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From the Women’s Health Initiative to the combination of estrogen and selective estrogen receptor modulators to avoid progestin addition
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ARTICLE IN PRESS Maturitas xxx (2015) xxx–xxx
Contents lists available at ScienceDirect
Maturitas journal homepage: www.elsevier.com/locate/maturitas
Review article
From the Women’s Health Initiative to the combination of estrogen and selective estrogen receptor modulators to avoid progestin addition Marie-Cécile Valera, Pierre Gourdy, Florence Trémollières, Jean-Franc¸ois Arnal ∗ U1048- I2MC Inserm and Université Toulouse III, Toulouse and Toulouse University Hospital, Toulouse, France
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Article history: Received 10 July 2015 Accepted 13 July 2015 Available online xxx Keywords: Estrogen receptor Menopause Tissue selective estrogen complex
a b s t r a c t The female life expectancy rose from an average of 48 years to over 80 years in a century. The decline in the endogenous production of estrogen (especially the main circulating physiological hormone, 17estradiol, E2) at menopause (51 years on average) often leads to functional disorders affecting the quality of life. Estrogen deficiency impacts different tissues and results in an increase of various diseases, such as osteoporosis or cardiovascular diseases. Hormone therapy (HT) for menopause is a rather new challenge which experienced vagaries following the women’s health initiative (WHI) study conducted in largely post-menopausal women. In the first part of this review, we will try to summarize the main conclusions of the WHI trials, in particular the timing effect as well as the deleterious impact of the associated progestin, medroxyprogesterone acetate (MPA). Hormone therapy, particularly the conjugated equine estrogen (CEE) combined with the MPA favor the occurrence of breast cancer, whereas conversely selective estrogen receptor modulators (SERMs, such as tamoxifen or raloxifene) that block the activity of estrogen receptor alpha (ERa) prevent the risk of recurrence of ERa-positive breast cancers. A new strategy of ERa modulation called tissue selective estrogen complex (TSEC), combines (1) CEE to maintain the benefits of estrogen (climacteric symptoms and prevention of osteoporosis) and (2) bazedoxifene, which is not only a SERM, but which also induces a rapid degradation of ERa in the uterus and in the breast, thereby prevents the stimulatory effects of estrogens on epithelial proliferation of these two sex targets. In the second part of this review, we will summarize the recognized benefits of the TSEC approach, and our current knowledge of its potential benefits and risks. © 2015 Elsevier Ireland Ltd. All rights reserved.
Contents 1. 2. 3. 4.
5. 6. 7. 8. 9.
Lessons from the women’s health initiative . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 1.1. Risk of coronary events. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .00 Risk of venous thromboembolism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 Risk of breast cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 Limitations of the WHI study . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 4.1. The age of the participants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 4.2. The use of CEE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 And now, what can we do? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 What are the recognized benefits of this TSEC, and what are its potential benefits and risks balance? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 6.1. Demonstrated beneficial effects of TSEC [11]. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 Potential benefits of the TSEC . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 Potential risks of TSEC . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
∗ Corresponding author. E-mail address: [email protected] (J.-F. Arnal). http://dx.doi.org/10.1016/j.maturitas.2015.07.012 0378-5122/© 2015 Elsevier Ireland Ltd. All rights reserved.
Please cite this article in press as: M.-C. Valera, et al., From the Women’s Health Initiative to the combination of estrogen and selective estrogen receptor modulators to avoid progestin addition, Maturitas (2015), http://dx.doi.org/10.1016/j.maturitas.2015.07.012
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Disclosure/conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
1. Lessons from the women’s health initiative 1.1. Risk of coronary events More than a decade ago, two randomized studies, part of the women’s health initiative (WHI, funded by the National Institute of Health in the USA) have tried to objectify the benefits and risks of hormone therapy (HT). This study had two arms. A first arm included about 16,000 postmenopausal women who were randomized to receive either treatment with conjugated equine estrogens (CEE, Premarin) with medroxyprogesterone acetate (MPA) or placebo [1]. The association of a progestin in women with a uterus is necessary because prolonged treatment with estrogen alone increases the risk of endometrial cancer, while the excess risk can be cleared by the anti-proliferative action of the progestin. After a follow-up of just over 5 years, the study was stopped because it did not allow to confirming the expected benefits, especially in terms of prevention of coronary artery events. Indeed, while observational studies suggested an atheroprotective effect and a prevention of coronary risk [2], this randomized study revealed, on contrary, an increased risk in the group of women who had more than 20 years of menopause at baseline (Fig. 1). These first results discredited HT for a long time. The second arm of the study included hysterectomized postmenopausal women receiving either CEE alone or placebo [3]. After a mean follow up of almost 7 years, this second study showed no worsening of coronary risk, and even a clear tendency to coronary protection in women with less than 10 years since menopause at baseline (Figs 1 and 2). However, the number of subjects was not sufficient to demonstrate a significant coronary prevention with estrogens alone in early postmenopausal women. Accordingly, the various analyzes carried out since the publication of these two studies showed not only a major interaction between the occurrence of coronary events and the age of women at the initiation of the treatment, but also a deleterious impact of the association of MPA to CEE [4,5] on coronary risk. In conclusion, because of these two randomized studies, the issue of coronary protection with hormone therapy remains controversial, although it is now accepted that both the “timing“effect and the combination of estrogen with a progestin play an important, even a decisive role for the lack of coronary pro-
Fig. 1. Relative risk of coronary heart disease in the Women Health Initiative. HT = Hormone Therapy; CEE = conjugated equine estrogens (Premarin® ); MPA = medroxyprogesterone acetate. Adapted from Rossouw et al. [4].
tection in the WHI study. Finally, it can be underlined that such result could have been predicted through the remarkable work of T. Clarkson in cynomolgus monkeys [6,7]. Indeed, both the “timing” effect and the antagonism effect of MPA on the favourable impact of estrogen on coronary atheroma had been previously reported in ovariectomized monkey receiving a cholesterol-rich diet ... albeit the WHI study was already on the way! 2. Risk of venous thromboembolism Another well recognized deleterious effect of estrogen is the increased risk of venous thrombosis and pulmonary embolism. The WHI study confirmed that oral estrogen-progestin combination increases the risk for venous thromboembolism. Interestingly, a non-significant trend towards increased risk was observed in hysterectomized women treated with CEE alone [3]. Numerous data suggest that the oral route of administration of estrogen is a major determinant of this increase in thrombotic events [8]. The confirmation of the neutral effect of non oral estrogen (transdermal patch, transdermal gel) by a randomized trial is however not available. Finally, the risk of stroke is also increased both by CEE only as well as by estrogen plus progestin combination. The pathophysiological mechanisms of the increased risk of venous thrombosis, as well as of stroke, are poorly understood and deserve an effort of modelization in animals. During the 10 first years after menopause, the main risk of death excess due to HT is VT-PE, whereas the risk of stroke increases later in life. 3. Risk of breast cancer The WHI study has provided crucial information on the relationship between HT and breast cancer risk. While the first arm of the WHI study found an increased risk of breast cancer in estrogenprogestin therapy [9], the second arm of the study including women with prior hysterectomy shows that CEE only does not increase the risk of breast cancer, but unexpectedly decreases this risk (with a p value just equal to 0.05) [3]. Unfortunately, the importance of this information was undervalued at the time of its publication because of the discredit of CEE + MPA hormone therapy on coronary risk observed in the WHI which was published earlier in 2002.
Fig. 2. Summary of the coronary risk of HT in observational and intervention studies. HT = Hormone Therapy; CEE = conjugated equine estrogens (Premarin® ); MPA = medroxyprogesterone acetate. *Statistically significant.
Please cite this article in press as: M.-C. Valera, et al., From the Women’s Health Initiative to the combination of estrogen and selective estrogen receptor modulators to avoid progestin addition, Maturitas (2015), http://dx.doi.org/10.1016/j.maturitas.2015.07.012
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4. Limitations of the WHI study 4.1. The age of the participants The prescription of a HT is often motivated to alleviate the climacteric symptoms (hot flushes, night sweats, insomnia, vaginal dryness ...) and/or to prevent osteoporosis. Estrogens are potent agents to prevent postmenopausal bone loss and the microarchitectural damages thereby decreasing the subsequent risk of fracture. Therefore, in clinical practice, the treatment is proposed at the onset of estrogen deficiency signs in early menopause. One can then ask questions about the age of the women in the WHI study, where almost a quarter of the women were over 70 years. The main two reasons for this choice were: (i) First, it was considered unethical to give a placebo to women with climacteric symptoms, and these symptoms were even part of exclusion criteria (which is paradoxical from the point of view of clinical practice); (ii) second, the risk of coronary accident at the age of menopause is very low, while it increases by a factor of about 10 over the next decade, which led to include women over the age of 60-year old. 4.2. The use of CEE While the estrogen used in Europe is essentially estradiol (E2, currently synthesized from phytoestrogens), USA use the “historical” treatment of menopause, namely a mixture of estrogens purified from the urine of pregnant mares (Premarin® ). CEE contains a majority of estrone sulfate, and only 3% of estradiol. The various constituents of Premarin® have the potential to modulate the estrogen receptor (ER) differently from that induced by the natural hormone, estradiol. Thus, since the European prescription habits are different than in the USA, the results of the WHI can not be extrapolated to the European population. Thirteen years after the publication of the first arm of the WHI study, what can be reasonably concluded on the beneficial actions of estrogen in postmenopausal women? First of all, it is indisputable that estrogen treatment is by far the most effective treatment for the climacteric symptoms, and is beneficial effect for bone protection is no longer a matter of discussion. Another lesson revealed by the WHI is the preventive effect of estrogens on the type 2 diabetes, which was very significant in both arms of this study. However, the use of oral estrogens is limited by three main adverse effects: (1) the increase in the incidence of endometrial cancer (in the absence of a progestin); (2) the increase in the incidence of breast cancer (when associated to a progestin); (3) the increase in the frequency of VT-PE events.
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bazedoxifene (BZA) with Premarin® [12]. This treatment has been marketed in the US for one year as Duavee® , and has also been approved by the EMA (http://www.ema.europa.eu/ema/index. jspcurl=pages/medicines/human/medicines/002314/smops/ Positive/human smop 000743.jsp&mid=WC0b01ac058001d127), although it is not yet commercially available in Europe. Finally, it must be underlined that BZA is not only a SERM, but it also induces a rapid degradation of ERa in some tissues, such as the uterus and the breast [13]. 6. What are the recognized benefits of this TSEC, and what are its potential benefits and risks balance? 6.1. Demonstrated beneficial effects of TSEC [11]. Several clinical studies have helped to define the doses at which Premarin® still acts on hot flashes while bazedoxifene efficiently blocks the unwanted effects of estrogen on the sexual targets. Double-blind clinical studies have shown that treatment with TSEC compared to placebo, leads to a significant improvement in symptoms of menopause, including hot flushes, vaginal atrophy and dryness and quality of life. It prevents the effects of estrogen deficiency on bone resorption with a reduction in bone turnover markers and a prevention of bone loss. The results of these studies are detailed in [11]. Finally, after two years of treatment, mammographic density is not changed [14,15]. 7. Potential benefits of the TSEC As mentioned above, while the estrogen plus progestin combination increases the risk of breast cancer in the WHI, hysterectomized women treated with CEE alone (without progestin) developed fewer breast cancer than women receiving placebo. All currently available SERMs (Tamoxifen, Raloxifene) decrease the risk of breast cancer in primary or secondary prevention. In addition, studies of breast cancer cells in culture [16], and in animal models of breast cancer [17], all suggest a protective effect of CEE + BAZ combination, and show an effective blocking of the proliferative effect of Premarin® by BAZ. It can be reasonably expected that the CEE + BZA association will not increase the risk of breast cancer. Nevertheless, the direct demonstration has not been done by a randomized study. The WHI study showed a clear trend toward protection of coronary disease by CEE alone. The interaction between Premarin and BZA is not easy to predict, but, based on modelization in non-human primates which appears well correlated to clinical studies [6,7], if not a protection, at least a neutrality on coronary risk could be expected.
5. And now, what can we do? 8. Potential risks of TSEC Estrogens, particularly CEE in combination with MPA, favor the occurrence of breast cancer, and this risk is not acceptable since the benefits of this association do not balance the adverse effects. Conversely, drugs that block the activity of estrogen receptor alpha (ERa), such as selective estrogen receptor modulators (SERMs, including tamoxifen and raloxifene), or aromatase inhibitors have demonstrated their efficacy in the treatment of breast ERa-positive cancers, and very significantly prevent the risk of recurrence [10]. The ideal HT would be the one that would maintain the beneficial effects of estrogen (climacteric symptoms and prevention of osteoporosis) without any stimulatory effect on epithelial proliferation of the target organs, uterus and the breast. This could be achieved by a new generation of molecules called Tissue Selective Estrogen Complex (TSEC) [11] that combines a SERM to one or more estrogens. In this context, Pfizer has developed the combination of
Unlike the protection provided by estrogens on the arterial side (if estrogens are administered in early menopause), it is now clear that any oral estrogens (either E2, Ethinyl Estradiol, or CEE in combination with a progestin or not), but also SERMs, all increase the risk of venous thromboembolism (TV) and its potentially fatal complication pulmonary embolism (PE), which represents, along with the risk of breast cancer, the main limitation for the prescription of HT. In a randomized trial comparing placebo and CEE + BZA in approximately 2000 postmenopausal women,there was no difference in the risk of VT/EP, although the power of this trial was not sufficient to properly assess this risk, VT accidents being a rare event in early menopause [18]. Finally, the coagulation parameters are slightly modified, and there was no potentiation of hepatic effects
Please cite this article in press as: M.-C. Valera, et al., From the Women’s Health Initiative to the combination of estrogen and selective estrogen receptor modulators to avoid progestin addition, Maturitas (2015), http://dx.doi.org/10.1016/j.maturitas.2015.07.012
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of Premarin/BZA combination compared to the administration of each of these two treatments given alone in the randomized trials that are mentioned above [18]. In order to improve our knowledge of the pathophysiology of the estrogen – thrombotic risk relationship, we are currently working to evaluate the impact of estrogen therapy (E2) in various mouse models of thrombosis [19]. 9. Conclusion The WHI study did not fully allow to answering the question of the coronary protection by estrogens, mainly because of the issue of the therapeutic “window/timing” hypothesis. However, these studies have highlighted the deleterious effect of MPA not only on the coronary risk, but also on the risk of breast cancer. This led to the development of alternative therapeutic strategies to avoid the harmful estrogen-progestin combination effect: the TSECs combine a SERM to conjugated estrogens, the later maintaining the benefits of estrogens (climacteric symptoms and bone protection) while the former prevents their proliferative effects on the uterus and breast. Thus, the Premarin/BZA combination could represent the first menopause treatment which would not increase the risk of breast cancer, although this benefit needs to be directly demonstrated through appropriate clinical trials. With regard to the VTE risk, which is difficult to modelize in or ex vivo, it needs to be clarified through new experimental work as well as the follow-up of women who are given the TSEC Duavee® in the USA. In conclusion, TSEC could allow the “rebirth” of the HT in postmenopausal women, a treatment which was taken by about 50% of the postmenopausal women before the results of the WHI study, but which felt under 10% over the next 12 to 13 years after the publication of this trial.
[4]
[5]
[6] [7]
[8]
[9]
[10]
[11] [12] [13]
[14]
Disclosure/conflict of interest
[15]
JFA received a financial support from Pfizer to study the impact of TSEC in mouse models of thrombosis.
[16]
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Please cite this article in press as: M.-C. Valera, et al., From the Women’s Health Initiative to the combination of estrogen and selective estrogen receptor modulators to avoid progestin addition, Maturitas (2015), http://dx.doi.org/10.1016/j.maturitas.2015.07.012
ARTICLE IN PRESS Maturitas xxx (2015) xxx–xxx
Contents lists available at ScienceDirect
Maturitas journal homepage: www.elsevier.com/locate/maturitas
Review article
From the Women’s Health Initiative to the combination of estrogen and selective estrogen receptor modulators to avoid progestin addition Marie-Cécile Valera, Pierre Gourdy, Florence Trémollières, Jean-Franc¸ois Arnal ∗ U1048- I2MC Inserm and Université Toulouse III, Toulouse and Toulouse University Hospital, Toulouse, France
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Article history: Received 10 July 2015 Accepted 13 July 2015 Available online xxx Keywords: Estrogen receptor Menopause Tissue selective estrogen complex
a b s t r a c t The female life expectancy rose from an average of 48 years to over 80 years in a century. The decline in the endogenous production of estrogen (especially the main circulating physiological hormone, 17estradiol, E2) at menopause (51 years on average) often leads to functional disorders affecting the quality of life. Estrogen deficiency impacts different tissues and results in an increase of various diseases, such as osteoporosis or cardiovascular diseases. Hormone therapy (HT) for menopause is a rather new challenge which experienced vagaries following the women’s health initiative (WHI) study conducted in largely post-menopausal women. In the first part of this review, we will try to summarize the main conclusions of the WHI trials, in particular the timing effect as well as the deleterious impact of the associated progestin, medroxyprogesterone acetate (MPA). Hormone therapy, particularly the conjugated equine estrogen (CEE) combined with the MPA favor the occurrence of breast cancer, whereas conversely selective estrogen receptor modulators (SERMs, such as tamoxifen or raloxifene) that block the activity of estrogen receptor alpha (ERa) prevent the risk of recurrence of ERa-positive breast cancers. A new strategy of ERa modulation called tissue selective estrogen complex (TSEC), combines (1) CEE to maintain the benefits of estrogen (climacteric symptoms and prevention of osteoporosis) and (2) bazedoxifene, which is not only a SERM, but which also induces a rapid degradation of ERa in the uterus and in the breast, thereby prevents the stimulatory effects of estrogens on epithelial proliferation of these two sex targets. In the second part of this review, we will summarize the recognized benefits of the TSEC approach, and our current knowledge of its potential benefits and risks. © 2015 Elsevier Ireland Ltd. All rights reserved.
Contents 1. 2. 3. 4.
5. 6. 7. 8. 9.
Lessons from the women’s health initiative . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 1.1. Risk of coronary events. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .00 Risk of venous thromboembolism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 Risk of breast cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 Limitations of the WHI study . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 4.1. The age of the participants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 4.2. The use of CEE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 And now, what can we do? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 What are the recognized benefits of this TSEC, and what are its potential benefits and risks balance? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 6.1. Demonstrated beneficial effects of TSEC [11]. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 Potential benefits of the TSEC . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 Potential risks of TSEC . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
∗ Corresponding author. E-mail address: [email protected] (J.-F. Arnal). http://dx.doi.org/10.1016/j.maturitas.2015.07.012 0378-5122/© 2015 Elsevier Ireland Ltd. All rights reserved.
Please cite this article in press as: M.-C. Valera, et al., From the Women’s Health Initiative to the combination of estrogen and selective estrogen receptor modulators to avoid progestin addition, Maturitas (2015), http://dx.doi.org/10.1016/j.maturitas.2015.07.012
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Disclosure/conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
1. Lessons from the women’s health initiative 1.1. Risk of coronary events More than a decade ago, two randomized studies, part of the women’s health initiative (WHI, funded by the National Institute of Health in the USA) have tried to objectify the benefits and risks of hormone therapy (HT). This study had two arms. A first arm included about 16,000 postmenopausal women who were randomized to receive either treatment with conjugated equine estrogens (CEE, Premarin) with medroxyprogesterone acetate (MPA) or placebo [1]. The association of a progestin in women with a uterus is necessary because prolonged treatment with estrogen alone increases the risk of endometrial cancer, while the excess risk can be cleared by the anti-proliferative action of the progestin. After a follow-up of just over 5 years, the study was stopped because it did not allow to confirming the expected benefits, especially in terms of prevention of coronary artery events. Indeed, while observational studies suggested an atheroprotective effect and a prevention of coronary risk [2], this randomized study revealed, on contrary, an increased risk in the group of women who had more than 20 years of menopause at baseline (Fig. 1). These first results discredited HT for a long time. The second arm of the study included hysterectomized postmenopausal women receiving either CEE alone or placebo [3]. After a mean follow up of almost 7 years, this second study showed no worsening of coronary risk, and even a clear tendency to coronary protection in women with less than 10 years since menopause at baseline (Figs 1 and 2). However, the number of subjects was not sufficient to demonstrate a significant coronary prevention with estrogens alone in early postmenopausal women. Accordingly, the various analyzes carried out since the publication of these two studies showed not only a major interaction between the occurrence of coronary events and the age of women at the initiation of the treatment, but also a deleterious impact of the association of MPA to CEE [4,5] on coronary risk. In conclusion, because of these two randomized studies, the issue of coronary protection with hormone therapy remains controversial, although it is now accepted that both the “timing“effect and the combination of estrogen with a progestin play an important, even a decisive role for the lack of coronary pro-
Fig. 1. Relative risk of coronary heart disease in the Women Health Initiative. HT = Hormone Therapy; CEE = conjugated equine estrogens (Premarin® ); MPA = medroxyprogesterone acetate. Adapted from Rossouw et al. [4].
tection in the WHI study. Finally, it can be underlined that such result could have been predicted through the remarkable work of T. Clarkson in cynomolgus monkeys [6,7]. Indeed, both the “timing” effect and the antagonism effect of MPA on the favourable impact of estrogen on coronary atheroma had been previously reported in ovariectomized monkey receiving a cholesterol-rich diet ... albeit the WHI study was already on the way! 2. Risk of venous thromboembolism Another well recognized deleterious effect of estrogen is the increased risk of venous thrombosis and pulmonary embolism. The WHI study confirmed that oral estrogen-progestin combination increases the risk for venous thromboembolism. Interestingly, a non-significant trend towards increased risk was observed in hysterectomized women treated with CEE alone [3]. Numerous data suggest that the oral route of administration of estrogen is a major determinant of this increase in thrombotic events [8]. The confirmation of the neutral effect of non oral estrogen (transdermal patch, transdermal gel) by a randomized trial is however not available. Finally, the risk of stroke is also increased both by CEE only as well as by estrogen plus progestin combination. The pathophysiological mechanisms of the increased risk of venous thrombosis, as well as of stroke, are poorly understood and deserve an effort of modelization in animals. During the 10 first years after menopause, the main risk of death excess due to HT is VT-PE, whereas the risk of stroke increases later in life. 3. Risk of breast cancer The WHI study has provided crucial information on the relationship between HT and breast cancer risk. While the first arm of the WHI study found an increased risk of breast cancer in estrogenprogestin therapy [9], the second arm of the study including women with prior hysterectomy shows that CEE only does not increase the risk of breast cancer, but unexpectedly decreases this risk (with a p value just equal to 0.05) [3]. Unfortunately, the importance of this information was undervalued at the time of its publication because of the discredit of CEE + MPA hormone therapy on coronary risk observed in the WHI which was published earlier in 2002.
Fig. 2. Summary of the coronary risk of HT in observational and intervention studies. HT = Hormone Therapy; CEE = conjugated equine estrogens (Premarin® ); MPA = medroxyprogesterone acetate. *Statistically significant.
Please cite this article in press as: M.-C. Valera, et al., From the Women’s Health Initiative to the combination of estrogen and selective estrogen receptor modulators to avoid progestin addition, Maturitas (2015), http://dx.doi.org/10.1016/j.maturitas.2015.07.012
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4. Limitations of the WHI study 4.1. The age of the participants The prescription of a HT is often motivated to alleviate the climacteric symptoms (hot flushes, night sweats, insomnia, vaginal dryness ...) and/or to prevent osteoporosis. Estrogens are potent agents to prevent postmenopausal bone loss and the microarchitectural damages thereby decreasing the subsequent risk of fracture. Therefore, in clinical practice, the treatment is proposed at the onset of estrogen deficiency signs in early menopause. One can then ask questions about the age of the women in the WHI study, where almost a quarter of the women were over 70 years. The main two reasons for this choice were: (i) First, it was considered unethical to give a placebo to women with climacteric symptoms, and these symptoms were even part of exclusion criteria (which is paradoxical from the point of view of clinical practice); (ii) second, the risk of coronary accident at the age of menopause is very low, while it increases by a factor of about 10 over the next decade, which led to include women over the age of 60-year old. 4.2. The use of CEE While the estrogen used in Europe is essentially estradiol (E2, currently synthesized from phytoestrogens), USA use the “historical” treatment of menopause, namely a mixture of estrogens purified from the urine of pregnant mares (Premarin® ). CEE contains a majority of estrone sulfate, and only 3% of estradiol. The various constituents of Premarin® have the potential to modulate the estrogen receptor (ER) differently from that induced by the natural hormone, estradiol. Thus, since the European prescription habits are different than in the USA, the results of the WHI can not be extrapolated to the European population. Thirteen years after the publication of the first arm of the WHI study, what can be reasonably concluded on the beneficial actions of estrogen in postmenopausal women? First of all, it is indisputable that estrogen treatment is by far the most effective treatment for the climacteric symptoms, and is beneficial effect for bone protection is no longer a matter of discussion. Another lesson revealed by the WHI is the preventive effect of estrogens on the type 2 diabetes, which was very significant in both arms of this study. However, the use of oral estrogens is limited by three main adverse effects: (1) the increase in the incidence of endometrial cancer (in the absence of a progestin); (2) the increase in the incidence of breast cancer (when associated to a progestin); (3) the increase in the frequency of VT-PE events.
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bazedoxifene (BZA) with Premarin® [12]. This treatment has been marketed in the US for one year as Duavee® , and has also been approved by the EMA (http://www.ema.europa.eu/ema/index. jspcurl=pages/medicines/human/medicines/002314/smops/ Positive/human smop 000743.jsp&mid=WC0b01ac058001d127), although it is not yet commercially available in Europe. Finally, it must be underlined that BZA is not only a SERM, but it also induces a rapid degradation of ERa in some tissues, such as the uterus and the breast [13]. 6. What are the recognized benefits of this TSEC, and what are its potential benefits and risks balance? 6.1. Demonstrated beneficial effects of TSEC [11]. Several clinical studies have helped to define the doses at which Premarin® still acts on hot flashes while bazedoxifene efficiently blocks the unwanted effects of estrogen on the sexual targets. Double-blind clinical studies have shown that treatment with TSEC compared to placebo, leads to a significant improvement in symptoms of menopause, including hot flushes, vaginal atrophy and dryness and quality of life. It prevents the effects of estrogen deficiency on bone resorption with a reduction in bone turnover markers and a prevention of bone loss. The results of these studies are detailed in [11]. Finally, after two years of treatment, mammographic density is not changed [14,15]. 7. Potential benefits of the TSEC As mentioned above, while the estrogen plus progestin combination increases the risk of breast cancer in the WHI, hysterectomized women treated with CEE alone (without progestin) developed fewer breast cancer than women receiving placebo. All currently available SERMs (Tamoxifen, Raloxifene) decrease the risk of breast cancer in primary or secondary prevention. In addition, studies of breast cancer cells in culture [16], and in animal models of breast cancer [17], all suggest a protective effect of CEE + BAZ combination, and show an effective blocking of the proliferative effect of Premarin® by BAZ. It can be reasonably expected that the CEE + BZA association will not increase the risk of breast cancer. Nevertheless, the direct demonstration has not been done by a randomized study. The WHI study showed a clear trend toward protection of coronary disease by CEE alone. The interaction between Premarin and BZA is not easy to predict, but, based on modelization in non-human primates which appears well correlated to clinical studies [6,7], if not a protection, at least a neutrality on coronary risk could be expected.
5. And now, what can we do? 8. Potential risks of TSEC Estrogens, particularly CEE in combination with MPA, favor the occurrence of breast cancer, and this risk is not acceptable since the benefits of this association do not balance the adverse effects. Conversely, drugs that block the activity of estrogen receptor alpha (ERa), such as selective estrogen receptor modulators (SERMs, including tamoxifen and raloxifene), or aromatase inhibitors have demonstrated their efficacy in the treatment of breast ERa-positive cancers, and very significantly prevent the risk of recurrence [10]. The ideal HT would be the one that would maintain the beneficial effects of estrogen (climacteric symptoms and prevention of osteoporosis) without any stimulatory effect on epithelial proliferation of the target organs, uterus and the breast. This could be achieved by a new generation of molecules called Tissue Selective Estrogen Complex (TSEC) [11] that combines a SERM to one or more estrogens. In this context, Pfizer has developed the combination of
Unlike the protection provided by estrogens on the arterial side (if estrogens are administered in early menopause), it is now clear that any oral estrogens (either E2, Ethinyl Estradiol, or CEE in combination with a progestin or not), but also SERMs, all increase the risk of venous thromboembolism (TV) and its potentially fatal complication pulmonary embolism (PE), which represents, along with the risk of breast cancer, the main limitation for the prescription of HT. In a randomized trial comparing placebo and CEE + BZA in approximately 2000 postmenopausal women,there was no difference in the risk of VT/EP, although the power of this trial was not sufficient to properly assess this risk, VT accidents being a rare event in early menopause [18]. Finally, the coagulation parameters are slightly modified, and there was no potentiation of hepatic effects
Please cite this article in press as: M.-C. Valera, et al., From the Women’s Health Initiative to the combination of estrogen and selective estrogen receptor modulators to avoid progestin addition, Maturitas (2015), http://dx.doi.org/10.1016/j.maturitas.2015.07.012
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of Premarin/BZA combination compared to the administration of each of these two treatments given alone in the randomized trials that are mentioned above [18]. In order to improve our knowledge of the pathophysiology of the estrogen – thrombotic risk relationship, we are currently working to evaluate the impact of estrogen therapy (E2) in various mouse models of thrombosis [19]. 9. Conclusion The WHI study did not fully allow to answering the question of the coronary protection by estrogens, mainly because of the issue of the therapeutic “window/timing” hypothesis. However, these studies have highlighted the deleterious effect of MPA not only on the coronary risk, but also on the risk of breast cancer. This led to the development of alternative therapeutic strategies to avoid the harmful estrogen-progestin combination effect: the TSECs combine a SERM to conjugated estrogens, the later maintaining the benefits of estrogens (climacteric symptoms and bone protection) while the former prevents their proliferative effects on the uterus and breast. Thus, the Premarin/BZA combination could represent the first menopause treatment which would not increase the risk of breast cancer, although this benefit needs to be directly demonstrated through appropriate clinical trials. With regard to the VTE risk, which is difficult to modelize in or ex vivo, it needs to be clarified through new experimental work as well as the follow-up of women who are given the TSEC Duavee® in the USA. In conclusion, TSEC could allow the “rebirth” of the HT in postmenopausal women, a treatment which was taken by about 50% of the postmenopausal women before the results of the WHI study, but which felt under 10% over the next 12 to 13 years after the publication of this trial.
[4]
[5]
[6] [7]
[8]
[9]
[10]
[11] [12] [13]
[14]
Disclosure/conflict of interest
[15]
JFA received a financial support from Pfizer to study the impact of TSEC in mouse models of thrombosis.
[16]
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Please cite this article in press as: M.-C. Valera, et al., From the Women’s Health Initiative to the combination of estrogen and selective estrogen receptor modulators to avoid progestin addition, Maturitas (2015), http://dx.doi.org/10.1016/j.maturitas.2015.07.012