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Home , Estetrol, Estetrol (medication), Hot flash

CE: D.C.; MENO-D-20-00177; Total nos of Pages: 3; MENO-D-20-00177

Menopause: The Journal of The North American Society Vol. 27, No. 8, pp. 000-000 DOI: 10.1097/GME.0000000000001601 ß 2020 by The North American Menopause Society

EDITORIAL for menopause symptoms: the Cinderella of or just another fairy tale? Nancy King Reame, MSN, PhD, FAAN

espite the advent of lower dosing, transdermal deliv- affinity (<5%) compared to E2.3 Interest was, however, ery, and targeted use in younger age groups, safety renewed in the 2000s when preclinical and pharmacokinetic D concerns persist regarding the potential for - studies showed that estetrol elicits considerable estrogenic based menopause therapy (MHT) to raise effects in rat models for both hot flashes and loss, but cancer and thromboembolism risk. In the last few decades a with minimal stimulation of and breast.4 More recent wealth of scientific advances has revealed the molecular biol- translational studies5 showed that E4 was bestowed with an ogy of the estrogen receptors (ERs) a and b, opening up new intriguing ER pharmacology, unique from SERMs, thus directions for their pharmaceutical manipulation and promise pushing it to center stage for its potential as the first native to improve hormone therapies. With the help of the ER knock- estrogen with selective action in tissues (NEST). out mouse model, an array of estrogen-mediated actions in Unlike other estrogens, which interact with both a and b tissues throughout the body was elucidated, followed by the receptors at the cell surface and in the nucleus, E4 not only emergence of new compounds with -dependent, ER preferentially binds to the ERa subtype, but does so in a distinct agonistic, antagonistic, and mixed actions.1 Although several non-SERM way. Estetrol is endowed with a unique capability of the first- and second-generation compounds, known as to uncouple ERa modulation: activating the nuclear ERa to selective ER modulators or SERMs, have proven to be impor- induce genomic transcription while blocking membrane ERa at tant therapies in the treatment of and , the cell surface that normally triggers rapid downstream signal no SERM to date has achieved a profile conducive to managing transduction in the cytoplasm.6 This property of E4 is the basis the full spectrum of menopausal symptoms. In fact, most for its tissue-specific action and unusual pharmacodynamic SERMs tend to exacerbate rather than alleviate vasomotor profile. As the final product of human , symptoms (VMS) and exhibit agonistic actions on the liver, estetrol has been shown in pharmacokinetic studies to have raising concerns about stroke and cardiovascular disease risk essentially no active metabolic end products, minimal first-pass similar to those associated with conventional MHT.2 Now metabolism, a high oral availability, an elimination half-life comes a breakthrough compound that demonstrates unique of approximately 28 hours, and reduced estrogenic impact on ER-binding activity, distinct from SERMs, with potential for hepatic synthesis of hemostasis parameters7,8 – all important enhanced safety. Surprisingly, this super , purported to attributes of an oral, liver-friendly candidate for MHT. have all the attributes of and few of its flaws, did not Now under development by Mithra Pharmaceuticals originate in a sophisticated steroid biochemistry laboratory. (Liege, Belgium, www.mithra.com) as an oral contraceptive Instead, scientists had to look no further than the of (in combination with ) and MHT products, these pregnant women for the next exciting innovation. attributes of E4 have been mostly supported in phase 1 and Estetrol is the lesser-known, understudied ‘‘stepsister’’ of early phase 2 clinical studies. In a 4-week, multiple- rising estradiol (E2), (E3), and (E1), produced in dose study in 49 postmenopausal women, even the lowest nature only during human and only by the fetal doses studied (2 and 10 mg) improved VMS and vaginal liver where needed to convert E2 and E3 into E4 are cytology.9 Although a placebo control was lacking, effects exclusively found. Although first described in the late 1960s in a comparator group treated with 2 mg by Diczfalusy and proposed as a marker of fetal well-being (EV) were similar. In the safety portion of that study a dose- (still under study), it was abandoned by the pharmaceutical dependent estrogenic effect (dose range of 2-40 mg) was industry as a possible contraceptive due to its much lower ER observed on endocrine parameters, bone turnover markers, lipids, and lipoproteins, but with only modest detriment to 10 Received May 6, 2020; revised and accepted May 7, 2020. and hemostatic values. At the same time, From the Columbia University School of Nursing, New York, NY. endometrial proliferation at the 10 mg dose was pronounced Funding/support: None reported. and similar to that seen in the EV group, prompting reviewers Financial disclosure/conflicts of interest: None reported. to note that perhaps the best indication for E4 use might be as Address correspondence to: Nancy King Reame, MSN, PhD, FAAN, Emerita Professor, Columbia University School of Nursing, New York, an estetrol-only therapy for vaginal atrophy at a dose low 11 NY. E-mail: [email protected] enough to avoid endometrial effects.

Menopause, Vol. 27, No. 8, 2020 1

Copyright ß 2020 The North American Menopause Society. Unauthorized reproduction of this article is prohibited. CE: D.C.; MENO-D-20-00177; Total nos of Pages: 3; MENO-D-20-00177

EDITORIAL

Building on this preliminary work, Gaspard et al12 report in Although investigators acknowledge that part of the prob- this issue of Menopause the first round of results on VMS and lem may have been due to the small sample size, another study overall safety from the E4Relief trial – a phase 2b multicenter, limitation might be the failure to adequately exclude placebo randomized, placebo-controlled, double-blind, dose-finding responders during screening. It has been estimated that in the study designed to determine the minimally effective oral dose last decade, a rising placebo response rate may be contributing of estetrol for VMS relief in postmenopausal women. (Data on to a 15% increase in failed phase 2 clinical trials.14 One well- of hemostasis, lipids and glucose metabolism, and established approach for reducing placebo effects in drug vaginal symptoms and quality of life will be published in later trials is to include a run-in period, where every eligible reports). Recruited from six European countries, a total of 257 volunteer is blinded and receives a placebo for a week or participants, ages 40 to 65 years, were randomized to placebo or so, to identify and exclude placebo responders before ran- treatment groups (approximately 45 per group) of E4 (2.5, 5, domization. In a recent meta-analysis of intervention 10, or 15 mg), and compared at baseline, 4, and 12 weeks on trials, Li et al15 concluded that the intertrial variability of the VMS features (daily electronic diaries) and safety measures placebo response was significantly lower in trials with a run- including endometrial thickness and bleeding patterns. Women in period versus those without, leading them to recommend qualified to participate in the trial if they had not had a period for the incorporation of a run-in period into study design to at least 6 months either due to hormonally-defined natural improve the sensitivity and accuracy of the efficacy measures. menopause or hysterectomy, had 7 or more moderate to severe Had such an approach been used in this trial, it is possible that hot flushes per day, or 50 or more moderate to severe hot flushes lower doses may have also shown efficacy. in the week before baseline; and for those with natural meno- Building on these E4Relief findings as well as other prelimi- pause, had findings on transvaginal ultrasound of a bilayer nary reports of favorable secondary outcomes and safety endometrial thickness of 5 mm or lesser. At study completion, measures for cardiovascular risk,16,17 two world-wide phase nonhysterectomized participants received 2 weeks of progestin 3 trials (study I in Europe, Russia, and South America; study II therapy ( 10 mg). in North America), already in the recruitment phase (Clinical- Study results were somewhat surprising in that the minimum Trials.gov NCT04209543), should better define the appropriate efficacy dose for VMS relief also carried notable estrogenic balance between E4 efficacy for VMS relief and safety. It is, effects on the . In this larger and longer controlled however, noteworthy that the lower doses used in the study trial, only the highest E4 dose (15 mg) demonstrated a signifi- reported here will not be tested in the E4 Comfort trial; only oral cantly greater reduction in VMS frequency and severity com- doses of 15 and 20 mg will be compared against placebo for up pared to placebo. At this dose, the improvement in VMS over to 1 year in large cohorts of postmenopausal women (n ¼ 1,200 placebo at week 4 was already marked, and by week 12, a in study I; n ¼ 1,000 in study II). Changes in frequency and highly significant response was demonstrated (>80% of par- severity of moderate to severe VMS in postmenopausal women ticipants achieved at least 75% lower frequency) similar to that will be monitored at 4 and 12 weeks, and then followed for an seen in studies of estradiol therapy. Although there were no additional 40 weeks, along with vaginal symptoms, multiple unexpected adverse events and no , safety parameters, and quality of life measures.18 safety profiles indicated a clear dose-dependent, stimulatory How these higher doses of longer duration will impinge on effect on the endometrium, with endometrial biopsy required in the promising benefit/risk profile remains to be seen. Happy 13% of volunteers, mostly in the highest dose groups, due to ever-after-endings to such trials are seldom realistic. (Already abnormal bleeding. recruitment is temporarily on hold as of April 1, 2020 due to the But as pointed out by the investigators, the failure of lower Covid 19 pandemic). But if the study aims are met, and results E4 doses (eg, 10 mg) to achieve superior VMS effects over indicate improved outcomes with a lower impact on hemostatic placebo may in part be due not to the failure of the drug, but to and metabolic factors, then estetrol is likely to emerge as the the success of the placebo, which demonstrated a mean per- chosen princess from the dingy cellar of forgotten compounds, centage decline in VMS frequency from baseline of 65% to be crowned the first NEST molecule for safer hot flash relief. by week 12. Notably excessive, even for hot flash studies,13 Only time will tell whether the shoe fits. the investigators attribute the large placebo-induced VMS improvement in part to elevated E2 values in controls (as high REFERENCES as 180 pg/mL), suggesting the possibility of serendipitous follicular development or the undisclosed use of estrogenic 1. Pickar JH, MacNeil T, Ohleth K. SERMs: progress and future perspec- tives. Maturitas 2010;67:129-138. compounds during study. (The inclusion of participants who 2. Mirkin S, Pickar JH. Selective estrogen modulators (SERMs): a met the weaker eligibility criteria for postmenopause as review of clinical data. Maturitas 2015;80:52-57. 6 months amenorrhea in the presence of a single measure of 3. Holinka CF, Diczfalusy E, Coelingh Bennink HJ. Estetrol: a unique steroid in human pregnancy. J Steroid Biochem Mol Biol 2008;110:138-143. E2 of <20 pg/mL may have also contributed.) To their credit, 4. Coelingh Bennink HJ, Holinka CF, Diczfalusy E. Estetrol review: profile the authors demonstrated in post hoc analyses that neither study and potential clinical applications. Climacteric 2008;11 (suppl 1):47-58. site nor country of residence was associated with response rates, 5. Abot A, Fontaine C, Buscato M, et al. The uterine and vascular actions of estetrol delineate a distinctive profile of alpha modula- but acknowledge that other possible contributing factors were tion, uncoupling nuclear and membrane activation. EMBO Mol Med not systematically assessed. 2014;6:1328-1346.

2 Menopause, Vol. 27, No. 8, 2020 ß 2020 The North American Menopause Society

Copyright ß 2020 The North American Menopause Society. Unauthorized reproduction of this article is prohibited. CE: D.C.; MENO-D-20-00177; Total nos of Pages: 3; MENO-D-20-00177

EDITORIAL

6. Arnal JF, Lenfant F, Metivier R, et al. Membrane and nuclear estrogen women (E4 RELIEF); part 1: vasomotor symptoms and overall safety. receptor alpha actions: from tissue specificity to medical implications. Menopause 2020;27:XXX-XXX. Physiol Rev 2017;97:1045-1087. 13. Freeman EW, Ensrud KE, Larson JC, et al. Placebo improvement in 7. Hammond GL, Hogeveen KN, Visser M, Coelingh Bennink HJ. Estetrol pharmacologic treatment of menopausal hot flashes: time course, dura- does not bind binding globulin or increase its production by tion, and predictors. Psychosom Med 2015;77:167-175. human HepG2 cells. Climacteric 2008;11 (suppl 1):41-46. 14. Kemp AS, Schooler NR, Kalali Ah. et al. What is causing the reduced 8. Visser M, Holinka CF, Coelingh Bennnk HJ. First human exposure to drug-placebo difference in recent schizophrenic clinical trials and what exogenous single-dose oral estetrol in early postmenopausal women. can be done about it? Schizophr Bull 2010;36:506-509. Climacteric 2008;11 (suppl 1):31-40. 15. Li L, Xu L, Wu J, Dong L, Lv Y, Zheng Q. Quantitative analysis of 9. Coelingh Bennink HJ, Verhoeven C, Zimmerman Y, et al. Clinical effects placebo response and factors associated with menopausal hot flashes. of the fetal estrogen estetrol in a multiple-rising-dose study in postmen- Menopause 2017;24:932-937. opausal women. Maturitas 2016;91:93-100. 16. Genazzani AR, Gaspard U, Foidart JM. Oral investigational drugs 10. Coeling Bennink HJT, Verhoeven C, Zimmerman Y, Visser M, Foidart currently in phase I or phase II for the amelioration of menopausal JM, Gemzell-Danielsson K. Pharmacodynamic effects of the fetal estro- symptoms. Expert Opin Investig Drugs 2019;28:235-247. gen estetrol in postmenopausal women: results from a multiple-rising- 17. Grandi G, Del Savio MC, Da Silva-Filho AL, Facchinetti F. Estetrol (E4): dose study. Menopause 2017;24:677-685. the new estrogenic component of combined oral contraceptives. Expert 11. Rosen T, Bachman G. Menopausal health: the potential for fetal-placental Rev Clin Pharmacol 2020; [Epub ahead of print]. estrogen use. Maturitas 2016;91:145-146. 18. Utian W, Lobo R, Mawet M, et al. A Phase 3 Protocol to assess the efficacy 12. Gaspard U, Taziaux M, Mawet M, et al. A multicenter, randomized study and safety of estetrol (E4), a promising new treatment for menopausal to select the minimum effective dose of estetrol (E4) in postmenopausal vasomotor symptoms. Menopause 2019;26:1480. Abstract P-71.

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Copyright ß 2020 The North American Menopause Society. Unauthorized reproduction of this article is prohibited.