Abstract
Considerable advances have been made in the field of combined oral contraceptives since their introduction 50 years ago. This ongoing evolution has been focused on reducing the estrogen dose and synthesizing new progestogens. A recently launched combination of ethinylestradiol 20 μg and drospirenone 3 mg demonstrates the advantages of a lower estrogen dose with the antimineralocorticoid activity of drospirenone that is responsible for the drug's significant antiandrogenic and antimineralocorticoid effects, reflected clinically in lower rates of adverse events including less fluid retention. In addition to the drug's contraceptive efficacy, its effects on the skin and other classic noncontraceptive benefits, the ethinylestradiol 20 μg and drospirenone 3 mg combination has demonstrated highly satisfactory results in women with premenstrual dysphoric syndrome.
Keywords
In view of the large number of currently available contraceptive formulations, critical analysis based on evidence with a solid scientific grounding is crucial. In the last 50 years, a major evolution has occurred in oral contraception, focusing principally on the estrogen dose and the synthesis of new progestogens. The combination of different doses of ethinylestradiol (EE) with different progestogens is reflected in the wide variety of contraceptives available on the market worldwide, which, although attractive from the point of view of availability and possible therapeutic individualization, may, on the other hand, generate doubts regarding the real benefits or advantages of specific formulations in certain clinical situations. In this respect, knowledge on the most relevant pharmacological, metabolic and clinical aspects of the components of the combined oral contraceptives is extremely relevant.
The first pills contained rather high doses of EE, approximately 5–10 times higher than those found in current contraceptives. Pills with doses of EE below 50 μg are considered low-dose pills [1]. Therefore, the contraceptives containing EE 35, 30, 20 or 15 μg, all belong in this same category. Therefore what would be the principal differences between these low-dose compounds? What advantages have been gained from reducing the estrogen dose in recent years? These questions are pertinent and common in routine practice. At the same time, the progestogens, classified according to their biochemical and clinical characteristics and combined with different doses of EE, may also generate queries when having to select the most appropriate contraceptive for a particular patient.
In general, contraceptives containing an association of low-dose EE and progestogens structurally related to progesterone, testosterone and spironolactone are already available [1].
Comparative analysis of the estrogen element is limited to the doses used. On the other hand, the progestogens are analyzed according to their ability to bind with the steroid receptors. An important factor in a progestogen is its selectivity index, defined as the relationship between the affinity of the steroid for the progesterone receptors and other receptors [2]. The more selective the progestogen, the greater its affinity for the progesterone receptor and the poorer its affinity for other receptors. This concept is particularly useful when evaluating different progestogens in oral contraception. In accordance with their chemical structure, progestogens related to progesterone tend to be more selective than those structurally related to testosterone as a result of the greater affinity of the latter for the androgen receptor. Conversely, the effect on a receptor may determine the pharmacological activity of the progestogen. In this respect, progestogens may be classified in accordance with their particular characteristics, the majority of which refer to their progestogenic, estrogenic, glucocorticoid, androgenic, antiandrogenic and antimineralocorticoid effects. In brief, 19-nortestosterone-derivative progestogens such as levonorgestrel, desogestrel (DSG) and gestodene exert androgenic activity, although this has no clinical significance at the doses used in contraception; on the other hand, dienogest, a nonethinylated progestin that is structurally related to testosterone, has antiandrogenic activity. Progestogens structurally related to progesterone, such as cyproterone acetate, chlormadinone acetate and drospirenone (DRSP) have an antiandrogenic effect. Of this group, DRSP is the only compound that has been shown to have an antimineralocorticoid effect. The high selectivity of DRSP, as shown by its pharmacological profile, which is close to that of endogenous progesterone, has also been demonstrated [2].
The contraceptive combination of 20 μg of EE and 3 μg of DRSP was recently approved in a 24-day regimen with a 4-day intake of a placebo. In addition to the contraceptive characteristics of this compound, the new contraceptive was also evaluated in patients with premenstrual dysphoric disorder (PMDD), demonstrating highly satisfactory results for the treatment of this clinical condition [3,4], thus making this combination a landmark in the development of modern contraception.
DRSP 3 mg & EE 20 μg
Pharmacology
Pharmacokinetics of ethinylestradiol
Following oral administration of the EE 20 μg/DRSP 3 μg combination, EE is rapidly absorbed, reaching peak serum levels after approximately 1.5 h, as reported in a study conducted in healthy young women. The absorption rate was maintained with little variation throughout 13 cycles of follow-up [5].
No clinically relevant difference was found in the absorption rate and distribution of EE between different ethnic groups.
Ethinylestradiol binds almost totally to serum albumin (~98.5%) [Schering AG, Unpublished Data]. Following oral administration, EE passes through the enterohepatic circulation and is excreted as glucuronide and sulfate conjugates in urine and feces [6]. The mean total clearance of EE following intravenous administration is 2.3–7 ml/min/kg with an elimination half-life (t½) of approximately 24 h [6].
Systemic exposure to EE was increased by repeat administration, with an increase in the mean value of the area under the curve (AUC) for serial time–concentration from baseline to 24 h (AUC 24) of 65%, occurring between days 1 and 21 at the end of the first treatment cycle (280 vs 461 ng/h/l), with a mean accumulation rate of 2.1 [5]. AUC 24 values at the end of cycles 6, 9 and 13 were similar to those found on day 21 of the first cycle [5].
Following administration of a single dose of EE/DRSP, the absolute bioavailability of EE was approximately 40%, whereas relative bioavailability (compared with the suspension) was 117% [101].
Oral absorption of EE is affected by food. Maximum concentration values (Cmax) may be reduced by up to 40% and absorption by up to 20% [101]. This, however, is not considered clinically relevant [7] and the EE/DRSP combination may be administered with no concern regarding meal times.
Pharmacokinetics of DRSP
Drospirenone is quickly and extensively absorbed following oral administration, with little variation between cycles. The mean bioavailability of DRSP was reported as 76 ± 13% following an oral dose of 2 mg of the compound [7].
The Cmax of DRSP was reached after 1.5–2 h, the time until Cmax (Tmax) following administration of a single dose of EE/DRSP (n = 13) [5]. Mean Tmax following administration of EE/DRSP did not differ between treatment cycles [5]. Serum levels of DRSP are linearly related to dose following oral doses of 0.1–10 mg [8].
Following a 2-mg dose of oral DRSP, absolute mean bioavailability was 76% and relative bioavailability (in comparison to that obtained with a suspension) after a single dose of EE/DRSP was 107% [4]. After a daily dose of EE 20 μg/DRSP 3 mg, the state of equilibrium of DRSP was evaluated over 7 days, with a two-to-threefold increase in DRSP values [8].
Mean Cmax more than doubled in relation to the initial value in healthy young women (n = 12) after completing the first treatment cycle (21 pills), 36.9 versus 87.5 g/l on days 1 and 21 of the cycle [5]. However, serum levels of DRSP failed to return to baseline values in the 7-day pill-free period, leading to a slight accumulation of the drug that reached a state of equilibrium by the end of the sixth cycle [5].
The AUC value for DRSP of 1889 μg.h/l, calculated on the 21st day of the first cycle, increased to 2228 μg.h/l by the end of the sixth cycle, remaining constant at this level thereafter [5].
The state of equilibrium values for the AUC 24 for DRSP was also reached at the end of the sixth cycle [1]. The AUC 24 values almost tripled between day 1 and 21 of the first cycle (288 vs 826.5 μgh/l). At the end of the sixth cycle, AUC 24 increased to 930 μg h/l, a value similar to that found at the end of the 13th cycle (968 μg h/l) [5].
The pharmacokinetic profile of DRSP following a single dose remained unchanged when the drug was combined with 20 μg of EE [6].
In a study in which a combination of 3 mg of DRSP and 20 μg of EE was administered consecutively for 21 days to healthy Caucasian and Japanese women (n = 48), no clinically relevant differences were obsereved between the two ethnic groups with respect to the pharmacokinetics of DRSP [Schering AG, Unpublished Data].
Drospirenone absorption is also slowed by food. The rate, but not the extent, of the systemic absorption of DRSP is affected by simultaneous ingestion of tablets of DRSP/EE and food; however, this effect is not considered to be clinically relevant [9].
The apparent distribution volume of DRSP following a 500-μg intravenous dose is approximately 4 l/kg [101].
Circulating DRSP binds almost totally to serum proteins: approximately 95–97% of the drug is believed to bind to albumin [10]. Unlike other progestogens, DRSP does not bind to sex hormone-binding globulin (SHBG) or to corticosteroid-binding globulin; therefore, its pharmacokinetic profile remains unaffected by the underlying increase induced by EE in the levels of these two proteins [8,10].
Drospirenone is extensively metabolized in the liver prior to being eliminated, with only traces of the drug being excreted in an unaltered state in urine or feces. Excretion is almost complete 10 days after a single dose and the feces:urine excretion ratio is 1.2:1.4. The two principal metabolites found in plasma are the acid form of DRSP formed by the opening of the lactone ring and 4,5-dihydroDRSP-3-sulfate. These metabolites are pharmacologically inactive and are formed without any involvement of the CYP enzymes [7,8].
The mean total clearance of DRSP has been calculated at 1.5 ± 0.2 ml/min/kg following an intravenous dose of 500 μg [7,8]. After taking the DRSP 3 mg/EE 30 μg combination daily for 21 days, the terminal mean half-life of DRSP was calculated at 30.9 ± 13.7 h at the end of the first cycle; 32.5 ± 12.5 h at the end of the sixth cycle; 31.4 ± 12.3 h at the end of the ninth cycle; and 31.1 ± 11.3 h at the end of the 13th cycle. Post-maximum serum levels of DRSP declined biphasically, with a mean terminal half-life of 31-33 h over the period evaluated [Schering AG, Unpublished Data].
Therefore, the hormone-free interval of 4 days does not result in complete elimination of DRSP from the systemic circulation prior to initiating the next cycle of use.
Principal properties
Inhibition of ovulation & other contraceptive effects
Combined oral contraceptives inhibit follicular development and ovulation, suppressing the hypothalamic–pituitary–ovarian axis. Studies that evaluated the effects of various doses of DRSP alone or in combination with EE on ovulation inhibition demonstrated that DRSP inhibited cervical function and reduced spinnbarkeit and the degree of cervical mucus crystallization in all the groups in which it was used, irrespective of dose, thus providing additional contraceptive effects [1]. Ovarian activity was compared between two groups using DRSP 3 mg/EE 20 μg, on a 24/4 regimen and a 21/7 regimen. Follicle-stimulating hormone (FSH), lutenizing hormone levels (LH), estradiol and progesterone levels were compared with baseline levels. When the Hoogland score (a low score is indicative of ovarian suppression) was compared between the two groups, that of the 24/4 group was 6.01 times higher (95% CI: 2.29–17.94) compared with that of the group using the 21/7 regimen [11]. Both dose regimens effectively suppressed ovarian activity; however, the 24/4 regimen was associated with greater suppression, reflecting the possible higher contraceptive efficacy of this dose formulation [12].
Endometrial effects
Long-term use (13 cycles) of DRSP 3 mg and EE 30 μg in a 21/7 dose regimen was found to have a marked antiproliferative effect on the endometrium of healthy, menstruating women, similar to that found with other combined oral contraceptives [13].
The antiproliferative effects on the endometrium are caused principally by the progestogen. In addition, with a low estrogen dose and 3 extra days of hormone use per cycle, the EE 20 μg/DRSP 3 mg combination was expected to exert a marked antiproliferative effect on the endometrium at least comparable with that of the oral contraceptive combination of DRSP 3 mg with EE 30 μg. The EE 20 μg/DRSP 3 mg combination results in less fluctuation in endogenous estrogen.
Receptor binding
The receptor-binding profile of DRSP reflects the high antimineralocorticoid and antiandrogenic activity of the progestogen [14,15].
Drospirenone exerts no androgenic, estrogenic or antiglucocorticoid activity and its receptor-binding profile is very similar to that of progesterone; however, it exerts less antiandrogenic activity and no glucocorticoid activity, although studies have shown affinity to the glucocorticoid receptor with moderate activity [16,17].
Animal studies have confirmed the findings of in vitro studies. For example, in in vivo rat models, DRSP was found to exert a progestogenic effect similar to that of norethisterone acetate and one-third of that found with cyproterone acetate. Mineralocorticoid activity was eight-times greater than that of spironolactone (as measured by the drug's effect on Na+/K+ excretion rate), while antiandrogenic activity was five- to ten-times greater than that of progesterone but less than that of cyproterone acetate [14,15].
Estrogenic activity
Estrogen acts synergically with DRSP to suppress the hypothalamic–pituitary axis by reducing FSH and LH. In addition, estrogen maintains the endometrium and helps prevent withdrawal bleeding.
Progestational activity
Drospirenone inhibits the stimulation of follicular activity and ovulation by suppressing LH. It also prevents conception by reducing sperm transport through modifications to the cervix and cervical mucus and affects implantation through endometrial atrophy. DRSP inhibits ovulation in a dose-dependent manner, with the results of randomized clinical trials indicating that the ideal dose is 3 mg.
Antimineralocorticoid property In clinical trials, DRSP, when administered alone or in combination with EE to healthy young women, has been found to exert an antimineralocorticoid effect on the renin–angiotensin–aldosterone system (RAAS) similar to that of endogenous progesterone [16,18].
In a normal menstrual cycle, urinary sodium, aldosterone excretion, plasma renin activity (PRA) and plasma aldosterone levels are significantly higher in the luteal phase of the cycle compared with the follicular phase. This physiological natriuresis occurs as a result of the progesterone activity that is predominant in this phase of the cycle [17].
Treatment with DRSP causes natriuresis irrespective of the amount of sodium and potassium in the diet [17].
Oelkers et al. studied 12 healthy women on a diet standardized with respect to sodium and potassium intake beginning on the third day of the menstrual cycle [19]. These women were randomized into two groups to receive DRSP 2 mg (n = 6) or placebo (n = 6) from days 8 to 13 of the cycle. Cumulative sodium excretion increased from a mean of 79 to 98.5 ± 8.3 mmol in the DRSP group compared with the placebo group. Increases in plasma aldosterone levels and urinary aldosterone excretion were also observed. No difference was found between the DRSP and placebo groups with respect to urinary potassium excretion or serum potassium levels. Treatment with DRSP significantly increases plasma renin activity [18] and the response is not dose-related [18], as shown in the study conducted by Olkers et al., in which a regimen of increasing doses of oral DRSP (0.5, 1, 2 or 3 mg once daily) failed to show any dose–response effect [19].
Plasma aldosterone levels increase with DRSP treatment [17,18]. In two small studies, DRSP 2 mg (n = 6 in each study) provoked a significant increase in aldosterone levels compared with baseline values (p < 0.05 and p < 0.01). No such increase was found with cyproterone acetate 1 mg (n = 6) [18] or with placebo (n = 6) [17].
Urinary aldosterone excretion increased in women taking DRSP [17]. Following administration of DRSP 2 mg (n = 6) from day 5 to day 25, significant natriuresis (p < 0.01) occurred in the first half of the cycle (between day 5 and day 13) compared with values in a control cycle. Urinary aldosterone excretion remained significantly higher in the second half of the treatment cycle (p < 0.05) compared with values found in the luteal phase of the control cycle [17]. By contrast, urinary aldosterone excretion remained relatively unchanged in women receiving cyproterone acetate 1 mg (n = 6) [18].
The effect of DRSP on PRA and plasma aldosterone is reversible, the increase in these parameters during the 21 days of active treatment with EE 30 μg/DRSP 2 or 3 mg (n = 35 in each group) generally returning to baseline values by the fifth treatment-free day of the cycle, hence within the hormone-free interval [18].
No significant alteration was found in the serum sodium, creatinine or potassium levels of women receiving 15–30 μg of EE/DRSP 3 mg (n = 60) or EE 30 μg/levonorgestrel 150 μg (n = 20) [19].
Nonetheless, as a consequence of the antimineralocorticoid effect of DRSP (comparable with a 25-mg dose of spironolactone), hyperkalemia may potentially develop in high-risk women, particularly those with kidney failure who take oral contraceptives containing DRSP concomitantly with potassium-sparing agents [101].
Treatment with DRSP 3 mg daily for 14 days had no clinically significant effect on serum potassium levels in women aged 30–60 years with mild (creatinine clearance [CrCl] 3–4.8 l/h [50–80 ml/min]) or moderate (CrCl 1.8–3 l/h [30–50 ml/min]) kidney failure on a potassiumpoor diet. However, in five of the seven women who were concomitantly taking potassium-sparing drugs, potassium levels increased on day 14 of the study (a mean increase of 0.33 mEq/l) [101].
In the long term, DRSP proved to be a strong stimulator of PRA and plasma aldosterone compared with levonorgestrel or DSG in combination with EE in women taking the drug as a contraceptive at the recommended doses [16,19]. Although mean PRA and serum aldosterone levels increased markedly during treatment with EE 15–30 μg and DRSP 3 mg (n = 60 [15] and n = 30 [18]) for six or 13 cycles compared with baseline values, EE 30 μg in combination with DSG 150 μg (n = 30) and EE 30 μg with levonorgestrel 150 μg (n = 20) had a minimal effect on these parameters [17,19].
The strong stimulus of RAAS by DRSP reflects a compensatory reaction to the loss of sodium [17,18].
Antiandrogenic activity
The beneficial effects of combined oral contraceptives on acne and other skin conditions are related to the direct inhibition of ovarian androgen secretion. Furthermore, the estrogen component of combined oral contraceptives increases plasma SHBG levels, which reduces the effects of free testosterone and other androgens.
Studies on receptor binding and transactivation, as well as studies of DRSP in animal models, have confirmed the significant antiandrogenic properties of this drug [15].
Drospirenone, cyproterone acetate, chlormadinone acetate and dienogest are the progestogens that, at therapeutic doses, have been shown to have antiandrogenic properties.
The combination of EE and DRSP reduces ovarian androgens and sebum production in the skin of healthy young women with mild-to- moderate acne as effectively as a pill containing EE 35 μg and cyproterone acetate 2 mg, a traditional progestogen with antiandrogenic activity [20].
Contraceptive efficacy
Large multicenter studies were conducted to evaluate the efficacy of the combined oral contraceptive containing DRSP 3 mg and EE 20 μg administered in a regimen of 24 days of active pill use followed by a 4-day hormone-free interval.
Bachmann et al. conducted a multicenter, open, noncomparative study in 35 centers in Austria, Argentina, Brazil, Poland and the USA [21]. Healthy women aged 17–36 years with a BMI of less than 35 kg/m2 were recruited. A total of 1018 women were analyzed over 11,140 cycles of use. During the study, 11 pregnancies occurred, resulting in an uncorrected Pearl Index (PI) of 1.29 (upper limit of the 95% CI: 2.30). A total of six of these pregnancies were attributed to problems related to compliance such as forgetfulness or irregular use, resulting in an adjusted PI of 0.72 (upper limit of the 95% CI: 1.69) based on 9010 treatment cycles. The cumulative-year pregnancy rate was 1.26% (95% CI: 0.52–2.01), corresponding to contraceptive protection of 99%.
Recently, Hernádi et al. conducted an open, multicenter, noncontrolled study in 50 European centers to evaluate the efficacy of this combined contraceptive [22]. Healthy women aged 18–35 years with a BMI less than 30 kg/m2 were administered this contraceptive pill for 13 cycles. The principal variable evaluated was the number of unplanned pregnancies. In the 1101 women evaluated, five pregnancies occurred over 13,248 treatment cycles resulting in a PI of 0.49 with an upper limit 95% CI of 1.14. Three of these pregnancies were attributed to noncompliance, resulting in an adjusted PI of 0.22 for ‘perfect use’ with an upper limit of the 95% CI of 0.80 based on 11,755 treatment cycles.
Based on these large studies, it was concluded that the combined oral contraceptive pill containing DRSP 3 mg and EE 20 μg on a 24/4 regimen is highly effective in nonobese women. The PI obtained with this formulation is similar to that of other low-dose combined oral contraceptives.
Clinical effects
General profile
In general, the EE/DRSP formulations are well tolerated and adverse events tend to be mild or moderate, and do not normally require any intervention [8]. The lower dose composition (EE20/DRSP) in a 24/4 regimen was evaluated over 13 cycles in 1027 participants in an open-label, noncomparative, multicenter study. Most adverse events were mild and transitory and considered typical of contraceptive pills. At least one adverse event possibly related to the drug occurred in 38.5% of participants. Headache was the most common side effect, being reported by 6.5% of participants, followed by breast pain (6.3%) and nausea (2.5%). The study medication was discontinued by 7.5% of the participants owing to adverse events [21].
A placebo-controlled study designed to evaluate the effect of treatment with EE20/DRSP in a 24/4 regimen on moderate acne was conducted in 534 women. At least one adverse event was reported by 63.9% of the users of the pill versus 48.1% of women in the placebo group. Treatment was discontinued due to adverse events in 6.4% of women in the EE20/DRSP group and 4.9% in the placebo group [23]. Another study with an identical design involving 538 women reported at least one adverse event in 55.2% of the participants in the EE20/DRSP group and 45.9% in the placebo group; however, only 5.9% of the women in the pill group and 3.4% in the placebo group discontinued treatment as a result of an adverse event [24].
The same formulation (EE20/DRSP) in a 21/7 regimen was also found to have a good safety profile and be well-tolerated by 516 women participating in a multicenter study in which the contraceptive pill was evaluated over 26 treatment cycles. The adverse events observed during treatment were those typically associated with contraceptive pills and the majority of participants (86.8%) claimed to be satisfied or very satisfied with the treatment [25].
The EE20/DRSP combination was evaluated in a 24/4 regimen in a large European study involving 1101 women, 961 of whom completed 13 cycles of treatment. Adverse events occurred in 47.8% of the participants. Of these, the adverse event may have been related to the study medication in 21.2% of the participants. The most common adverse events were metrorrhagia (8.0%) followed by amenorrhea (4.5%), cephalea (2.9%), painful breasts (1.3%) and nausea (1.1%). As many as 25 serious adverse events occurred in 22 women; however, 24 of these events were not considered to be related to the study medication while the other was considered as probably not being related to the medication. A total of 61 women (6.3%) discontinued the medication as a consequence of adverse events, which were considered to be possibly related to the study medication in 52 of these cases [22].
The EE20/DRSP pill (24/4 regimen) was compared with a combined oral contraceptive pill (COC) containing EE 20 μg and DSG (21/7 regimen) in a randomized study involving over 450 women. The incidence of adverse events was similar in both groups and considered typical of those generally found with contraceptive pills. A total of 8 serious adverse events occurred (1.8%), three in the DRSP group and five in the DSG group; however, none of these events were considered to be related to the study drugs. In the EE20/DRSP group, cephalea was the most common adverse event (3.1%) followed by metrorrhagia and painful breasts (2.6% each) and nausea (1.7%), among others. Cephalea and metrorrhagia were also the two most common adverse events with the DSG combination pill [26].
The use of COCs is classically associated with alterations in lipid and carbohydrate profiles and in coagulation parameters. In an open-label study, healthy women were randomized to EE 20 μg/DRSP 3 mg or EE 20 μg /DSG 150 μg for seven cycles [27]. A nonsignificant increase was found in total cholesterol in the two treatment groups. A significant increase in HDL and triglycerides occurred; however, the reduction found in LDL levels failed to reach statistical significance in either group. No statistically significant variations were found in the carbohydrate profile. Moreover, the alterations found in parameters related to fibrinolysis were not statistically significant: a decrease occurring in antithrombin III and in activated proteins C and S, while PAI-1 levels remained unchanged. Conversely, a nonsignificant increase in fibrinogen levels was found, while total activated thromboplastin time remained unchanged and thrombin time decreased. These results demonstrated that EE 20 μg/DRSP 3 mg has a good safety profile comparable with EE 20 μg/DSG 150 μg.
Cycle control
Cycle control is good with the EE30/DRSP formulation. As usually observed with combined contraceptive pills, particularly those of more recent generations, breakthrough bleeding is more common at the beginning of use, with rates decreasing significantly thereafter. This was shown in a study with 326 users of EE30/DRSP in which 220 of these women completed 13 cycles of use. Breakthrough bleeding including both bleeding and spotting was reported by 24.7% of the women. In the second cycle, this rate fell to 18%, then to 15.1, 13.1, 9.8 and 11.7% at the end of the third, fourth, fifth and sixth cycles, respectively. The authors reported that in each cycle between 71 and 83% of the participants reported withdrawal bleeding lasting from 4 to 7 days. The volume of bleeding was considered normal by most of the participants. Amenorrhea occurred in only 3.2% of cycles [28].
More recently, another study that evaluated approximately 3400 women over six cycles of use of EE30/DRSP reported a major reduction in menstrual bleeding. Breakthrough bleeding occurred in 27.9% of users at baseline and in 5.4% in the sixth cycle of use. In addition, a reduction in the volume and duration of withdrawal bleeding was noted [29].
Bleeding profiles were analyzed using the 90-day reference periods as recommended by the WHO. A reduction occurred in the number of episodes and days and in the mean duration of bleeding/spotting between the first and the second periods, with these values then remaining stable in the third and fourth periods. Frequent bleeding was reported by 10.1% of women in the first period, falling to 3.8, 2.8 and 2.8% in the second, third and fourth periods, respectively. The percentage of women reporting infrequent bleeding increased from 3.1% in the first period to 8.1% in the second period, remaining stable thereafter. Only 0.7% of the participants discontinued the contraceptive pill because of irregular bleeding [21]. In a multicenter study with 516 participants evaluated over 26 cycles, the same formulation (EE20/DRSP) used on a 21/7 schedule also resulted in good cycle control. The discontinuation rate for bleeding-related problems in this study was 0.6% [25].
In a randomized comparative study between EE20/DRSP and EE20/DSG, bleeding profiles were similar with the two pills. The occurrence of unscheduled bleeding was also similar in both groups, with a rate of 8.8–17.3% in the DRSP group [26].
Bodyweight
In a multicenter study, the lower dose formulation, EE20/DRSP used in a 24/4 regimen was associated with no clinically significant change in bodyweight at cycle 13, but there was a slight decrease in bodyweight during cycles 1–13 ranging between 0.22 and 0.41 kg [21].
A large cross-sectional study conducted in Europe applied questionnaires to more than 12,200 women who had been using the EE20/DRSP formulation on a 21/7 regimen for at least 3 months. Around a third were new users of COCs, while the remaining two-thirds had switched from another pill or method. Almost 70% of those who had switched to EE20/DRSP due to weight-related problems with their previous pill reported having lost weight with EE20/DRSP; nevertheless, it should be taken into account that this was not a controlled study and this finding was based on information provided by the participant [30].
Therefore, data obtained from studies with an optimal level of evidence permit us to affirm that DRSP-containing COCs exert no significant effect on bodyweight, at least during the durations of use evaluated.
Blood pressure
In a 24/4 regimen, the EE20/DRSP formulation exerted no significant effect on blood pressure over 13 treatment cycles in the 1027 women who participated in a multinational multicenter study [21].
A study that compared EE20/DRSP with placebo in over 500 women for the treatment of moderate acne also failed to find any significant effect on blood pressure [23].
In conclusion, pills containing DRSP have little effect on blood pressure.
Skin conditions
Formulations containing progestogens with antiandrogenic activity may offer an additional advantage for skin conditions and DRSP is one of these progestogens. A placebo-controlled study evaluated the effect of the lower-dose formulation, EE20/DRSP, used in a 24/4 regimen, in 534 women aged 14–45 years with moderate acne. The likelihood of having clear or almost clear skin was 4.31-times greater with the active treatment than with placebo. The reduction in the number of acne lesions was close to 50% with hormone treatment and approximately 30% with placebo in the sixth cycle of pill use; however, the degree of reduction varied in accordance with the type of acne lesion and according to age; nevertheless, a greater improvement was generally found in younger women [23]. Another large, placebo-controlled study with an identical design randomized 538 women and reported very similar results [24].
In a large cross-sectional study conducted with the use of questionnaires, 3030 (70%) of the 4305 women with skin disorders prior to initiating use of EE20/DRSP on a 21/7 regimen reported an improvement [30].
Therefore, the combination of DRSP with 20 μg of EE was effective for the treatment of hyperandrogenic skin conditions.
Well-being
A multicenter study evaluated over 1000 women using EE20/DRSP in a 24/4 regimen, 86% of whom reported being satisfied or very satisfied with the study drug. The majority of participants reported no change or an improvement in physical (87.5%) and emotional (88.2%) well-being [21].
In a large cross-sectional study conducted in 12 European countries using questionnaires applied to more than 12,200 women who had been using the EE20/DRSP pill in a 21/7 regimen for at least 3 months, 95% of the women reported being satisfied with the method and 83% stated that they would recommend the pill to a friend [29].
Well-being was also evaluated in a large multi-center study conducted in Europe in which EE20/DRSP was administered in a 24/4 regimen, with 89.2% of the participants reporting that their emotional well-being had remained the same or improved compared with pretreatment. With respect to physical well-being, this percentage was 88.7% [22].
Compared with EE20/DSG (in a 21/7 regimen), EE20/DRSP (in a 24/4 regimen) was associated with slightly higher rates of emotional well-being classified as ‘better’ or ‘much better’ in relation to baseline evaluation (28.8 vs 25.4%). Emotional well-being remained unchanged in 62.4% of participants in the DRSP group and 65.5% in the DSG group, whereas for physical well-being these percentages were 61.1 and 63.6%, respectively [28].
Role of the EE/DRSP combination on a 24/4 regimen in current contraception
Estrogen dose & the effects of drospirenone on the RAAS
The combination of a highly selective progestogen such as DRSP with low doses of EE is an example of the parameters that have guided the evolution in combined oral contraception. The properties of DRSP are widely known and are basically characterized by their antimineralocorticoid and antiandrogenic activity, various studies having demonstrated their effects on fluid retention, bodyweight and skin-related aspects, in addition, of course, to their contraceptive efficacy [31,32]. These studies were conducted with the contraceptive containing DRSP 3 mg and EE 30 μg.
Previous studies have demonstrated that DRSP exerts an effect on premenstrual symptoms such as those associated with fluid retention (edema, mastalgia and weight gain) in addition to reducing irritability and tension as a result of the drug's antiandrogenic effect [33]. Nevertheless, it should be clear that irritability and tension have multi-factorial origin, not only due to excess androgen. What, then, would be the additional advantages of the association of this progestogen with a lower dose of EE?
Although not all users of oral contraceptives show clinical signs of fluid retention, EE exerts an impact on the liver that results in an increase in renin substrate, consequently activating the RAAS, leading to vasoconstriction and sodium and water retention. Lower estrogen doses appear to exert a lesser impact on the RAAS [34] as do progestogens with antimineralocorticoid characteristics such as DRSP.
Another relevant aspect to be considered when evaluating lower doses of EE in contraception concerns the adverse effects associated with this steroid. Patients with premenstrual syndrome or PMDD often report symptoms such as mastalgia, cephalea or edema, which are also some of the adverse events provoked by the estrogen component of oral contraceptives.
Adverse events may occur in users of contraceptive pills and often lead the patient to discontinue the method. Nausea, unexpected bleeding, mastalgia, mood swings, cephalea, weight gain, acne and dizziness are the most commonly reported side effects [35]. The risk of the user who experiences nausea, unexpected bleeding or mastalgia abandoning the method is twice that of the patient who has not experienced any of these side effects [35]. Pill users who develop side effects may benefit from a reduced dose. A significantly lower rate of side effects has been found with pills containing EE 20 μg compared with those found with 30 μg [36]. Nevertheless, the incidence of side effects is practically identical between users of pills containing EE 20 μg and those containing 15 μg [37]. Therefore, doses of contraceptive pills appear to have practically reached their limit insofar as undesirable side effects are concerned. However, a low rate of adverse events, in the region of 10%, is still found with even the lowest dose contraceptives and ideally should be resolved [37].
Indications in particular circumstances: premenstrual syndrome & premenstrual dysphoric syndrome
The reasoning behind the use of oral contraceptives for the therapeutic management of Premenstrual Syndrome (PMS) or Premenstrual Dysphoric Disorder (PMDD) is based on the possibility of improving the physical symptoms without having to resort to psychiatric medication, with the stigma attached to this form of therapy and the patient's fear of becoming dependent on the drug. In addition, in the case of oral contraceptives there is no association with sexual dysfunction, which is common with the use of antidepressants.
Although premenstrual symptoms affect a large number of women of reproductive age over extended periods of time and despite the fact that these women often opt for oral contraception, few studies have dealt with this subject. Nevertheless, analysis of the principal randomized, double-blind, placebo-controlled studies show that not all oral contraceptives effectively relieve the symptoms of PMS or PMDD.
The principal differences in the findings of studies on oral contraceptives and premenstrual disorders refer to whether the contraceptive regimen is monophasic or triphasic, the nature of the progestogen and the inherent characteristics of the hormone-free interval.
Two studies evaluated triphasic formulations. In the first, a randomized placebo-controlled study, the oral contraceptive successfully reduced physical symptoms; however, no effect was found on psychological symptoms. The second study in which the triphasic pill was compared with a monophasic formulation failed to show any benefits with the triphasic pill [38,39]. Indeed, most studies show that monophasic oral contraceptives are more effective in the control of premenstrual symptoms. On the other hand, it is important to emphasize the difficulty in evaluating symptoms of PMS or PMDD, which may be confused with the adverse events often associated with oral contraceptives such as mastalgia, cephalea, edema and depression. Therefore, attention should be paid to the contraceptive formulation. It is speculated that mood disorders experienced with the use of pills may be related to the progestogen used. In this case, 19-nortestosterone derivatives may be involved, since studies show that women with PMS have higher levels of free testosterone, suggesting that androgens would be associated with dysphoria and premenstrual irritation [40] as well as symptoms of impulsiveness [41]. Logically, aspects related to the androgenicity of the 19-nortestosterone-derivative progestogens should be taken into consideration, remembering that the more recently developed progestogens have a mild androgenic effect.
Another important aspect concerns the symptoms related to fluid retention such as mastalgia, edema and weight gain provoked by the estrogen component of the contraceptive. Although not all users of oral contraceptives show clinical signs of fluid retention, EE exerts an effect on the liver with a consequent increase in renin substrate and activation of the RAAS, leading to vasoconstriction, and sodium and water retention. Lower estrogen doses appear to exert less of an effect on RAAS [34], as does the use of progestogens with antimineralocorticoid characteristics such as DRSP. With respect to PMS/PMDD, studies show that DRSP may attenuate symptoms of fluid retention such as edema, mastalgia and weight gain [33], in addition to decreasing irritability and tension through its antiandrogenic effect.
A third aspect that should be taken into consideration when analyzing the role of oral contraceptives in the treatment of PMS/PMDD is the contraceptive pause. Sulak et al. evaluated women using oral contraceptives in a traditional regimen (21 days of pill use followed by a 7-day pause) and showed that some common adverse events during pill use may be exacerbated during the pill-free interval [42]. These 7-day pauses result in greater follicular growth, causing an increased production of endogenous hormones. Therefore, symptoms such as cephalea, dysmenorrhea, mastalgia, edema and mood swings are more frequent and more intense during the pill-free interval, leading to the hypothesis that abolishing or shortening this interval could result in additional benefits. Continuous use of contraceptives with a lower estrogen dose in the final stages of the contraceptive cycle represents another possibility.
The association of EE and DRSP was evaluated in a continuous-use regimen with a significant improvement in premenstrual symptoms [43,44]. Nevertheless, continuous regimens are not always acceptable, since many women feel uncomfortable using contraceptives that do not permit monthly bleeding. Use of the pill containing 20 μg EE and 3 mg DRSP in a 24-day regimen with a 4-day pause represents an attractive alternative for the treatment of PMS/PMDD by associating the lowest dose of estrogen with a progestogen that has antimineralocorticoid and antiandrogenic activity in a regimen with a short pill-free interval. These hypotheses regarding the improvement of premenstrual symptoms were confirmed in two randomized, placebo-controlled studies conducted in patients with a diagnosis of PMDD [3,4]. The results of these two studies demonstrated the superiority of the association of a low dose of EE and DRSP compared with placebo in improving the symptoms of patients with PMDD. An effective response was found (a reduction of at least 50% in symptom scores) in 48% of users of the contraceptive compared with 36% of the women who were administered placebo.
Conclusion
The combination of EE 20 μg with DRSP 3 mg represents a highly effective, low-dose contraceptive formulation with a corrected PI of 0.72, comparable with that of other oral contraceptives. DRSP, derived from spironolactone, exerts an effect on the RAAS, reducing symptoms related to fluid retention. Cycle control with the EE 20 μg/DRSP 3 mg combination is comparable with that of other low-dose contraceptives. Noncontraceptive benefits found with this contraceptive include an improvement in dysmenorrhea, acne and general well-being. Presented as a novel feature, the regimen of 24 days of active pill use followed by a 4-day pause, proved effective for the treatment of emotional and physical symptoms in women with premenstrual dysphoric syndrome, the most severe form of premenstrual syndrome.
Future perspective
For some years now the interval between packs of contraceptive pills has been gradually diminishing and governmental regulatory authorities in some countries have already approved formulations for continuous use in an attempt to reduce bleeding and perimenstrual symptoms [45,46]. Extended cycles are associated with a high rate of user satisfaction [46].
An EE30/DRSP combination has been evaluated and is already on the market in some countries. A rate of amenorrhea of over 60% has already been reported in studies of 6 or 12 months of continuous use, together with an improvement in perimenstrual symptoms such as dysmenorrhea, cephalea, edema, nausea and acne [44,47]. The EE20/DRSP COC is already available in an ‘almost continuous’ 24/4 regimen and advancement to continuous administration at this dose would appear a logical step for the near future. Other combined, low-dose oral contraceptives containing EE 20 μg have already been tested for use in extended cycles or continuously with good results [48–50]. Therefore, continuous administration of EE20/DRSP would appear to constitute an interesting perspective for the future since it combines the benefits of continuous use in the treatment of premenstrual symptoms and in bleeding patterns with the antimineralocorticoid effects of DRSP. Furthermore, this is the lowest dose of hormones on the market, thus complying with the pharmacological principle of using the lowest effective dose.
Executive summary
The combination of ethinylestradiol (EE) 20 μg and drospirenone (DRSP) 3 mg (EE20 μg/DRSP 3 mg) results in a combined oral contraceptive with a low dose of estrogen.
Its principal mechanism of action focuses on blocking ovulation by suppressing hormone levels and follicle-stimulating hormone levels.
Ethinylestradiol is rapidly absorbed following oral administration, reaching peak serum levels after approximately 1.5 h and binding almost completely to serum albumin (~98.5%).
Drospirenone is quickly and extensively absorbed following oral administration. The pharmacokinetic profile of drospirenone is unaffected by the increase in sex hormone-binding globulin or corticosteroid-binding globulin caused by EE. Nevertheless, drugs administered concomitantly that interfere with enterohepatic circulation or affect CYP expression may interact with the oral contraceptive.
Drospirenone is the only progestogen with antimineralocorticoid activity. The 3-mg dose is equivalent to spironolactone 25 mg, exerting a blocking effect on aldosterone and resulting in less fluid retention. It also has an antiandrogenic effect, with favorable repercussions on the skin, particularly with respect to oiliness, acne and hirsutism.
The corrected Pearl Index is 0.72 (95% CI: 1.69) based on 9010 cycles of use. The cumulative 1-year pregnancy rate calculated according to the Kaplan–Meier life table analysis was 1.26% (95%CI: 0.52–2.01), corresponding to a contraceptive protection of 99%.
In addition to improving the skin, associated menstrual symptoms and fluid retention, the EE20 μg/DRSP 3 mg combination was found to be effective in treating premenstrual dysphoric syndrome.
The contraceptive is generally well tolerated. Cephalea, painful breasts and nausea are the most commonly reported events, with rates of 6.5, 6.3 and 2.5%, respectively. Discontinuation of the method due to adverse events occurs in only 7.5% of cases.
The contraceptive containing EE20 μg/DRSP 3 mg is administered orally on a daily regimen for 24 consecutive days followed by a 4-day pause or 4 days of inactive pills. This regimen (24/4) offers better suppression of associated menstrual effects, particularly premenstrual symptoms.
Footnotes
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
No writing assistance was utilized in the production of this manuscript.