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

Figures & data

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.

Table I.  Summary of clinical studies in contraception involving combined oral contraceptives (COC) that incorporated estradiol (E₂) rather than ethinyl estradiol (EE).

Reference	Study design	n	Intervention	Key results
COCs apparently no longer in development
Astedt et al. 1979 [25]	Randomized Triple-blind	215	21/7 regimen for 12 cycles Micronized E2 4 mg/norethisterone 3 mg (Netagen 403) for 21 days followed by 7-day pill-free period OR Micronized E2 4 mg + E3 2 mg/norethisterone 3 mg (Netagen 423) for 21 days followed by 7-day pill-free period OR EE 50 µg/norethisterone 3 mg (Netasyn) for 21 days followed by 7-day pill-free period	No pregnancies. No thrombotic events. Discontinuation rates were similar between treatment groups (Netagen 403: n = 39; Netagen 423: n = 31; Netasyn: n = 35). The main reasons for discontinuation: amenorrhea and weight gain with Netagen 403; intermenstrual spotting with Netagen 423; nausea and weight gain with Netasyn.
Serup et al. 1979 [40],Serup et al. 1981 [39]	Randomized Double-blind	111	21/7 regimen for 12 cycles E2 4 mg/E3 2 mg/norethisterone acetate 3 mg for 21 days followed by 7-day pill-free period OR EE 50 µg/norethisterone acetate 3 mg for 21 days followed by 7-day pill-free period	No pregnancies. Spotting and breakthrough bleeding were significantly more common with natural estrogen than with EE (p < 0.01) and led to significantly more discontinuations (p < 0.001). Bleeding irregularities did not subside during the study.
World Health Organization 1980 [42]	Randomized Double-blind	925	21/7 regimen for 12 cycles Micronized E2 4 mg + E3 2 mg/norethisterone acetate 3 mg for 21 days followed by 7-day pill-free period OR EE 50 µg/norethisterone acetate 3 mg for 21 days followed by 7-day pill-free period	Annual failure rate was approximately 1 per 100 women in each treatment arm. Menstrual irregularities, including all menstrual complaints, amenorrhea, light bleeding and spotting, were significantly more common with natural estrogens than with EE (p < 0.01). Discontinuation rate at 1 year: 48.4% for EE and 51.5% for natural estrogens. Discontinuation for menstrual irregularities was significantly higher with natural estrogens (48 vs. 13 cases; p < 0.001). Menstrual irregularities were more common with natural estrogens during cycles 1–3, 10 and 12.
Schubert et al. 1987 [38]	Randomized Blinding not specified	10	21/7 regimen for 1 cycle E2 cyclo-octyl acetate 0.5 mg/DSG 150 µg for 21 days followed by 7-day pill-free period OR E2 cyclo-octyl acetate 0.5 mg/DSG 150 µg for 21 days followed by DSG 30 µg for 7 days	Follicular development and ovulation were inhibited. An unacceptable bleeding profile was observed – all women experienced breakthrough bleeding.
Wenzl et al. 1993 [41]	Single-arm Open-label	20	21/7 regimen for 2 cycles Micronized E2 1 mg/DSG 150 µg for 21 days followed by a 7-day pill-free period	Ovulation inhibition was observed in all women. Approximately two-thirds of women experienced withdrawal bleeding in each cycle. Bleeding during the treatment cycles was heavier and longer than the pre-treatment cycle. Two women discontinued due to unacceptable bleeding in cycle 1.
Csemiczky et al. 1996 [29]	Randomized Double-blind	29	21/7 regimen for 2 cycles Micronized E2 3 mg/DSG 150 µg for 21 days followed by DSG 30 µg for 7 days OR Micronized E2 3 mg/DSG 150 µg for 21 days followed by placebo for 7 days	Ovulation was suppressed in all women. Withdrawal bleeding occurred in 81% of women. Breakthrough bleeding and spotting were more common in DSG group (46.2% vs. 26.2%). No discontinuations due to bleeding disturbances were observed.
Kivinen and Saure 1996 [36]	Randomized Open-label	31	21/7 regimen for 6 cycles A: Micronized E2 1.5 mg/DSG 150 µg for 21 days followed by 7-day pill-free period OR B: Micronized E2 3 mg/DSG 150 µg for 21 days followed by 7-day pill-free period OR C: Micronized E2 3 mg/DSG 150 µg for 21 days followed by E2 1 mg for 7 days	Ovulation was suppressed in all women. The mean number of bleeding and/or spotting days per cycle was 11.2 for group A, 6.4 for group B and 6.2 for group C. The mean number of unexpected spotting/bleeding days per cycle was 4.3, 1.9 and 2.2, respectively. Discontinuations occurred in 3, 3 and 5 women, respectively. Reasons for discontinuation: unexpected bleeding and irritability; bleeding, nausea and headache; bleeding, breast tenderness, irritability.
Reference	Study design	n	Intervention	Key results
COCs in development or commercially available
Hirvonen et al. 1988 [33]	Randomized Double-blind	50	21/7 regimen for 6 cycles E2V 1 mg/CPA 1 mg for 10 days followed by E2V 2 mg/CPA 2 mg for 11 days followed by 7-day pill-free period (approved only in women >40 years or women 35–40 years in whom a COC containing EE is not appropriate) OR E2V 1 mg/norethisterone 1 mg for 10 days followed by E2V 2 mg/norethisterone 2 mg for 11 days followed by 7-day pill-free period (not commercially available)	Ovulation was inhibited in all women (except for one woman who ovulated during the first treatment cycle) in the E2V/CPA group. In the E2V/norethisterone group, ovulation occurred in 8 women. One additional woman in this group ovulated during all treatment cycles. Menstrual blood loss reduced in all women in the E2V/CPA group. In the E2V/norethisterone group, menstrual blood loss reduced in 40% and increased in 10% of women. The total number of bleeding days reduced with E2V/CPA and increased with E2V/norethisterone.
Hirvonen et al. 1995 [32]	Single-arm Open-label	288	21/7 regimen for 12 cycles E2V 1 mg/CPA 1 mg for 10 days followed by E2V 2 mg/CPA 2 mg for 11 days followed by 7-day pill-free period (approved only in women >40 years or women 35–40 years in whom a COC containing EE is not appropriate)	Ovulation was inhibited in 95% of women. Cumulative pregnancy rate was 0.4%. Intermenstrual bleeding was observed in 35.5% of women in cycle 3 and 24.5% of women in cycle 12. Bleeding became less frequent over time. Dysmenorrhea subsided over time.
Duijkers et al. 2010 [30]	Randomized Open-label	48	24/4 or 21/7 regimen for 6 cycles E2 1.5 mg/NOMAC 2.5 mg for 24 days followed by 4-day pill-free period OR EE 30 µg/drospirenone 3 mg for 21 days followed by 7-day pill-free period	Ovulation was suppressed in all women. Reductions in follicle size were observed with both treatments, from 19.3 mm to 6.9–8.2 mm with E2/NOMAC and from 19.6 mm to 7.4–10.8 mm with EE/drospirenone.
Chabbert-Buffet et al. 2011 [27]	Randomized Double-blind	41	21/7 regimen for 1 cycle E2 1.5 mg/NOMAC 0.625 mg for 21 days followed by 7-day pill-free period OR E2 5 mg/NOMAC 1.25 mg for 21 days followed by 7-day pill-free period OR E2 1.5 mg/NOMAC 2.5 mg for 21 days followed by 7-day pill-free period OR NOMAC 2.5 mg for 21 days followed by 7-day pill-free period	Ovulation was suppressed in all treatment groups. The lowest plasma E2 levels were observed with NOMAC 2.5 mg. The addition of E2 1.5 mg to NOMAC 2.5 mg resulted in statistically significant increases in E2 levels and decreases in mean follicle-stimulating hormone and luteinizing hormone levels.
Christin-Maitre et al. 2011 [28]	Randomized Double-blind	77	21/7- or 24/4-day regimen for 3 cycles E2 1.5 mg/NOMAC 2.5 mg for 24 days followed by E2 for 4 days OR E2 1.5 mg/NOMAC 2.5 mg for 21 days followed by E2 for 7 days	Ovulation was inhibited with both regimens. The largest follicular diameter was significantly smaller and mean follicle stimulating hormone levels were significantly lower with the 24/4 regimen than the 21/7 regimen (p < 0.05). The duration of total and withdrawal bleeding was significantly lower with the 24/4 regimen than the 21/7 regimen (p < 0.05).
Gaussem et al. 2011 [43]	Randomized Double-blind	90	21/7- or 24/4-day regimen for 3 cycles E2 1.5 mg/NOMAC 2.5 mg for 24 days followed by a 7-day pill-free period OR EE 20 µg/LNG 100 µg for 21 days followed by a 7-day pill-free period	This study compared the hemostatic effects of E2V/DNG with those of E2/NOMAC. E2V/DNG and E2/NOMAC were associated with similar effects on sex hormone-binding globulin, prothrombin fragment 1+2, fibrinogen and thrombin generation. Bleeding was assessed as a secondary outcome in this study. The duration of total bleeding, withdrawal bleeding and breakthrough bleeding appeared to be lower with E2/NOMAC than with EE/LNG.
Reference	Study design	n	Intervention	Key results
Hoffman et al. 1998 and 1999 [34,35]	Randomized Open-label Pilot study	20	28-day regimen for 6 cycles E2V 2 mg/DNG 2 mg for 24 days followed by E2V 2 mg for 4 days (development regimen within Qlaira^® development program) OR E2V 2 mg/DNG 2 mg for 7 days followed by E2V 4 mg/DNG 2 mg for 14 days followed by E2V 2 mg for 7 days (development regimen within Qlaira^® development program)	Ovulation was inhibited with both regimens. Withdrawal bleeding occurred in 91% of women in the first group and 87% of women in the second group. Irregular bleeding was observed in 60–75% of women.
Hoffman et al. 1998 and 1999 [34,35]	Not given Pilot study	100	25/3 regimen for 6 cycles E2V 3 mg for 3 days followed by E2V 2 mg/DNG 1 mg for 4 days followed by E2V 2 mg/DNG 2 mg for 16 days followed by E2V 1 mg for 2 days followed by placebo for 3 days (development regimen within Qlaira^® development program)	No pregnancies. By cycle 6, regular bleeding was noted in 97% of cycles. Intermenstrual bleeding was observed in 30% of cycles during cycles 1–3 and 15.6% of cycles at cycle 6.
Endrikat et al. 2008 [31]	Randomized Open-label	Study 1: 192 Study 2: 203	Various dynamic dosing regimens containing E2V/DNG for 3 cycles	The following regimen contained the lowest dose of DNG necessary for suppression of ovulation (defined as ovulation rate <5% with an upper limit of the 95% CI of <10% in cycle 2): E2V 3 mg alone for 2 days followed by E2V 2 mg/DNG 2 mg for 5 days followed by E2V 2 mg/DNG 3 mg for 17 days followed by E2V 1 mg alone for 2 days followed by placebo for 2 days. In cycle 2, the above regimen was associated with a Hoogland score of 5 or 6 in three of 96 women (3.1%; 90% CI = 0.2–6.1%). No safety concerns were raised with any of the regimens studied.
Ahrendt et al. 2008 [24]	Randomized Double-blind	798	26/2 or 21/7 regimen for 7 cycles E2V 3 mg alone for 2 days followed by E2V 2 mg/DNG 2 mg for 5 days followed by E2V 2 mg/DNG 3 mg for 17 days followed by E2V 1 mg alone for 2 days followed by placebo for 2 days OR EE 20 µg/LNG 100 µg for 21 days followed by placebo for 7 days	One pregnancy occurred in the EE/LNG group. Scheduled withdrawal bleeding occurred in 77.7–83.2% of E2V/DNG recipients and 89.5–93.8% of EE/LNG recipients. The intensity and duration of withdrawal bleeding was reduced with E2V/DNG compared with EE/LNG. Intracyclic bleeding was similar between the two COCs (10.5–18.6% vs. 9.9–17.1% per cycle).
Palacios et al. 2010 [37]	Single-arm Open-label	1377	26/2 regimen for 20 cycles E2V 3 mg alone for 2 days followed by E2V 2 mg/DNG 2 mg for 5 days followed by E2V 2 mg/DNG 3 mg for 17 days followed by E2V 1 mg alone for 2 days followed by placebo for 2 days	In this study in European women, this regimen was associated with an adjusted Pearl Index of 0.34. Overall, 2.5% of women prematurely discontinued treatment because of menstrual bleeding irregularities.
Natazia® Prescribing Information 2010 [26]	Single-arm Open-label	490	26/2 regimen for up to 28 cycles E2V 3 mg alone for 2 days followed by E2V 2 mg/DNG 2 mg for 5 days followed by E2V 2 mg/DNG 3 mg for 17 days followed by E2V 1 mg alone for 2 days followed by placebo for 2 days	In this study in North American women, this regimen was associated with an unadjusted Pearl Index of 1.64.

CI, confidence interval; CPA, cyproterone acetate; DSG, desogestrel; E₂V, estradiol valerate; E₃, estriol; LNG, levonorgestrel; NOMAC, nomegestrol acetate.

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].

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