madman
Super Moderator
Hard to believe I missed posting this one been sitting on this paper since 2022!
ABSTRACT
Introduction
Estrogens used in women’s healthcare have been associated with increased risks of venous thromboembolism (VTE) and breast cancer. Estetrol (E4), an estrogen produced by the human fetal liver, has recently been approved for the first time as a new estrogenic component of a novel combined oral contraceptive (E4/drospirenone [DRSP]) for over a decade. In phase 3 studies, E4/DRSP showed good contraceptive efficacy, a predictable bleeding pattern, and a favorable safety and tolerability profile.
Areas covered
This narrative review discusses E4ʹs pharmacological characteristics, mode of action,and the results of preclinical and clinical studies for contraception, as well as for menopause and oncology.
Expert opinion
Extensive studies have elucidated the properties of E4 that underlie its favorable safety profile. While classical estrogens (such as estradiol) exert their actions via both activation of nuclear and membrane estrogen receptor α (ERα), E4 presents a specific profile of ERα activation: E4 binds and activates nuclear ERα but does not induce the activation of membrane ERα signaling pathways in specific tissues. E4 has a small effect on normal breast tissue proliferation and minimally affects hepatic parameters. This distinct profile of ERα activation, uncoupling nuclear and membrane activation, is unique.
2. Introduction to estetrol (E4)
2.1. Chemistry
2.2. Pharmacokinetics
2.3. Mode of action of E4
2.3.1. Introduction to the molecular mechanisms of action of estrogens
2.3.2. The mode of action of E4: E4 has tissue specific properties
3. Phase 2 clinical trial results
3.1. Contraception
3.2 Enhanced safety: tissue-specific effects of E4 in the liver (hemostasis, lipids, renin-angiotensin-aldosterone system), breast, and cardiovascular system
3.2.1. Impact of E4 on hemostasis
3.2.2. Impact on lipids
3.2.3. Impact on the renin-angiotensin aldosterone system
3.2.4. Impact of E4 on normal and malignant breast tissue
3.2.5. Nuclear ERα mediated cardiovascular protection
4. Phase 3 clinical trial results
5. Other therapeutic applications for E4
5.1. Hormone replacement for menopause
5.2. Perimenopause, central nervous system disorders,vascular protection, and oncology
6. Conclusions
Natural and synthetic estrogens have been used for decades in contraception and MHT, with known but rare potential adverse events, such as increasing thrombosis and breast tissue proliferation. New estrogens with a better safety profile are an unmet medical need. The unique pharmacologic properties and molecular mechanisms of action of E4 suggest that it would provide a better benefit/risk ratio compared to other estrogens.
E4 is a native estrogen with differential action in tissues. The molecular nuclear mode of action of E4 is very similar to the actions of classic estrogens and is not like SERMs. Unlike other estrogens, the tissue selectivity of E4 is potentially a consequence of the differential activation of the nuclear and membrane ERα pathways; E4 does not stimulate the membrane ERα and antagonizes the membrane effects induced by E2. Clinical studies demonstrate that E4, in contrast to EE or E2, has little or no effect on circulating SHBG, angiotensinogen, triglycerides, or coagulation factors. This limitedi mpact of E4 on the liver represents an important facet of this innate molecule, which may have a safer profile regarding the risk of thromboembolic events.
The development of E4 in contraception, menopause, and prevention/treatment of hypoxic-ischemic encephalopathy is an example of how basic research and preclinical studies have guided the clinical characterization of E4 activities in humans and enabled precise delineation of its differences from the three other natural estrogens. These results also highlight the importance of the estrogenic component of COCs; the specific estrogen/progestin combination has an impact on the total estrogenicity of the formulation, its clinical use, and linked benefit/risk balance. Both preclinical and clinical data have shown the cardiovascular safety of E4, acting as a classic estrogen to induce a series of cardiovascular/arterial benefits through activation of the ERα nuclear pathway. At the sametime, E4 may pose less of a risk on thromboembolic events, such as VTE due to its neutral profile on the synthesis of hemostatic proteins. Finally, E4 has been shown to have a lower impact on breast tissue compared to other estrogens. Nevertheless, the effects of the tissue selectivity of E4, in particular in the liver and breast, will require further molecular studies for validation.
7. Expert opinion
With its unique profile of activity, E4 is a new chemical entity, distinct from all other estrogens as recognized by the EMA, FDA, and TGA. This estrogen, first described over 80 years, could fill the gap for a safer hormone therapy to address the needs of women during the reproductive (contraception), perimenopause, and menopause years. With its minimal impact on liver metabolism, hemostasis, lipids, RAAS, and breast, a low risk of drug–drug interactions, and its favorable VTE risk profile, E4 has the potential to be a safer estrogen.
Overall, E4 in combination with DRSP offers excellent cycle control with additional safety in a contraceptive indication.
Previous attempts to reduce the increased risk of VTE by decreasing the EE content resulted in poor cycle control and miserable tolerance. Replacement of EE by E2 also resulted in an increase in high rates of transient amenorrhea, spotting, and bleeding. This is the consequence of the transformation of E2 in the endometrium into estrone by the 17-β hydroxysteroid dehydrogenase type 2 induced by all progestins present inall COCs [135]. E4 escapes this inactivation, stabilizes the endometrium and provides a bleeding/spotting profile equivalent to that of the best EE containing COCs, together with comparable efficacy and tolerance, but with the potential for a considerably improved safety profile.
Many women will spend ≥40% of their lives in postmenopause. Current guidelines still highlight the need to inform women that there could be an increased risk of breast cancer, stroke, and VTE associated with MHT. They recommend limiting the MHT to the shortest possible period. E4 alone or in combination could become an ideal chronic treatment for aging women beyond a short-term treatment to alleviate hot flushes only. Other menopausal symptoms including changes in mood, sleep patterns, memory, bodyshape, as well as the onset urogenital symptoms can also be very distressing and affect a woman’s personal and social life.
Early-stage clinical oncologic studies point also to the safety of this new estrogen. We therefore consider that the introduction of E4 in women’s healthcare is a breakthrough with multiple therapeutic opportunities throughout women’s lives.
ABSTRACT
Introduction
Estrogens used in women’s healthcare have been associated with increased risks of venous thromboembolism (VTE) and breast cancer. Estetrol (E4), an estrogen produced by the human fetal liver, has recently been approved for the first time as a new estrogenic component of a novel combined oral contraceptive (E4/drospirenone [DRSP]) for over a decade. In phase 3 studies, E4/DRSP showed good contraceptive efficacy, a predictable bleeding pattern, and a favorable safety and tolerability profile.
Areas covered
This narrative review discusses E4ʹs pharmacological characteristics, mode of action,and the results of preclinical and clinical studies for contraception, as well as for menopause and oncology.
Expert opinion
Extensive studies have elucidated the properties of E4 that underlie its favorable safety profile. While classical estrogens (such as estradiol) exert their actions via both activation of nuclear and membrane estrogen receptor α (ERα), E4 presents a specific profile of ERα activation: E4 binds and activates nuclear ERα but does not induce the activation of membrane ERα signaling pathways in specific tissues. E4 has a small effect on normal breast tissue proliferation and minimally affects hepatic parameters. This distinct profile of ERα activation, uncoupling nuclear and membrane activation, is unique.
2. Introduction to estetrol (E4)
2.1. Chemistry
2.2. Pharmacokinetics
2.3. Mode of action of E4
2.3.1. Introduction to the molecular mechanisms of action of estrogens
2.3.2. The mode of action of E4: E4 has tissue specific properties
3. Phase 2 clinical trial results
3.1. Contraception
3.2 Enhanced safety: tissue-specific effects of E4 in the liver (hemostasis, lipids, renin-angiotensin-aldosterone system), breast, and cardiovascular system
3.2.1. Impact of E4 on hemostasis
3.2.2. Impact on lipids
3.2.3. Impact on the renin-angiotensin aldosterone system
3.2.4. Impact of E4 on normal and malignant breast tissue
3.2.5. Nuclear ERα mediated cardiovascular protection
4. Phase 3 clinical trial results
5. Other therapeutic applications for E4
5.1. Hormone replacement for menopause
5.2. Perimenopause, central nervous system disorders,vascular protection, and oncology
6. Conclusions
Natural and synthetic estrogens have been used for decades in contraception and MHT, with known but rare potential adverse events, such as increasing thrombosis and breast tissue proliferation. New estrogens with a better safety profile are an unmet medical need. The unique pharmacologic properties and molecular mechanisms of action of E4 suggest that it would provide a better benefit/risk ratio compared to other estrogens.
E4 is a native estrogen with differential action in tissues. The molecular nuclear mode of action of E4 is very similar to the actions of classic estrogens and is not like SERMs. Unlike other estrogens, the tissue selectivity of E4 is potentially a consequence of the differential activation of the nuclear and membrane ERα pathways; E4 does not stimulate the membrane ERα and antagonizes the membrane effects induced by E2. Clinical studies demonstrate that E4, in contrast to EE or E2, has little or no effect on circulating SHBG, angiotensinogen, triglycerides, or coagulation factors. This limitedi mpact of E4 on the liver represents an important facet of this innate molecule, which may have a safer profile regarding the risk of thromboembolic events.
The development of E4 in contraception, menopause, and prevention/treatment of hypoxic-ischemic encephalopathy is an example of how basic research and preclinical studies have guided the clinical characterization of E4 activities in humans and enabled precise delineation of its differences from the three other natural estrogens. These results also highlight the importance of the estrogenic component of COCs; the specific estrogen/progestin combination has an impact on the total estrogenicity of the formulation, its clinical use, and linked benefit/risk balance. Both preclinical and clinical data have shown the cardiovascular safety of E4, acting as a classic estrogen to induce a series of cardiovascular/arterial benefits through activation of the ERα nuclear pathway. At the sametime, E4 may pose less of a risk on thromboembolic events, such as VTE due to its neutral profile on the synthesis of hemostatic proteins. Finally, E4 has been shown to have a lower impact on breast tissue compared to other estrogens. Nevertheless, the effects of the tissue selectivity of E4, in particular in the liver and breast, will require further molecular studies for validation.
7. Expert opinion
With its unique profile of activity, E4 is a new chemical entity, distinct from all other estrogens as recognized by the EMA, FDA, and TGA. This estrogen, first described over 80 years, could fill the gap for a safer hormone therapy to address the needs of women during the reproductive (contraception), perimenopause, and menopause years. With its minimal impact on liver metabolism, hemostasis, lipids, RAAS, and breast, a low risk of drug–drug interactions, and its favorable VTE risk profile, E4 has the potential to be a safer estrogen.
Overall, E4 in combination with DRSP offers excellent cycle control with additional safety in a contraceptive indication.
Previous attempts to reduce the increased risk of VTE by decreasing the EE content resulted in poor cycle control and miserable tolerance. Replacement of EE by E2 also resulted in an increase in high rates of transient amenorrhea, spotting, and bleeding. This is the consequence of the transformation of E2 in the endometrium into estrone by the 17-β hydroxysteroid dehydrogenase type 2 induced by all progestins present inall COCs [135]. E4 escapes this inactivation, stabilizes the endometrium and provides a bleeding/spotting profile equivalent to that of the best EE containing COCs, together with comparable efficacy and tolerance, but with the potential for a considerably improved safety profile.
Many women will spend ≥40% of their lives in postmenopause. Current guidelines still highlight the need to inform women that there could be an increased risk of breast cancer, stroke, and VTE associated with MHT. They recommend limiting the MHT to the shortest possible period. E4 alone or in combination could become an ideal chronic treatment for aging women beyond a short-term treatment to alleviate hot flushes only. Other menopausal symptoms including changes in mood, sleep patterns, memory, bodyshape, as well as the onset urogenital symptoms can also be very distressing and affect a woman’s personal and social life.
Early-stage clinical oncologic studies point also to the safety of this new estrogen. We therefore consider that the introduction of E4 in women’s healthcare is a breakthrough with multiple therapeutic opportunities throughout women’s lives.
