An overview of the development of combined oral contraceptives containing estradiol: focus on estradiol valerate/dienogest

Abstract

Natural estrogens such as estradiol (E(2)) or its valerate ester (E(2)V) offer an alternative to ethinyl estradiol (EE). E(2)-containing combined oral contraceptives (COCs) have demonstrated sufficient ovulation inhibition and acceptable contraceptive efficacy. However, earlier formulations were generally associated with unacceptable bleeding profiles. Two E(2)V-containing preparations have been approved to date for contraceptive use: E(2)V/cyproterone acetate (CPA) (Femilar(®); only approved in Finland and only in women >40 years or women aged 35-40 years in whom a COC containing EE is not appropriate) and E(2)V/dienogest (DNG; Qlaira(®)/Natazia(®)). The objective of the current review is to provide an overview of the development of COCs containing natural estrogen, highlighting past issues and challenges faced by earlier formulations, as well as the current status and future directions. The majority of information to date pertains to the development of E(2)V/DNG.

Figure 1

Mean serum estradiol (E₂) concentration over 24 h following oral administration of estradiol valerate (E₂V)/dienogest (DNG) [17]. Zeun S, et al., Eur J Contracept Reprod Health Care, 2009;14(3):221–32, copyright© 2009, Informa Healthcare. Reproduced with permission of Informa Healthcare.

Figure 2

Mean ethinyl estradiol (EE) concentration over 24 hours following oral administration of EE 20 μg/levonorgestrel (LNG) 100 μg [18]. Endrikat J, et al., Eur J Contracept Reprod Health Care, 2002;7(2):79–90, copyright© 2002, Informa Healthcare. Reproduced with permission of Informa Healthcare.

Figure 3

Dosing regimen of an estradiol valerate (E₂V)/dienogest (DNG)-containing oral contraceptive administered using an estrogen step-down and progestogen step-up approach over a 28-day treatment cycle (with 26 days of active tablets). Numbers along the bottom of the figure correspond to days of the 28-day cycle.

Figure 4

Minimum mean (standard deviation [SD]) serum concentrations of estradiol during daily administration of a 28-day oral contraceptive containing estradiol valerate (E₂V)/dienogest (DNG) [50].