The February issue of “Climacteric” brought us various excellent reviews on the “Therapies for menopausal management – current status”, with, in our view, a “key statement” from Langer et al.  on the use of HRT, important contributions for “compounded bioidentical” products , and a review on misunderstandings and misconception of “bioidentical hormones” summarized by Stanczyk et al. . Despite limited data, the use of phytoestrogens may have a certain benefit on postmenopausal health, as reviewed by Rowe and Baber . Similar conclusions came from the review on “Traditional Chinese Medicine” from Wang et al , stressing the lack of good, randomized studies. From our own experience shared with other Chinese clinicians, Qin, Ruan, Ju et al . acupuncture in particular can be of great value and certainly avoids the possible risks of HRT. However, all those alternatives only can treat (certain) menopausal symptoms and, in contrast to HRT, cannot prevent fracture, do not reduce coronary heart disease, the incidence of diabetes, do not prevent dementia and are lacking the many beneficial effects of estrogen in almost all organ systems .
When asking “how to reduce the risk of HRT”, the four main risks observed in the most important trial, the Women’s Health Initiative (WHI), should be considered [7,8]: cardiovascular risk, venous thromboembolism, and breast cancer. In the following we discuss four main issues:
- Early Start: The “window of opportunity” means not to start in a situation where arterial plaques have already been produced . The placebo-controlled “Early vs. Late Intervention Trial with Estradiol (ELITE) demonstrated reduced progression of atherosclerosis with E2/progesterone < 6 years vs. >10 years postmenopausal , and a Finnish Registry Study in 489,105 postmenopausal women with 3.3 million exposure years of HRT observed lower cardiovascular mortality with E2-only or E2/progestogen in women < 60 years compared to older women . The Danish Osteoporosis Prevention Study (DOPS) found a 52% significant reduction of heart failure, myocardial infarction and death and no increased risk of stroke after 10 years with E2/NETA . At least four meta-analyses and a Cochrane systematic review confirm this principle of the “window of opportunity” .
- Choice of Estrogen: In the WHI, the estrogen component was “conjugated equine estrogens” (CEE). This is a mixture of at least 10 different biologically active components, whereby about 30% are only produced in horses and not in women. From a pharmacological point of view, it is not really possible to predict effects of any therapy which uses such a mixture [12,13]. In addition, we are not able to monitor therapy by assessing hormone levels. Therefore, the physiological estrogen estradiol (E2) has been preferably used in HRT for many years, especially in Europe , and is now being increasingly recommended in other countries such in China. The use of transdermal E2 can reduce the risk of venous thrombosis in contrast to all oral estrogens [1,14,15]. Patches or gels delivering E2 are therefore recommended in patients with increased risk of venous thrombosis [1,14,15].
- Choice of Progestogen: Adequate progestogen addition is urgently recommended in women with an intact uterus, the only indication for the progestogen addition. The dosage should be individually primarily dependent on the estrogen type and dose, for example as reviewed elsewhere regarding the choice of transdermal E2 combined with the various available progestogens . This initially may be more frequently necessary using progesterone instead of synthetic progestogens. Since dydrogesterone has stronger endometrial efficacy compared to progesterone , we frequently use it in China where we see in general more bleeding problems compared to Western women. In contrast to various synthetic progestogens, these more physiological progestogens do not further increase the estrogen induced risk of venous thromboembolism, do not antagonize the cardiovascular benefit of estrogens, and they may not increase the risk of breast cancer with at least up to 5-8 years of treatment [14,17-20].
In the WHI for CEE/MPA an increased risk of breast cancer (BC) was reported , in contrast to CEE-only , with significant decrease in compliant women , confirmed by several post-analyses up to 2020 as summarized by Langer et al . Their review also includes the recent meta-analysis of the “Collaborative Oxford Group (2019) which, however, in our view is especially subject to a variety of bias and confounding: About 40% came from the “million women study”, one of the worst studies using HRT .
- Reduction of BC risk: To minimize this risk, we recommend further research to exclude at least certain types of hormone-dependent increase in BC risk, as we have done within the last decade: We were first able to demonstrate that in presence of certain membrane-bound receptors (PGRMC1), synthetic progestogens but not progesterone stimulate estrogen-induced breast cell proliferation, using different types of BC cells and testing all available progestogens . An Editorial by FZ Stanczyk discussing our initial in-vitro research  suggested that the increase in breast risk in WHI could be explained by overexpression of these receptors, which motivated us to perform the next step and confirm these results in animal research [25,26]. We demonstrated a worst prognosis in patients with BC if these receptors are present in BC tissue . As we were recently able to confirm this predictive value from assessing PGRMC1 in the blood of BC patients , this could be an option to screen risk patients before starting HRT. Other research, for example assessing potential carcinogenic quinones as E2-metabolites, especially in situations of excessive oxidative stress such as induced by a poor environment, could lead to other mechanisms for BC development being excluded, which also could have consequences for the choice of HRT, since transdermal E2 use can avoid the production of these metabolites .
In absolute numbers the excessive BC risk is small, a rare event according to WHO criteria . However, we have to provide our patients with this information, and this risk indeed remains the only important risk which even cannot be excluded using progesterone or dydrogesterone (20,30). The solution could be to consider the individual risk dependent on known risk factors such as family risk, obesity, smoking etc. and to screen risk patients regarding certain well-defined mechanisms for BC development.
Prof. Xiangyan Ruan, MD, PhD
Prof. Alfred O. Mueck; MD, PharmD, PhD
Beijing Obstetrics and Gynaecology Hospital,
Capital Medical University, China
and Department of Women’s Health
University Hospitals of Tuebingen, Germany
- Langer RD, Hodis HN, Lobo RA, Allison MA. Hormone Replacement Therapy – where are we now? Climacteric. 2021;24(1):3-10.
- Stuenkel CA. Compounded menopausal hormone therapy – a physician perspective. Climacteric. 2021;24(1):11-18.
- Stanczyk FZ, Matharu H, Winer SA. Bioidentical hormones. Climacteric. 2021;24:38-45.
- Rowe IJ, Baber RJ. The effects of phytoestrogens on postmenopausal health. Climacteric. 2021;24(1):57-63.
- Wang YP, Yu Q. The treatment of menopausal symptoms by traditional Chinese medicine in Asian countries. Climacteric. 2021;24(1):64-67.
- Qin Y, Ruan X, Ju R, Pang J, et al. Acupuncture for menopausal symptoms in Chinese women: a systematic review. Climacteric. 2021;24(1):68-73.
- Rossouw JE, Anderson GL, Prentice RL, et al; Writing Group for the Women’s Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women. JAMA. 2002;288(3):321-333.
- Anderson GL, Limacher M, Assaf AR, et al; Women’s Health Initiative Steering Committee. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy. JAMA. 2004;291(14):1701-1712.
- Hodis HN, Mack WJ, Henderson VW, et al; ELITE Research Group. Vascular effects of early vs late postmenopausal treatment with estradiol. N Engl J Med. 2016;374(13):1221-1231.
- Mikkola TS, Ruomikowski P, Lyytinen H, et al. Estradiol-based postmenopausal hormone therapy and risk of cardiovascular and all-cause mortality. Menopause. 2015;22(9):976-983.
- Schierbeck LL, Rejnmark L, Tofteng CL, et al. Effect of hormone replacement therapy on cardiovascular events in recently postmenopausal women: randomised trial. BMJ. 2012;345:e6409.
- Lippert TH, Seeger H, Mueck AO. Clinical and pharmacological characteristics of the conjugated equine estrogens. Drug Therapy. 1999;17:362-364.
- Bhavnani BR, Stanczyk FZ. Pharmacology of conjugated equine estrogens: efficacy, safety and mechanism of action. J Steroid Biochem Mol Biol. 2014;142:16-29.
- L’hermite M, Simoncini T, Fuller S, Genazzani AR. Could transdermal estradiol+progesterone be a safer postmenopausal HRT? A review. Maturitas. 2008;60(3-4):185-201.
- Baber RJ, Panay N, Fenton A; IMS Writing Group. 2016 IMS Recommendations on women’s midlife health and menopause hormone therapy. Climacteric 2016;19(2):109-150.
- Mueck AO, Römer T. Choice of progestogen for endometrial protection in combination with transdermal estradiol in menopausal women. Horm Mol Biol Clin Investig. 2018;37(2).
- Mueck AO, Seeger H, Bühling KJ. Use of dydrogesterone in hormone replacement therapy. Maturitas. 2009;65 Suppl 1:S51-60.
- Fournier A, Berrino F, Riboli E, Avenel V, Clavel-Chapelon F. Breast cancer risk in relation to different types of HRT in the E3N-EPIC cohort. Int J Cancer. 2005;114(3):448-454.
- Fournier A, Berrino F, Clavel-Chapelon F. Unequal risks for breast cancer associated with different hormone therapies: results from the E3N cohort study. Breast Cancer Res Treat. 2008;107(1):103-111.
- Ruan X, Mueck AO. Choice of progestogen for HRT in menopausal women: Main issue breast cancer risk. Horm Mol Biol Clin Investig. 2018;37(1).
- Stefanik ML, Anderson GL, Margolis KL, et al; WHI Investigators. Effects of conjugated equine estrogens on breast cancer and mammography screening in postmenopausal women with hysterectomy. JAMA. 2006;295(14):1647-1657.
- Stevenson JC, Farmer RDT. HRT and breast cancer: a million-women study ride again. Climacteric. 2020;23(3):226-228.
- Ruan X, Neubauer H, Yang Y, et al. Progestogens and membrane-initiated effects on the proliferation of human breast cancer cells. Climacteric. 2012;15(5):467-472.
- Stanczyk FZ. Can the increase in breast cancer observed in the estrogen plus progestin arm of the Women’s Health Initiative trial be explained by progesterone receptor membrane component 1? Menopause. 2011;18(8):833-834.
- Zhao Y, Ruan X, Wang H, et al. The presence of membrane-bound progesterone receptor induces growth of breast cancer with norethisterone but not with progesterone: a xenograft model. Maturitas. 2017;102:26-33.
- Ruan X, Gu M, Cai G, et al. Progestogens and PGRMC1-dependent breast cancer tumor growth: An in-vitro and xenograft study. Maturitas. 2019;123:1-8.
- Ruan X, Zhang Y, Mueck AO, et al. Increased expression of progesterone membrane component 1 is associated with aggressive phenotype and poor prognosis in ER-positive and –negative breast cancer. Menopause. 2017;24(2):203-209.
- Ruan X, Cai G, Wei Y, et al. Association of circulating Progesterone Receptor Membrane Component-1 (PGRMC1) with breast tumor characteristics and comparison with known tumor markers. Menopause. 2020;27(2):183-193.
- Mueck AO, Seeger H, Shapiro S. Risk of breast cancer during hormone replacement therapy: mechanisms. Horm Mol Biol Clin Invest. 2010;3(1):329–339.
- Fournier A, Fabre A, Mesrine S, et al. Use of different postmenopausal hormone therapies and risk of histology- and hormone receptor-defined invasive breast cancer. J Clin Oncology. 2008;26(8):1260-1268.
- Langer RD, Hodis HN, Lobo RA, Allison MA. Hormone Replacement Therapy – where are we now? Climacteric. 2021;24(1):3-10.
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