Ethinylestradiol/Dienogest in Oral Contraception

The low-dose combined oral contraceptive of ethinylestradiol 30 μg and dienogest 2 mg was launched in Germany in 1995, and is now the most commonly prescribed oral contraceptive in this country. Dienogest is a novel 19-nortestosterone-derived progestin with a unique pharmacokinetic and pharmacological profile, including antiandrogenic properties. Clinical studies have demonstrated that ethinylestradiol/dienogest is a reliable ovulation inhibitor with high contraceptive efficacy that is comparable with other combined oral contraceptives. It also provides effective cycle control, with reduced intensity and duration of menstrual bleeding, and improves dysmenorrhoea. The combination of ethinylestradiol and dienogest reduces serum androgen levels, and increases the levels of thyroid hormones; however, although thyroid hormone levels increase, there is no increased activity due to increases in transporter protein. Like other low-dose oral contraceptives, ethinylestradiol/dienogest has only minor influences on lipid and carbohydrate metabolism, adrenal hormones and blood pressure parameters, and appears to have a balanced effect on the haemostatic system. Ethinylestradiol/dienogest also has beneficial effects on hair and skin; a number of studies have reported decreased hair and skin greasiness, and improvements in acne vulgaris following treatment with ethinylestradiol/dienogest. After discontinuation of ethinylestradiol/dienogest, there may be a small delay in conception during the first three cycles, but there is no subsequent impairment of fertility. Furthermore, the duration of use of ethinylestradiol/dienogest does not seem to influence the rate of conception or time to conception. Ethinylestradiol/dienogest is well tolerated; adverse reactions associated with treatment include breast pain, headache and nausea/vomiting. These adverse reactions are rare and decrease in incidence over time. Similar content being viewed by others Recent development of oral contraceptives has focused on decreasing unwanted side effects.[1] Over the last few decades, reduction of the dose of ethinylestradiol in combined oral contraceptives has decreased the incidence of adverse effects, especially cardiovascular complications.[2,3] Progestogen components with antiestrogenic and androgenic activity also contribute to increased risks of stroke and ischaemic heart disease.[4–6] Therefore, new progestogens with weak or no androgenic actions have been developed.[7] Dienogest, which has been used in Germany since 1995, is a 19-nortestosterone-derived progestin with a 17α-cyanomethyl group instead of a 17α-ethinyl group (figure 1).[8–10] Dienogest has a unique pharmacokinetic and pharmacological profile, combining some properties of 19-nortestosterone derivatives with those of progesterone derivatives.[9,10] In contrast to other nortestosterone derivatives, dienogest has no estrogenic, antiestrogenic or androgenic activity, but instead has strong antiandrogenic properties.[11] In 1995, the low-dose monophasic combined oral contraceptive of ethinylestradiol 30 μg and dienogest 2 mg was introduced into the German market. Because of its high contraceptive efficacy and favourable safety profile, ethinylestradiol/dienogest is now the most commonly prescribed oral contraceptive in Germany, and in parts of Eastern Europe. Ethinylestradiol/dienogest is also currently used in Austria and Portugal, and it will be marketed in Spain starting April 2010.[3,12,13] Due to its antiandrogenic effects, this contraceptive is well suited to women with acne vulgaris and seborrhoea.[1] This article reviews the pharmacokinetic and pharmacodynamic profile of ethinylestradiol and dienogest, and discusses contraceptive efficacy, cycle control, effects on hair and skin, and tolerability of this combined oral contraceptive. Medical literature on the use of ethinylestradiol/dienogest published since 1980 was identified using MEDLINE and EMBASE. Additional references were obtained by manual selection of reference lists of published articles. 1. Pharmacokinetics 1.1 Ethinylestradiol Ethinylestradiol undergoes hepatic first-pass metabolism and enterohepatic recirculation.[14] Oral ethinylestradiol is rapidly absorbed from the stomach and upper intestine in the fasting individual; usually, 90% is absorbed in the first hour. The time to peak concentration of ethinylestradiol is usually 1–2 hours. The bioavailability of ethinylestradiol is about 25–65%, and the elimination half-life is about 6–27 hours.[14] However, the pharmacokinetics of ethinylestradiol show large inter- and intra-individual variability.[15] 1.2 Dienogest The pharmacokinetics of oral dienogest are linear (i.e. proportional to dose).[8,16] The oral bioavailability of dienogest is about 90%. Dienogest is eliminated relatively rapidly; the terminal elimination half-life was 7.5–8.9 hours after single oral doses of dienogest 2–8 mg or dienogest 2 mg plus ethinylestradiol 30 μg.[16] According to two pharmacokinetic studies of dienogest alone or in combination with ethinylestradiol 30 μg, maximum serum concentrations were generally reached after 1–3 hours.[8] Maximum serum concentrations of dienogest after single and multiple doses were 23 and 32 ng/mL, respectively, when administered alone, and 51 and 69 ng/mL when administered with ethinylestradiol. Clearance of dienogest was about 4 L/h after a single dose and was unchanged with multiple doses of dienogest alone, but decreased to about 3 L/h after multiple doses of dienogest in combination with ethinylestradiol.[8] These results show that, typically for nortestosterone-derived progestins, the pharmacokinetics of dienogest are not linear when combined with ethinylestradiol.[8] 2. Pharmacodynamic Profile of Ethinylestradiol/Dienogest 2.1 Antiandrogenic Properties The combination of ethinylestradiol and dienogest reduces serum androgen levels. Following ethinylestradiol/dienogest treatment, serum levels of sex hormone-binding globulin increased significantly, and there were significant decreases in total and free testosterone levels.[17–19] During treatment with ethinylestradiol/dienogest, antiandrogen activity can be detected after 3–6 days and steady-state levels of androgen parameters were reached within 3 months.[17] 2.2 Effects on Thyroid Hormones Ethinylestradiol/dienogest treatment results in an increase in the levels of thyroid hormones; during treatment with ethinylestradiol/dienogest, steady-state levels of thyroid hormones were reached within 3 months.[17] Studies have demonstrated significant increases in serum levels of the transporter protein thyroxine-binding globulin,[17,19] and total T3 and T4,[17] after receiving ethinylestradiol/dienogest. However, levels of free T3 and free T4 did not change significantly, indicating that the activity of both was unaffected.[17] This lack of increased thyroid function activity is due to increases in thyroxine-binding globulin. 2.3 Effects on Carbohydrate Metabolism In a study subgroup of 29 women, the effects of ethinylestradiol/dienogest on carbohydrate metabolism were measured over three cycles of treatment.[1] Similar to other low-dose ovulation inhibitors, ethinylestradiol/dienogest caused a slight increase in serum insulin levels and insulin resistance. There were small but significant increases in fasting serum levels of insulin and C-peptide, although values generally remained within the normal range. There were no significant increases in glucose levels, glycosylated haemoglobin levels or the insulin/glucose ratio.[1] 2.4 Effects on Lipid Metabolism Ethinylestradiol/dienogest significantly increased levels of triglycerides, very low-density lipoprotein cholesterol, high-density lipoprotein (HDL) cholesterol and apolipoprotein A1, and there was a slight increase in apolipoprotein B, in a small substudy of 20 women.[1] There were no significant changes in total cholesterol and lipoprotein(a), and levels of low-density lipoprotein cholesterol tended to decrease.[1] Another study of 25 volunteers who received six cycles of ethinylestradiol/dienogest 30 μg/2 mg showed nonsignificant increases in HDL cholesterol, a significant increase in apolipoprotein A1 and a significant reduction in lipoprotein(a); these changes were more favourable than for ethinylestradiol combined with levonorgestrel.[7] Dienogest alone, when used for the treatment of endometriosis, had no significant effects on lipid metabolism.[20] Therefore, the effects of ethinylestradiol/dienogest on lipid metabolism are predominantly caused by the estrogen component, but are similar to those described for other estrogen-predominant low-dose ovulation inhibitors and are not thought to be deleterious.[1] 2.5 Effects on Haemostasis Ethinylestradiol/dienogest appears to have a balanced effect on the haemostatic system, with minimal stimulation of both procoagulant and fibrinolytic activities.[21] Treatment with this combined oral contraceptive led to significant increases in factor VII, protein C and fibrinolytic activity, compared with placebo[21] and baseline levels.[1,22] 2.6 Effects on Insulin-Like Growth Factor I and Growth Hormone In a small study of nine healthy women, the mean insulin-like growth factor I levels decreased by 30% (p = 0.008), but there was no significant change in the mean plasma levels of growth hormone following one treatment cycle with ethinylestradiol/dienogest.[23] 2.7 Effects on Adrenal Hormones and Serum Blood Pressure Parameters Ethinylestradiol/dienogest has only mild effects on adrenal and serum blood pressure parameters.[24] After six cycles of treatment with ethinylestradiol/dienogest 30 μg/2 mg, serum cortisol levels increased significantly (by 74–100% vs control cycle; p < 0.05), as did those of three comparator combined oral contraceptive ethinylestradiol formulations (ethinylestradiol/dienogest 20 μg/2 mg, ethinylestradiol/estradiol valerate/dienogest 10 μg/2 mg/2 mg and ethinylestradiol/levonorgestrel 20 μg/100 μg). There were no significant between-group differences.[24] Angiotensin II levels were unchanged during the first three cycles and then decreased significantly (vs control cycle) in the sixth cycle in the ethinylestradiol/dienogest 30 μg/2 mg and the three comparator groups, but there was no significant change in endothelin-1 levels in any treatment group.[24] 3. Mechanism of Action of Ethinylestradiol/Dienogest The contraceptive activity of dienogest is effected via several different mechanisms of action, including specific effects on the ovaries to modulate ovarian function.[25] Also, dienogest exerts its antiproliferation activity by growth suppression of endometrial cells.[11,26–29] The precise mechanism of the antiproliferation effect is unknown, but dienogest is thought to exert its inhibitory effect via receptors other than progesterone.[29] Dienogest has weak antigonadotrophic activity; inhibition of ovulation is thought to occur mainly via peripheral actions rather than central effects on the hypothalamus-pituitary axis resulting in suppression of gonadotrophin secretion.[10,11,25,30] 4. Contraceptive Efficacy of Ethinylestradiol/Dienogest Generally, combined oral contraceptives have a Pearl Index of about 0.2.[31] Ethinylestradiol/dienogest 30 μg/2 mg is a reliable ovulation inhibitor. In a phase III study of 2290 women who received up to 22 cycles of treatment (28 183 treatment cycles in total), the adjusted Pearl Index was 0.21.[1] Two studies that investigated the contraceptive efficacy of ethinylestradiol/dienogest in the Czech Republic[12] and Poland[13] enrolled 557 and 431 healthy women, for a total of 6051 and 4608 treatment cycles, respectively. In the Czech study, the adjusted Pearl Index was 0.198.[12] No women in the Polish study became pregnant (unadjusted Pearl Index of 0).[13] In a postmarketing surveillance study of 16 087 women over 92 146 treatment cycles, the adjusted Pearl Index was 0.09.[2] These data demonstrate that ethinylestradiol/dienogest has high contraceptive efficacy. Other low-dose monophasic oral contraceptives containing desogestrel, levonorgestrel or gestodene have a Pearl Index of between about 0.1 and 0.8.[32–35] Therefore, ethinylestradiol/dienogest has comparable contraceptive efficacy to other similar oral contraceptives. 5. Cycle Control On average, ethinylestradiol/dienogest treatment led to reduced intensity of menstrual bleeding and decreased duration of menstruation, but did not affect cycle length.[1,12,13] These studies also demonstrated marked reductions in the frequency of dysmenorrhoea. In the phase III trial of over 2000 women, dysmenorrhoea was common at baseline (28.8%), but decreased to 12.9% in the first dosing cycle and had completely disappeared after the sixth cycle.[1] In the Czech study, the incidence of dysmenorrhoea decreased from 50% at baseline to about 10% from cycle 4 onwards;[12] in the Polish study, the incidence decreased from 35% at baseline to about 10% from cycle 3 onwards.[13] At baseline, breakthrough bleeding and spotting were reported by 12.8% of women in the Czech study and 10% of women in the Polish study; in cycle 1, the incidences increased to 29% and 30%, respectively. By cycle 6 or 7, the incidence of breakthrough bleeding and spotting had decreased to less than the baseline rates.[12,13] In the postmarketing surveillance study (n = 16 087), the incidences of spotting and breakthrough bleeding were 5% and 3.4%, respectively, in the first cycle, but the incidences rapidly decreased thereafter (figure 2).[2] The baseline incidences of spotting and breakthrough bleeding were 6.6% and 8.0%, respectively, in the phase III study.[1] The overall rate of intermenstrual bleeding increased to 21.5% during the first cycle, but by the third cycle, the incidences of spotting and breakthrough bleeding were lower than baseline rates. After a year of treatment, the incidences of spotting and breakthrough bleeding had decreased to 2.8% and 4.2%, respectively.[1] Silent menstruation (absence of withdrawal bleeding) was most common in the first cycle of ethinylestradiol/dienogest treatment in the Czech and Polish studies (4.8% and 3.7%, respectively), but decreased to about 3% for subsequent cycles.[12,13] Similarly, the phase III study reported silent menstruation in 3% of cycles on average.[1] In the postmarketing surveillance study, 5.9% of women experienced silent menstruation and the overall incidence per cycle was about 2% (figure 2).[2] 6. Fertility after Discontinuation of Ethinylestradiol/Dienogest Two studies have investigated fertility in women who discontinued treatment with ethinylestradiol/dienogest to become pregnant.[3,36] About 60%[36] and 56%[3] of women conceived within the first three cycles after ethinylestradiol/dienogest discontinuation (figure 3). Within 1 year, the cumulative pregnancy rates were 94%[3] and 95%.[36] A study of fertile women who were trying to become pregnant reported pregnancy rates of 64% after three menstrual cycles and 91% after 12 cycles.[37] Therefore, there may be a small delay in conception during the first three cycles after discontinuation of ethinylestradiol/dienogest, but there is no subsequent impairment of fertility. Furthermore, the duration of use of ethinylestradiol/dienogest did not appear to influence the rate of conception or the time between discontinuation and conception.[3,36] 7. Effects of Ethinylestradiol/Dienogest on Hair and Skin 7.1 Acne Vulgaris Ethinylestradiol/dienogest has a beneficial effect on acne. In 525 women with mild to moderate papulopustular acne, six cycles of ethinylestradiol/dienogest led to significantly greater improvements than placebo and non-inferiority to ethinylestradiol/ciproterone acetate in inflammatory lesion count and total lesion count, and a significantly greater proportion of patients had acne improvement (91.9% vs 76.2%; measured by the Investigator Global Assessment).[38] Of 6004 women with acne at the beginning of a postmarketing surveillance study, 29.1% had healed acne and 61.5% had improved acne after six cycles of treatment (figure 4). Healing of acne was observed more frequently in women who had mild acne at baseline than in women who had moderate or severe acne.[39] In the Czech and Polish studies, 113 and 59 patients, respectively, were diagnosed with acne at baseline. After cycle 12, 58% of patients in the Czech study had improved acne and 18% had healed acne; the corresponding values in the Polish study were 54% and 37%, respectively.[12,13] 7.2 Greasy Hair and Skin In the postmarketing surveillance study, hair greasiness decreased overall (table I).[39,40] After three cycles, the proportion of women with severe hair greasiness had decreased from 11.3% to 1.5%, and the proportion with moderate greasiness decreased from 27.4% to 17%. After six cycles, the incidence of severe and moderate hair greasiness was <1% and 6%, respectively, and the proportion with no greasiness had increased by 26% compared with baseline. In a subjective assessment completed by 8221 women, 69.8% reported that their hair became greasy less rapidly.[39,40] Similarly, of 279 and 402 women with greasy hair in the Czech and Polish studies, 32% and 54%, respectively, experienced an improvement after 12 cycles.[12,13] Ethinylestradiol/dienogest also led to large reductions in the incidence of greasy skin disorders (table I).[39,40] At baseline, severe and moderate symptoms of greasy skin disorders were present in 15.6% and 39.2% of women, but after six treatment cycles were present in only <1% and 7.6%, respectively. Of 7985 women who completed a subjective assessment, 81.4% reported fewer symptoms of greasy skin disorders.[39,40] 7.3 Overall Effect on Hair and Skin In an evaluation of the effect of ethinylestradiol/dienogest on skin and hair (a survey completed by 10 534 women), 36.8% of respondents rated the effect as very good, 50.7% rated it as good, 9.5% as satisfactory and only 3.0% as unsatisfactory.[39,40] 8. Safety and Tolerability Overall, ethinylestradiol/dienogest has very good tolerability. In the postmarketing surveillance study, 914 participants (5.7%) reported 1289 adverse drug reactions.[2,41] Table II shows the most common adverse reactions, which included breast pain (1.46%), weight gain (1.11%), headache (0.98%) and nausea/vomiting (0.96%). Six serious adverse reactions were thought to be possibly or probably related to ethinylestradiol/dienogest. These reactions were thrombosis (n = 2), pulmonary embolism (1), disturbed liver function (2) and metaplasia of the exocervix (1). All subjects with serious adverse reactions fully recovered. As shown in figure 5, the tolerability of ethinylestradiol/dienogest was rated as very good by 47% of subjects and good by 41% during cycles 1–3; during cycles 4–6, 60% rated the tolerability as very good and 34% rated it as good.[2,41] The most common adverse events in the phase III multicentre trial (n = 2290) were headache, breast tension, nausea/vomiting, depression and oedema. In cycle 3, these adverse events had incidences of 0.5–12.3%, but the incidences decreased throughout the trial (0–3.5% at cycle 18).[1] Similarly, in the Czech and Polish studies, adverse events experienced by ≥1% of participants in any cycle included breast tenderness, gastric complaints, headache, increased and decreased libido, and depressive mood. These events tended to decrease in frequency over time, and were usually mild or moderate in severity.[12,13] The incidences of the most common adverse events with ethinylestradiol/dienogest are comparable with those observed in clinical trials of similar oral contraceptives. Over a number of studies with ethinylestradiol/desogestrel, average incidences of headache, breast tenderness and nausea were about 5%, 4% and 2%, respectively, and changes in bodyweight were minor.[34] Two studies of ethinylestradiol/gestodene reported headache in 2.1% and 3.0% of participants, nausea in about 2%, weight gain in 1.4% and weight loss in 0.6%.[32,33] Similarly, with ethinylestradiol/levonorgestrel, the incidences were headache 14%, nausea 7%, breast pain 4% and depression 2%.[35] In the postmarketing surveillance study of ethinylestradiol/dienogest, the incidence of superficial phlebitis/thromboembolic event was 0.05%.[41] The phase III study reported one case of thrombophlebitis of the leg, corresponding to a rate of 0.45 events per 1000 women-years.[1] This incidence is similar to that reported in a trial of 96 000 women who received ethinylestradiol/gestodene where the incidence of thrombotic events was 0.65 per 1000 woman-years.[33] Incidence rates of venous thromboembolism for desogestrel- and levonorgestrel-containing oral contraceptives have been estimated at 0.535 and 0.271 per 1000 woman-years, respectively.[42] In the Czech and Polish studies, no thrombophlebitic events occurred.[12,13] 9. Conclusions Ethinylestradiol/dienogest is a reliable ovulation inhibitor, with contraceptive efficacy that is comparable with other low-dose combined oral contraceptives. It provides good cycle control, with reduced intensity and duration of menstrual bleeding, and improves dysmenorrhoea. Like other low-dose oral contraceptives, ethinylestradiol/dienogest has only minor influences on lipid and carbohydrate metabolism, adrenal hormones and blood pressure serum parameters, and appears to have a balanced effect on the haemostatic system. This contraceptive also has beneficial effects on hair and skin; a number of studies have reported decreased hair and skin greasiness, and improvements in acne vulgaris. Ethinylestradiol/dienogest does not appear to affect fertility following discontinuation. This oral contraceptive has been associated with good tolerability over almost 15 years of use; the rate of adverse events is low and they are usually mild to moderate in severity. Furthermore, patient satisfaction with ethinylestradiol/dienogest is high, with the majority of patients rating the tolerability and effect on hair and skin as good or very good.

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Dr Pérez-Campos has acted as a consultant, participated in advisory boards, provided expert testimony, received honoraria for lectures and symposia, and received grants for clinical research from the following companies: MSD, Bayer Schering Pharma, Juste Laboratories, Grunenthal and Wyeth Pharma, Merck Serono, HRA Pharma and Janssen-Cilag. Medical writing assistance for this article was provided by Lucy Ebden of inScience Communications. This assistance was funded by Effik. Author information Authors and Affiliations Corresponding author Rights and permissions About this article Cite this article Pérez-Campos, E.F. Ethinylestradiol/Dienogest in Oral Contraception. Drugs 70, 681–689 (2010). https://doi.org/10.2165/11536320-000000000-00000 Published: Issue date: DOI: https://doi.org/10.2165/11536320-000000000-00000