Elsevier

Contraception

Volume 81, Issue 1, January 2010, Pages 8-15
Contraception

Review article
Review of clinical experience with estradiol in combined oral contraceptives

https://doi.org/10.1016/j.contraception.2009.08.010Get rights and content

Abstract

Previous attempts to replace ethinylestradiol (EE) with 17β-estradiol (E2) in combined oral contraceptives (COCs) have proved unsatisfactory in terms of bleeding outcomes. A review of previous studies of E2-based COCs has shown that, despite good ovulation inhibition, bleeding irregularities affected up to 100% of women, often resulting in high rates of discontinuation (up to 42%). Suggested reasons for the bleeding irregularities observed with these predominantly monophasic estradiol-progestin preparations included suboptimal doses of E2 and an inappropriate estrogen/progestin ratio. The progestin used in the investigated formulations (e.g., norethisterone acetate, desogestrel and cyproterone acetate) may also have affected the overall bleeding profile. More recent studies of a multiphasic COC containing estradiol valerate (E2V) and dienogest (DNG) indicate efficient ovulation inhibition and acceptable cycle control. In a randomized, double-blind trial that compared E2V/DNG with a monophasic COC comprising EE/levonorgestrel (LNG), the occurrence of scheduled withdrawal bleeding per cycle with E2V/DNG and EE/LNG was 77.7–83.2% and 89.5–93.8%, respectively. The intensity and duration of withdrawal bleeding was reduced with E2V/DNG. The incidence of intracyclic bleeding was similar with E2V/DNG (10.5–18.6%) and EE/LNG (9.9–17.1%). This review shows that after several unsatisfactory attempts to develop E2-based COCs, more recent studies employing endometrial-focused progestins, e.g., DNG, and multiphasic dosing regimens appear to be a promising approach for an E2-based COC that provides efficient ovulation inhibition and acceptable cycle control.

Introduction

Combined oral contraceptives (COCs) are a widely used and well accepted form of contraception. COCs are highly effective when used consistently and correctly [1], and are well tolerated by most women.

COCs contain a combination of an estrogen and a progestin. Since their introduction, several progestins have been developed for use in COCs [2], [3], [4], [5]. Conversely, the estrogen component has remained largely unchanged, with the vast majority of COCs containing ethinylestradiol (EE) or, more commonly in the past, mestranol, the 3-methyl ether of EE. The estrogen component of COCs is responsible for suppressing follicle-stimulating hormone (FSH), providing endometrial stability, and potentiating the activity of the progestin component, e.g., by increasing progestin receptor concentrations. In addition to their desired effects on the reproductive organs, estrogens induce synthesis of hepatic proteins such as coagulation and fibrinolysis factors, angiotensinogen, sex hormone-binding globulin (SHBG), cortisol-binding globulin and lipoproteins [6], [7], [8], [9].

Since their introduction, efforts have been made to improve the tolerability of COCs, to reduce their side effects and to broaden the choice for women using COCs as their method of contraception. For example, concerns about estrogen-associated adverse effects such as venous thromboembolism (VTE) have led to progressive reductions in the dose of EE used in COCs, with the reduction of the EE content of COCs from 50 to 30 mcg, resulting in a lower incidence of venous and arterial thromboembolism (ATE) [10], [11]. More recently, the EE dose has been further reduced; presently, COCs containing a daily dose of EE as low as 20 mcg and even 15 mcg are available. However, it is unlikely that the dose of EE in COCs will be further reduced; data indicate that progressive reductions to very low doses of EE have resulted in higher rates of early discontinuation from clinical trials (primarily due to adverse events such as irregular bleeding), as well as an increased risk of bleeding disturbances (including amenorrhea/infrequent bleeding, irregular, prolonged or frequent bleeding, and breakthrough bleeding or spotting), compared with COCs containing higher doses of EE [12]. While healthcare providers and women may select COCs containing EE 20 mcg based on the perception that such products have an improved safety profile (owing to the reduced dose of the estrogen component), there has so far been no conclusive evidence to support this belief [12]. Only recently conducted studies seem to suggest a benefit for preparations containing a dose of EE lower than 30 mcg [13]. That said, studies have suggested that a daily dose of EE as low as 10 mcg may still have potentially adverse effects on hemostatic parameters [7].

The development of hormonal contraceptives containing natural estrogens (i.e., estradiol [E2], which is structurally identical to endogenous 17β-estradiol) has become appealing. Such COCs would be expected to have good tolerability, and their availability would broaden the choice of contraceptives available to women. E2 is the most potent natural estrogen and is the major estrogen secreted by the ovaries [14]. Preliminary data from clinical studies investigating COCs based on natural estrogens (estriol [E3], E2, and estradiol valerate [E2V]) appeared promising in terms of their effects on lipids, surrogate parameters of hemostasis [7], [8], [9], [15] and other indicators of hepatic protein synthesis, such as SHBG and angiotensinogen [16], [17]. Specifically, the induced changes in serum lipids and lipoproteins with these compounds appeared to be less pronounced and, qualitatively, more benign than preparations containing EE. Bostofte et al. [15] compared the effect of two formulations containing the same progestin, i.e., norethisterone acetate 3 mg, but different estrogens (E2 4 mg plus E3 2 mg versus EE 50 mcg). The formulation containing EE 50 mcg was associated with a significant increase in serum triglycerides (p<.001) and β-lipoproteins (p<.01); however, no such change was observed in subjects receiving the formulation containing E2, which was found to significantly decrease serum cholesterol, phospholipids and α-lipoprotein (all p<.05) [15].

Despite the fact that several studies investigating E2-containing COCs have been conducted over the past 30 to 40 years, so far, no such product has been made available on a global basis. Studies have shown that, although sufficient inhibition of ovulation and contraceptive efficacy can be achieved when EE is replaced with E2, until now, efforts to use E2 in COCs have largely failed to achieve a satisfactory level of bleeding control. That said, newer studies combining E2 with other progestins (i.e., dienogest [DNG]) in multiphasic regimens appear promising in overcoming this problem, and have demonstrated acceptable cycle control while maintaining contraceptive efficacy.

The objective of this review is to provide an overview of available data from studies of E2-containing COCs. The main focus of the review will be to outline the efficacy and tolerability of various E2-containing COC regimens, with an emphasis on contraceptive efficacy and cycle control data. Data will largely be presented in chronological order.

Section snippets

Experience with COCs containing estradiol

In 1980, the World Health Organization (WHO) Task Force on Oral Contraception reported the results of a randomized, double-blind, 1-year study of two COCs containing norethisterone acetate 3 mg in combination with either EE 50 mcg or micronized E2 4 mg plus E3 2 mg [18]. Out of 925 women who entered the study, 458 received the COC containing the natural estrogens, i.e., E2 plus E3. The two COCs had the same contraceptive efficacy, but the incidence of various menstrual irregularities was

Discussion

The data presented in this review show that several COCs based on a combination of progestins and natural estrogens have been investigated in the past decades. Although many studies confirmed good ovulation inhibition with these drug combinations, large-scale data confirming their contraceptive efficacy are not available in most instances. Nevertheless, it appears to be possible to achieve good contraceptive efficacy with drug combinations that neither contain the potent estrogen EE (as with

Conclusions

Previous attempts to use natural estrogens, such as E2, in COCs have proved unsatisfactory in terms of cycle control. Suggested reasons for this have included suboptimal doses of E2 and an inappropriate estrogen/progestin ratio. The progestin used in the investigated formulations may also have affected the overall bleeding profile. More recent studies employing endometrial-focused progestins, e.g., DNG, in combination with E2V in multiphasic dosing regimens, appear to be a promising approach

Acknowledgments

Editorial assistance for the development of this manuscript was provided by Andrea Machlitt from Bayer Schering Pharma and Lyndal McMillan and Danielle Turner from Wolters Kluwer Health. Funding for this editorial assistance was provided by Bayer Schering Pharma AG.

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