madman
Super Moderator
Primary choice of estrogen and progestogen as components for HRT: a clinical pharmacological view (2022)
X. Ruan & A. O. Mueck
ABSTRACT
Prescribing hormone replacement therapy (HRT) requires consideration of the selection of its two components, estrogen, and progestogen. In terms of estrogen, the decision is mainly whether to use estradiol (E2) or conjugated equine estrogens (CEE). These are the components needed to efficiently treat climacteric symptoms or/and prevent osteoporosis, currently the only labeled indications. There is still controversy regarding the adequate dosages comparing E2 and CEE; however, the consensus is that the differences in the efficacy of E2 and CEE are not a real issue. Therefore, other criteria have to be used. The first reason to add the progestogen is to avoid the development of endometrial cancer (i.e. to achieve ‘endometrial safety’). Any available ‘fixed-combined’ HRT preparation has to be tested for sufficient endometrial efficacy because the first question the health authorities ask before product registration relates to endometrial safety. We can generally rely on the endometrial safety of these fixed-combined products. However, it could be that we want to use ‘free’ combinations, which are necessary if we use transdermal E2 (patches, gel, spray), but also to individualize schedules, for example when treating bleeding problems. The question here is how to attain knowledge about the endometrial efficacy of the different progestogens and how to monitor therapy. We will try to answer these two questions from a ‘clinical pharmacology’ point of view, as a discipline that preferably considers pharmacological properties, but also relates to clinical practice, to achieve individualized therapy with optimal efficacy, best tolerability, and minimal risks.
Which studies should we use for the choice of HRT?
Choice of the estrogen: use of CEE still up to date?
Choice of progestogen: primarily dependent on endometrial efficacy
Open questions to the use of progesterone
Outlook and conclusion
Besides the more ‘classical pharmacological view’ – that is, separating issues according to pharmacokinetics and pharmacodynamics – there are new tools, like ‘pharmacogenomics’, which might come to some different conclusions evaluating the action of hormones. However, regarding CEE the problem remains that due to the variability of the mixture and the necessity to consider at least 10 different components, any prediction of the net effect for the individual patient seems to be difficult or even impossible. Furthermore, it seems unlikely that the assessment from other options of pharmacological view should result in advantages over the use of the physiological hormone E2 since primarily its deficit is the reason for any use of HRT.
Besides the type of estrogen, the dosage is important, which for example should be lower in obese and in older patients. To reduce cardiovascular risks, for any HRT early initiation is most important; the concept of the ‘window of opportunity is now in general accepted. For the choice of HRT in the future, we would like to predict whether it can be further verified that, if the use of progesterone can avoid the increased risk of breast cancer in contrast to (certain?) synthetic progestogens, at least in women expressing these predictive markers, the answer regarding the ‘first choice’ of the progestogen component will be ‘progesterone’, together with closer monitoring of endometrial safety. This also considers the mostly neutral metabolic and vascular effects of progesterone, which do not antagonize the estrogenic cardiovascular benefits, in contrast to synthetic progestogens such as MPA [66], the progestogen used in the WHI trial. What already seems clear is the choice of the estrogen component in cardiovascular risk patients, which should be transdermal E2.
However, as we have stressed already in our introduction, the main focus of our review is not on this combination because this has been discussed in many other recent papers. We rather wanted to add another view, with our main conclusion to choose E2 instead of CEE and regarding the progestogen component to consider in the first line the endometrial efficacy and tools for endometrial monitoring.
Limitations
There are some limitations regarding our view of the choice of HRT. First, in many countries, there are significant limitations of available HRT options, which means that prescribing has to be realistic and pragmatic. Second, many women prefer oral HRT even after the benefits and risks have been explained, and this should be offered as an option unless there are specific risk factors (e.g. increased risk of venous thromboembolism). As we have reported on the basis of observation of millions of patients, this risk especially in China (and maybe also in other Asian countries) is very low [67]. So still every day about 100 women in our Chinese specialized Menopause Clinic indeed get oral HRT. Third theoretical pharmacokinetics and pharmacodynamics do not always translate into the same efficacy and safety in each individual
X. Ruan & A. O. Mueck
ABSTRACT
Prescribing hormone replacement therapy (HRT) requires consideration of the selection of its two components, estrogen, and progestogen. In terms of estrogen, the decision is mainly whether to use estradiol (E2) or conjugated equine estrogens (CEE). These are the components needed to efficiently treat climacteric symptoms or/and prevent osteoporosis, currently the only labeled indications. There is still controversy regarding the adequate dosages comparing E2 and CEE; however, the consensus is that the differences in the efficacy of E2 and CEE are not a real issue. Therefore, other criteria have to be used. The first reason to add the progestogen is to avoid the development of endometrial cancer (i.e. to achieve ‘endometrial safety’). Any available ‘fixed-combined’ HRT preparation has to be tested for sufficient endometrial efficacy because the first question the health authorities ask before product registration relates to endometrial safety. We can generally rely on the endometrial safety of these fixed-combined products. However, it could be that we want to use ‘free’ combinations, which are necessary if we use transdermal E2 (patches, gel, spray), but also to individualize schedules, for example when treating bleeding problems. The question here is how to attain knowledge about the endometrial efficacy of the different progestogens and how to monitor therapy. We will try to answer these two questions from a ‘clinical pharmacology’ point of view, as a discipline that preferably considers pharmacological properties, but also relates to clinical practice, to achieve individualized therapy with optimal efficacy, best tolerability, and minimal risks.
Which studies should we use for the choice of HRT?
Choice of the estrogen: use of CEE still up to date?
Choice of progestogen: primarily dependent on endometrial efficacy
Open questions to the use of progesterone
Outlook and conclusion
Besides the more ‘classical pharmacological view’ – that is, separating issues according to pharmacokinetics and pharmacodynamics – there are new tools, like ‘pharmacogenomics’, which might come to some different conclusions evaluating the action of hormones. However, regarding CEE the problem remains that due to the variability of the mixture and the necessity to consider at least 10 different components, any prediction of the net effect for the individual patient seems to be difficult or even impossible. Furthermore, it seems unlikely that the assessment from other options of pharmacological view should result in advantages over the use of the physiological hormone E2 since primarily its deficit is the reason for any use of HRT.
Besides the type of estrogen, the dosage is important, which for example should be lower in obese and in older patients. To reduce cardiovascular risks, for any HRT early initiation is most important; the concept of the ‘window of opportunity is now in general accepted. For the choice of HRT in the future, we would like to predict whether it can be further verified that, if the use of progesterone can avoid the increased risk of breast cancer in contrast to (certain?) synthetic progestogens, at least in women expressing these predictive markers, the answer regarding the ‘first choice’ of the progestogen component will be ‘progesterone’, together with closer monitoring of endometrial safety. This also considers the mostly neutral metabolic and vascular effects of progesterone, which do not antagonize the estrogenic cardiovascular benefits, in contrast to synthetic progestogens such as MPA [66], the progestogen used in the WHI trial. What already seems clear is the choice of the estrogen component in cardiovascular risk patients, which should be transdermal E2.
However, as we have stressed already in our introduction, the main focus of our review is not on this combination because this has been discussed in many other recent papers. We rather wanted to add another view, with our main conclusion to choose E2 instead of CEE and regarding the progestogen component to consider in the first line the endometrial efficacy and tools for endometrial monitoring.
Limitations
There are some limitations regarding our view of the choice of HRT. First, in many countries, there are significant limitations of available HRT options, which means that prescribing has to be realistic and pragmatic. Second, many women prefer oral HRT even after the benefits and risks have been explained, and this should be offered as an option unless there are specific risk factors (e.g. increased risk of venous thromboembolism). As we have reported on the basis of observation of millions of patients, this risk especially in China (and maybe also in other Asian countries) is very low [67]. So still every day about 100 women in our Chinese specialized Menopause Clinic indeed get oral HRT. Third theoretical pharmacokinetics and pharmacodynamics do not always translate into the same efficacy and safety in each individual
