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Estetrol As Estrogen in a Combined Oral Contraceptive, from the First In-Human Study to the Contraceptive Efficacy

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Estetrol As Estrogen in a Combined Oral Contraceptive, from the First In-Human Study to the Contraceptive Efficacy Estetrol as estrogen in a combined oral contraceptive, from the first in-human study to the contraceptive efficacy Marie Mawet, Ulysse Gaspard, Jean-Michel Foidart University of Liège, Liège, Belgium ABSTRACT Even though the use of combined oral contraceptive (COC) has numerous health benefits, it is associated with an in- creased risk of venous thromboembolism (VTE). Currently, the second generation COCs [ethinylestradiol (EE) with lev- onorgestrel (LNG)] are considered as the safest regarding the VTE risk but the androgenicity of LNG is responsible for undesirable side effects (acne, hirsutism and mood alteration) jeopardizing compliance. In the opposite, the use of less androgenic progestins or anti-androgenic progestins such as drospirenone (DRSP) is better tolerated but doubles the risk of VTE in comparison with EE/LNG. Replacing EE by a natural estrogen has been suggested to improve the VTE risk. Estetrol (E4) is a natural estrogen only produced by the human fetal liver. In-vivo and in-vitro fundamental studies suggest that E4 is safer than EE and estradiol (E2) on important estrogenic targets such as breast tissue and synthesis of liver proteins (responsible for hemostasis impairments associated with the use of estrogens). A vast clinical program has re- cently been conducted in order to evaluate the use of E4 as estrogen in a COC. A dose-finding program studied different combinations of E4 with DRSP or LNG. Ovulation inhibition, bleeding pattern, and tolerance were used to select the best E4-COC for further evaluation. All the E4-COCs tested were safe and capable of blocking ovulation. However, 15 mg E4 with 3 mg DRSP was associated with the best bleeding pattern and the highest tolerance. In addition, the changes in hemostasis parameters elicited by 15 mg E4/DRSP were significantly less pronounced than those recorded with EE/ DRSP, and similar or even lower than those seen with the safe EE/LNG. This combination was therefore selected to be further evaluated in a Phase 3 program where it confirmed its excellent safety and contraceptive efficacy. KEYWORDS Combined oral contraceptive, estetrol, drospirenone. Introduction Article history Received 17 Feb 2021 - Accepted 08 Mar 2021 Although the progestin component of combined oral con- traceptive (COC) is sufficient to ensure adequate ovulation in- Contact Marie Mawet; [email protected] hibition, the addition of an estrogen is crucial to provide an University of Liège, Liège, Belgium. acceptable bleeding pattern. Since the launch of the first COC in 1961, there has been a constant effort to develop new proges- tins in order to improve the safety and tolerability of the earliest in COC during more than four decades. After initial unsuc- combinations. Indeed, the androgenicity of the first progestins cessful attempts, estradiol (E2) was finally introduced into two was held responsible of metabolic impairment (insulin resist- COCs in the early 2010’: in the form of the pro-drug E2 valer- ance and deleterious effect on plasma lipid levels). It was also ate in combination with dienogest (E2V/DNG) and in the form associated with a series of undesirable side effects, like weight of E2 in combination with nomegestrol acetate [4, 5]. However, gain, acne, oily hair, seborrhea, and hirsutism [1, 2]. Research these E2-containing COCs are less prescribed as over 95% of in women’s health has therefore focused on developing less combined hormonal contraceptive users still utilize an EE-con- androgenic compounds. The two last decades have even seen taining product. the advent of anti-androgenic progestins. One of them, dros- Estrogens (and particularly the potent EE) modify the syn- pirenone (DRSP), also displays anti-mineralocorticoid activity. thesis of hepatic proteins, including those of haemostasis [6]. Combined to EE, DRSP has been demonstrated to maintain Hemostasis is a subtle balance between pro-coagulation, an- blood pressure, slightly decrease body weight, improve acne ti-coagulation and fibrinolysis. Estrogens alter this balance by and hirsutism, and improve premenstrual dysphoric disorder [3]. decreasing natural anticoagulant and favouring pro-coagula- On the other side, only three different estrogens have been tion; this is the reason why venous thromboembolism (VTE) used in COC since 1961: the first one was the pro-drug me- risk is increased in COC users [7] (Figure 1 A and B). stranol rapidly replaced by its potent active form, ethinylestra- Decreasing the amount of EE in COC from > 75 to 20 mcg diol (EE). Ethinylestradiol has remained the only estrogen used has undoubtedly decreased the incidence of VTE [8]. But epi- European Gynecology and Obstetrics. 2021; 3(1):13-21 Licens terms 13 Mawet M et al. Figure 1 Global impact of estrogens or combined oral contraceptives on hemostasis (A) and resultant effects on hemostasis parameters considered as relevant for the evaluation of the risk of venous thromboembolism (B). Adapted from “Oral contraceptives and HRT: risk of thrombosis”, Gialeraki A. et al, 2018, Clinical and Applied Thrombosis/Hemostasis, 24, p. 217. Copyright 2017 by The Author(s) (A) and from “APC resistance: biological basis and acquired influences”, Castoldi E. & Rosing J., 2010, Journal of Thrombosis and Haemostasis, 8, p. 445. Copyright 2009 by International Society on Thrombosis and Haemostasis (B). A B demiological studies have shown that the combination of less on coagulation. This is the reason why E2 was introduced in androgenic/anti-androgenic progestins, even to low dose of EE, COCs. The current E2-containing COCs try to minimize the has re-enhanced the incidence of VTE, because the resultant incidence of unscheduled bleeding but the bleeding pattern dif- estrogenicity of these combinations is higher with these pro- fers from the EE-COCs as 15-25% of users present with occa- gestins than with the androgenic ones [9, 10] (Figure 2). sional amenorrhea [12, 13]. Currently, studies are still necessary A further decrease in EE content is associated with a barely to confirm the lower VTE incidence with these preparations. acceptable bleeding pattern. No new estrogen has been introduced since 1943 but a vast In general, the lower dose estrogen pills (20 mcg or less) clinical program has recently been conducted to evaluate the are associated with higher unscheduleld bleeding episodes potential of estetrol (E4) as estrogen in a COC. The goal of this which could increase discontinuation rate [11]. Therefore, the article is to summarize the current published knowledge on E4 other option was to replace EE by an estrogen with less impact and on the first E4-based COC. 14 European Gynecology and Obstetrics. 2021; 3(1):13-21 E4/DRSP COC, review of the clinical development Figure 2 Evolution of combined oral contraceptives composition from 1960 to 2000: in association with the androgenic progestin levonorgestrel, a progressive decrease in ethinylestradiol (EE) content from 150 to 20 mcg/day has permitted a decrease of the risk of venous thromboembolism (VTE). Development of less/anti-androgenic progestin in the 1980s has decreased the androgenic side effects of COCs but combinations of these progestins even to low dose EE were associated with a new increase of the VTE risk. Levonorgestrel (LNG) • Androgenic Progestin Acne, hirsutism, mood alteration, weight gain, androgenicity alteration of metabolic parameters Drospirenone (DRSP) • Anti-androgenic • Anti-mineralocorticoid EE content Improvement of acne, hirsutism, no HBP, From >75 mcg/d no weight increase, improvement of mood, to 20 mcg/d neutral on metabolic parameters Mestranol (150 mcg EE) Norethynodrel VTE risk 1960 1980 2000 What is estetrol? activity on the endometrium and on the vaginal epithelium, to decrease vasomotor symptoms, to restore bone mineral density, The natural estrogen family encompasses 4 estrogens dif- to protect against atherosclerosis, and to confer vasorelaxation fering on the number of hydroxyl groups: estrone (E1), estradi- [18-24]. These characteristics are shared with the other estrogens ol E2, estriol (E3) and the less known, estetrol (E4). Estetrol, a like E2 and EE. However, unlike these estrogens, different four hydroxylated estrogen, was discovered at the Karolinska studies have shown that E4 estrogenic activity is much weaker Institute (Sweden) in 1965 by Egon Diczfalusy and co-work- on breast tissue (either normal or cancerous) and on liver [25-28]. ers in the urines of pregnant women [14]. Its synthesis starts This distinct profile of E4 is probably best explained by its from E2 and necessitates the activity of two enzymes (16- and interaction with estrogen receptors (ERs). In the cells, estro- 15α-hydroxylase) only present in the liver of the human fe- gens act via two types of ERs: ERα and ERβ. Estetrol has a 5 tus [15]. Estetrol crosses the placenta and is detectable in the fold higher affinity for ERα than for ERβ [29]. The ERs are ei- mother’s blood from the first weeks of pregnancy onwards. The ther located in the cell membrane and in the cell nucleus. Estro- concentration in E4 increases throughout the pregnancy in both gens classically activate both membrane and nuclear receptors. mother and fetus and, at term, is on average 12 times higher in This is not the case of E4: like the other estrogens, it activates the child plasma than in the mother plasma: mean concentra- the nuclear receptor but it antagonizes the membrane receptor tions (standard deviation) of 9,034 (2,968) pg/ml and 723 (290) and, consequently, the response to E4 will differ from that of pg/ml, respectively. Short after birth, the enzymes necessary to the other estrogen in functions of the target tissue. This could its synthesis are not active anymore, explaining why the con- explain the weak effect of E4 on certain target tissues (e.g. the centration in E4 decreases rapidly in the new-born plasma [16]. liver and the breast) versus its full estrogenic potential on other In the first decade following its discovery, E4 was exten- tissues (uterus, vagina, hypothalamus-pituitary-ovarian axis, sively studied as it was hoped to be a good marker of fetal brain, bone) [23, 30, 31].
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