How to Reduce the Main Risk of Menopausal Hormone Therapy (MHT, HRT, HT)

Most societies with interest in the field of estrogen/progestogen-therapy in peri- and postmenopausal women have now agreed to give this important area of gynecology the name “Menopausal Hormone Therapy” (MHT) instead of “hormone replacement therapy” (HRT) or “hormone therapy” (HT). The different terminology

there is no difference between the use of CEE and E2, if both given orally. Even a reduction of breast cancer, which has been shown with CEE in the WHI (estrogen-only arm) recently has been seen also using E2 in MHT. However, since E2 in contrast to CEE also can be used transdermally (patches, gel), there is a difference in the risk profile: the use of transdermal E2 can reduce the risk of venous thrombosis in contrast to all oral estrogens. So, in patients with increased risk of venous thrombosis (which according to own research is very rare in China in contrast to Western World!), the use of patches or gels delivering E2 through the skin directly in the systemic system urgently is recommended.

Progestogens: Which choice in MHT considering breast, endometrium and cardiovascular system?
The primary indication to use a progestogen in MHT is endometrial protection from unopposed estrogen therapy. Adequate progestogen addition urgently is recommended in women with intact uterus. Progestogen is not generally indicated with estrogen therapy post hysterectomy. Progestogens should have a high endometrial efficacy protecting the endometrium from estrogen induced hyperproliferation which could lead via hyperplasia to endometrial cancer. Clinically the addition to estrogen replacement should lead to regular bleeding pattern in sequential MHT and rapid amenorrhoe in continuous combined MHT.
In addition the most important criteria for the choice of a progestogen in MHT is tissue neutrality -no proliferation effects in the breast, neutral in the vasculature and in the metabolic system maintaining beneficial effects in lipids and glucose metabolism.
Progesterone, the physiological progestogen, mostly meets those criteria, and also its retroisomer dydrogesterone, which has stronger endometrial efficacy. In contrast to various synthetic progestogens these more physiological progestogens do not further increase the estrogen induced risk of venous thromboembolism, they do not antagonize the cardiovascular benefit of estrogens, and they may not increase the risk of breast cancer at least up to 8 years treatment, derived from clinical data and main mechanisms of carcinogenicity. A recent Editorial of the journal "Menopause" suggested that the increase in breast risk in WHI could be explained by overexpression of certain membrane-bound steroid receptors.
Own work showed that progesterone does not, in contrast to most synthetic progestogens. Other benefits of certain progestogens like the potency of drosperinone to maintain or even decrease the blood pressure can be considered at an individual basis, e.g. in cardiovascular risk patients, but are of secondary importance.

MHT and the Breast
Physicians and patients mostly fear the risk of breast cancer using MHT although the morbidity and mortality is less than 10% compared to the risk of cardiovascular diseases which is more than 50%. The Women's Health Initiative (WHI) has been the only study for treatment of postmenopausal women with MHT performed within a double-blind placebo-controlled design, assessing clinical endpoints in large patient samples. In the estrogen-only arm for hysterectomized women CEE was used, in the combined arm MPA was added. For the combined MHT (n = 16,608) a relative risk of breast cancer (BC) of 1.26 (95% CI 1.00-1.59) was reported.
No increased risk for women using CEE-only (n = 10,739) was seen, even a significant decrease in compliant women which For the "total evidence" also observational studies should be considered for the choice of an optimal therapy. In about 20 studies using combined MHT an increased BC risk has been observed comparable with the WHI study. At this time only for the use of the natural progesterone or its retroisomer dydrogesterone no increase of BC risk or at least a significantly lower risk has been seen in observational studies in contrast to other tested synthetic progestogens like norethisterone or medroxyprogesterone acetate.
However, certain patients may be of higher risk, and we hope to be able soon to identify those patients by screening for special risk factors in their breast tissue and also now in blood assessing new markers to predict breast cancer risk (like PGRMC1) and their hormonal profiles (search for genotoxic hormone metabolites and genetic polymorphisms of protective enzymes). Nevertheless, MHT with the best benefit/risk ratio should be used to minimize possible risks.