Director, IntimMedicine Specialists
Washington, DC, USA


  1. Sriprasert I, Hodis HN, Bernick B, Mirkin S, Mack WJ. Effects of Estradiol Dose and Serum Estradiol Levels on Metabolic Measures in Early and Late Postmenopausal Women in the REPLENISH Trial. J Womens Health (Larchmt) 2020 Jul 9.
  2. Hodis HN, Mack WJ, Henderson VW, et. al. Vascular Effects of Early versus Late Postmenopausal Treatment with Estradiol. N Engl J Med 2016; 374:1221-31.
  3. Mirkin S, Amadio JM, Bernick BA, et al. 17beta-Estradiol and natural progesterone for menopausal hormone therapy: REPLENISH phase 3 study design of a combination capsule and evidence review. Maturitas 2015; 81:28–35.
  4. Oliver-Williams C, Glisic M, Shahzad S, et al. The route of administration, timing, duration and dose of postmenopausal hormone therapy and cardiovascular outcomes in women: a systematic review. Hum Reprod Update. 2019;25(2):257-271.
  5. Abou-Ismail MY, Citla Sridhar D, Nayak L. Estrogen and thrombosis: A bench to bedside review. Thromb Res. 2020;192:40-51.
  6. Olié V, Canonico M, Scarabin PY. Risk of venous thrombosis with oral versus transdermal estrogen therapy among postmenopausal women. Curr Opin Hematol. 2010;17(5):457-463.
  7. Curb JD, Prentice RL, Bray PF, et al. Venous Thrombosis and Conjugated Equine Estrogen in Women Without a Uterus. Arch Intern Med. 2006;166(7):772–780.
  8. Smith NL, Blondon M, Wiggins KL, et al. Lower Risk of Cardiovascular Events in Postmenopausal Women Taking Oral Estradiol Compared With Oral Conjugated Equine Estrogens. JAMA Intern Med. 2013
  9. Blondon M, van Hylckama Vlieg A, Wiggins KL, et al, Rosendaal FR, Heckbert SR, Psaty BM, Smith NL. Differential associations of oral estradiol and conjugated equine estrogen with hemostatic biomarkers. J Thromb Haemost. 2014 Jun;12(6):879-86.
  10. Clarkson TB, Meléndez GC, Appt SE. Timing hypothesis for postmenopausal hormone therapy: its origin, current status, and future, Menopause 2013; 20(3): 342-353.
  11. Canonico M, Plu-Bureau G, Scarabin PY. Progestogens and venous thromboembolism among postmenopausal women using hormone therapy. Maturitas. 2011;70(4):354-360.
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