The benefits of estetrol addition to drospirenone for contraception

Abstract

Ethinylestradiol and drospirenone combined oral contraceptive formulations have been marketed for >20 years. Drospirenone has antimineralocorticoid and anti-androgenic effects that may offer several health benefits. Recently, 2 new drospirenone-containing oral contraceptives entered the market, 1 as a progestin-only pill containing 4 mg drospirenone and the other as a combined oral contraceptive containing 15 mg estetrol and 3 mg drospirenone. Estetrol has a unique differential effect on nuclear and membrane estrogen α-receptors when compared with other estrogens, leading to low impact on the liver, breast, and hemostasis parameters and a beneficial effect on the endometrium, vagina, cardiovascular system, bone, and brain. Phase 3 clinical studies demonstrated that the Pearl Index (pregnancies per 100-woman-years) for drospirenone alone is 4.0 in the United States and 0.93 in the European Union and for the estetrol-drospirenone combination it is 2.65 and 0.44, respectively. Drospirenone alone demonstrates high rates of unscheduled bleeding and low rates of scheduled bleeding, whereas the estetrol-drospirenone combination demonstrates a predictable and regular bleeding profile for most users with a high stable rate of scheduled bleeding and a low rate of unscheduled bleeding, reported primarily as spotting only. The adverse event profiles and discontinuation rates owing to adverse events are comparable, and no clinically significant effects were observed on metabolic parameters with either product. Hemostatic assays for drospirenone do not fully evaluate all parameters although the testing that is available suggests negligible effects, whereas validated hemostatic assays demonstrate that the estetrol-drospirenone combination has limited impact on hemostasis. The introduction of 4 mg drospirenone and 15 mg estetrol with 3 mg drospirenone are valuable additions to the contraceptive market. Adding estetrol to 3 mg drospirenone provides advantages of contraceptive efficacy and a regular, predictable bleeding profile with minimal impact on hemostasis parameters.

Keywords: E4; EE; contraception; drospirenone; estetrol; ethinylestradiol.

Figure 1

Bleeding with 15mgE4/3mgDRSP, 20μgEE/3mgDRSP and 4mgDRSP E4-DRSP data from Kaunitz et al's Contraception 2022, EE-DRSP data from the US Food and Drug (FDA) assessment report YAZ 2006 and DRSP alone data from the FDA assessment report SLYND. DRSP, drospirenone; E4, estetrol; EE, ethinylestradiol.

Figure 2

Bleeding for 15mgE4/3mgDRSP (A) and for 4mgDRSP (B) A, E4-DRSP phase 3 trial Euopean Union and Russia, Gemzell-Danielsson et al BJOG 2021. B, DRSP phase 3 trial European Union, Archer et al Contraception 2015. DRSP, drospirenone; E4, estetrol.

Figure 3

Impact of POPs and COCs on coagulation factors, nAPCsr and VTE risk The impact of POPs and COCs on some individual coagulation factors has been extracted from Palacios et al and Douxfils et al (A). The correlation between nAPCsr results and relative risk for VTE was extracted from Douxfils et al, whereas desogestrel data are extracted from QUALIblood s.a. (unpublished data). The VTE risk was either extracted from Lidegaard et al or recovered by the in silico model of Morimont et al. COCs, combined oral contraceptive; nAPCsr, endogenous thrombin potential-based activated protein C resistance (ETP-based APC), expressed as normalized APC sensitivity ratio; POP, progestin-only pill; VTE, venous thromboembolism.

Figure 4

Endogenous thrombin potential(ETP)-based activated protein C(APC) resistance assay The ETP-based APC resistance assay permits the evaluation of congenital and acquired APC resistance by using data from thrombin generation curves. Thrombin generation curves (thrombograms) reflect the amount of thrombin produced over time in a measurement well. Several parameters can be extracted from this curve but for the sake of the ETP-based APC resistance assay, only the area under the curve of the thrombograms, reflecting the endogenous thrombin potential (ETP), was used. In the ETP-based APC resistance assay, thrombograms are generated in the absence (——— continuous line) and in presence (——- dotted lines) of APC. The resistance towards APC in a subject's plasma, for example, with an APC resistant phenotype (continuous and dotted pink lines), is compared with the resistance obtained in a pool of plasma from normal subjects (continuous and dotted blue lines). This method of calculation permits to express the results in terms of normalized activated protein C sensitivity ratio (nAPCsr). nAPCsr results scale from 0 to 10, which ease its interpretation. Therefore, the higher the nAPCsr, the higher the resistance toward APC. The normal range in a young and healthy population not taking combined hormonal contraceptives (CHCs) is from 0.00 to 2.08. Women taking EE/LNG COCs usually express nAPCsr results around 3.50. As stated in by the plasma coagulation inhibitors subcommittee of the International Society on Thrombosis and Haemostasis (ISTH) Scientific and Standardisation Committee (SSC), the ETP-based APC resistance assay has to be used for assessment of hormone-induced APC resistance since clotting (ie, aPTT-based) APC resistance assays are insensitive to this acquired APC resistance condition.