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Abstract

Background:

Several promising new medications containing low-dose estradiol (E2) in combination with a progestin and an additional component, such as gonadotropin-releasing hormone antagonists, are currently being developed for use in pre-menopausal women.

Objective:

This pooled analysis was designed to estimate the thromboembolic safety profile of E2 and its ester, estradiol valerate (E2Val), when used in combined hormonal treatments in a pre-menopausal population.

Methods:

Data regarding users of combined oral contraceptives (COCs) and combined menopausal hormonal therapy (MHT) containing either E2/E2Val or ethinylestradiol (EE) ⩽ 30 µg were retrieved from five large prospective, non-interventional, cohort studies in Europe, US, and Canada with similar study design but differing medication cohorts. Propensity score sub-classification was applied to balance baseline parameters between cohorts and time-to-event analysis of venous thromboembolic events (VTE) was carried out based on the extended Cox model to calculate crude and adjusted hazard ratios (HR).

Results:

(1) Crude incidence rates of VTE were higher in MHT users compared to pre-menopausal COC users, (2) the VTE risk in menopausal users of E2/E2Val-norethindrone acetate was not higher than that in menopausal users of E2/E2Val-progestin (adjusted HR 0.71; 95% confidence interval, 0.41-1.26) and (3) the VTE risk in pre-menopausal users of E2/E2Val-progestin was similar, or lower, than pre-menopausal users of EE⩽30µg-progestin (adjusted HR 0.49; 95% confidence interval, 0.28–0.84).

Conclusion:

Our data presents a solid safety assessment of combined hormonal preparations containing E2/E2Val. We conclude that the risk of E2/E2Val-norethindrone acetate in pre-menopausal users is unlikely to be higher than the known risk of COCs containing EE ⩽ 30 µg-progestin.

Keywords

Epidemiology medical treatment women’s health endometriosis myomas

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References

ASRM. Combined hormonal contraception and the risk of venous thromboembolism: a guideline. Fertil Steril 2017; 107: 43–51.

Stenchever

MA.

Risks of oral contraceptive use in women over 35. J Reprod Med 1993; 38: 1030–1035.

Curtis

Tepper

Jatlaoui

, et al. U.S. Medical eligibility criteria for contraceptive use, 29 July 2016.

Dinger

Bardenheuer

Heinemann

Drospirenone plus estradiol and the risk of serious cardiovascular events in postmenopausal women. Climacteric 2016; 19: 349–356.

Grodstein

Manson

Colditz

, et al. A prospective, observational study of postmenopausal hormone therapy and primary prevention of cardiovascular disease. Ann Intern Med 2000; 133: 933–941.

Pickar

Archer

Kagan

, et al. Safety and benefit considerations for menopausal hormone therapy. Expert Opin Drug Saf 2017; 16: 941–954.

Harman

Vittinghoff

Brinton

, et al. Timing and duration of menopausal hormone treatment may affect cardiovascular outcomes. Am J Med 2011; 124: 199–205.

Writing Group for the Women's Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the women’s health initiative randomized controlled trial. JAMA 2002; 288: 321–333.

Allison

Manson

Langer

, et al. Oophorectomy, hormone therapy, and subclinical coronary artery disease in women with hysterectomy: the Women’s Health Initiative coronary artery calcium study. Menopause 2008; 15: 639–647.

10.

Giordano

Hage

Xing

, et al. Estrogen and cardiovascular disease: is timing everything? Am J Med Sci 2015; 350: 27–35.

11.

Stewart

Black

Choosing a combined oral contraceptive pill. Aust Prescr 2015; 38: 6–11.

12.

Fruzzetti

Trémollieres

Bitzer

An overview of the development of combined oral contraceptives containing estradiol: focus on estradiol valerate/dienogest. Gynecol Endocrinol 2012; 28: 400–408.

13.

H-M

Chang

H-M

Leung

PCK

. Gonadotropin-releasing hormone analogs: mechanisms of action and clinical applications in female reproduction. Front Neuroendocrinol. 2021; 60: 100876.

14.

Dinger

Bardenheuer

Assmann

International active surveillance study of women taking oral contraceptives (INAS-OC Study). BMC Med Res Methodol 2009; 9: 77.

15.

Dinger

Heinemann Lothar

, et al. The safety of a drospirenone-containing oral contraceptive: final results from the European Active Surveillance Study on oral contraceptives based on 142,475 women-years of observation. Contraception 2007; 75: 344–354.

16.

Dinger

Do Minh

Heinemann

Impact of estrogen type on cardiovascular safety of combined oral contraceptives. Contraception 2016; 94: 328–339.

17.

Dinger

Möhner

Heinemann

Cardiovascular risks associated with the use of drospirenone-containing combined oral contraceptives. Contraception 2016; 93: 378–385.

18.

Dinger

Minh

Buttmann

, et al. Effectiveness of oral contraceptive pills in a large U.S. cohort comparing progestogen and regimen. Obstet Gynecol 2011; 117: 33.

19.

Rothman

Poole

A strengthening programme for weak associations. Int J Epidemiol 1988; 17: 955–959.

20.

Guo

Frase

. Propensity score analysis: statistical methods and applications. (Advanced Quantitative Techniques in the Social Sciences, 11). 2nd ed. Los Angeles: Sage Publications Inc.

21.

Rosenbaum

Rubin

DB.

The central role of the propensity score in observational studies for causal effects. Biometrika 1983; 70: 41–55.

22.

SAS Institute Inc. The SAS system for Windows. Cary, NC: SAS Institute Inc., 2013.

23.

Kat

de, Dam

Onland-Moret

, et al. Unraveling the associations of age and menopause with cardiovascular risk factors in a large population-based study. BMC Med 2017; 15: 2.

24.

Atsma

Bartelink

Grobbee

, et al. Postmenopausal status and early menopause as independent risk factors for cardiovascular disease: a meta-analysis. Menopause 2006; 13: 265–279.

25.

Kuh

Langenberg

Hardy

, et al. Cardiovascular risk at age 53 years in relation to the menopause transition and use of hormone replacement therapy: a prospective British birth cohort study. BJOG 2005; 112: 476–485.

26.

As-Sanie

Becker

Johnson

, et al. Efficacy and safety of relugolix combination therapy in women with endometriosis-associated pain: phase 3 randomized, double-blind, placebo-controlled study (spirit 2). Fertil Steril 2020; 114: e77.

27.

Lamb

YN.

Elagolix: first global approval. Drugs 2018; 78: 1501–1508.

28.

Pohl

Marchand

Fawkes

, et al. Gonadotropin-releasing hormone receptor antagonist mono- and combination therapy with estradiol/norethindrone acetate add-back: pharmacodynamics and safety of OBE2109. J Clin Endocrinol Metab 2018; 103: 497–504.

29.

Schlaff

Ackerman

Al-Hendy

, et al. Elagolix for heavy menstrual bleeding in women with uterine fibroids. N Engl J Med 2020; 382: 328–340.

30.

Pohl

Marchand

Bell

, et al. Effects of combined GnRH receptor antagonist linzagolix and hormonal add-back therapy on vaginal bleeding-delayed add-back onset does not improve bleeding pattern. Reprod Sci 2020; 27: 988–995.

31.

Dinger

Möhner

Heinemann

Cardiovascular risk associated with the use of an etonogestrel-containing vaginal ring. Obstet Gynecol 2013; 122(4): 800–808.

32.

Junge

Mellinger

Parke

, et al. Metabolic and haemostatic effects of estradiol valerate/dienogest, a novel oral contraceptive: a randomized, open-label, single-centre study. Clin Drug Investig 2011; 31: 573–584.

33.

Klipping

Duijkers

Parke

, et al. Hemostatic effects of a novel estradiol-based oral contraceptive: an open-label, randomized, crossover study of estradiol valerate/dienogest versus ethinylestradiol/levonorgestrel. Drugs R D 2011; 11: 159–170.

34.

Nelson

Parke

Mellinger

, et al. Efficacy and safety of a combined oral contraceptive containing estradiol valerate/dienogest: results from a clinical study conducted in North America. J Womens Health (Larchmt) 2014; 23: 204–210.

35.

Risk Factors for Venous Thromboembolism (VTE), https://www.heart.org/en/health-topics/venous-thromboembolism/risk-factors-for-venous-thromboembolism-vte (Accessed 24 July 2019).

36.

Fewell

Davey Smith

Sterne

JAC

. The impact of residual and unmeasured confounding in epidemiologic studies: a simulation study. Am J Epidemiol 2007; 166: 646–655.

37.

Danziger

Zimolzak

AJ.

Secondary analysis of electronic health records: residual confounding lurking in big data: a source of error. Cham, CH, Springer, 2016.

Thromboembolic safety profile of low-dose estradiol (valerate) in combined hormonal preparations: Implications for the development of new hormonal endometriosis and uterine fibroid therapies

Abstract

Background:

Objective:

Methods:

Results:

Conclusion:

Keywords

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References