A 1-year pharmacokinetic investigation of a novel oral contraceptive containing drospirenone in healthy female volunteers.

Drospirenone is a novel synthetic progestogen with a pharmacological profile similar to that of natural progesterone. It has been developed in combination with ethinylestradiol for use as an oral contraceptive (EE/DRSP, Yasmin, Schering AG, Berlin, Germany). The pharmacokinetic characteristics of drospirenone and ethinylestradiol have been assessed in healthy female volunteers over a 1-year period. During each of the 13 treatment cycles, volunteers received the combined active ingredients for 21 days, followed by a 7-day, tablet-free interval. The concentrations of the serum proteins, sex hormone binding globulin (SHBG) and corticoid binding globulin (CBG), were determined at intervals after the cessation of treatment (day 21) at the end of cycles 1, 6, 9 and 13. Drospirenone and ethinylestradiol were found to be absorbed rapidly and to reach a peak concentration in serum 1.5-2.0 h after dosing. Serum concentrations ofdrospirenone declined, with mean terminal half-lives of 30.8-32.5 h. Accumulation of both drospirenone and ethinylestradiol was observed within a treatment cycle, with a mean accumulation ratio of 3.0 for drospirenone and 2.1 for ethinylestradiol. In addition, serum drospirenone concentrations increased between treatment cycles 1 and 6, but remained steady thereafter, as reflected in the AUC values determined at the end of treatment cycles 1, 6, 9 and 13. Serum SHBG and CBG concentrations declined in a biphasic manner after cessation of treatment at the end of cycle 13, and physiological steady-state concentrations were reached within 4-6 weeks. In conclusion, drospirenone was absorbed at a similar rate as other synthetic progestogens contained in various oral contraceptives, as indicated by similar tmax values. The terminal half-life of drospirenone was intermediate between those of 19-nortestosterone derivatives like desogestrel, levonorgestrel or gestodene and C21-progestogens like cyproterone acetate. Both active ingredients of the new contraceptive EE/DRSP showed accumulation within a treatment cycle, which is also the case with other synthetic progestogen/ethinylestradiol combinations. Similar to other oral contraceptives, a reversible induction of serum SHBG and CBG concentrations was observed under EE/DRSP treatment.     

The bioequivalence of the contraceptive steroids ethinylestradiol and drospirenone is not affected by co-administration of dehydroepiandrosterone

ABSTRACT

Objectives To study the effect of co-administration of 50 mg dehydroepiandrosterone (DHEA) on the bioequivalence of ethinylestradiol (EE) and drospirenone (DRSP) in women who were using a combined oral contraceptive (COC) containing 30 μg EE and 3 mg DRSP, and to estimate whether the addition of DHEA to this COC affects the serum levels and the bioequivalence of the synthetic contraceptive steroids.

Methods This was a randomised, double-blind, two-period crossover study. Participants received two EE/DRSP COC treatment cycles in random order, one with and one without daily 50 mg DHEA , separated by a 28-day wash-out cycle during which the subjects used an EE/levonorgestrel (LNG) COC without DHEA. Serum levels of EE and DRSP were measured according to a sampling scheme allowing pharmacokinetic evaluations.

Results Addition of DHEA to an EE/DRSP COC had no effect on serum levels of EE and DRSP. The COC regimens with and without DHEA were bioequivalent. Oestradiol levels were equally suppressed during pill intake, whether with placebo or DHEA.

Conclusion Adding DHEA to a COC containing EE and DRSP does not affect the pharmacokinetic properties of EE and DRSP. Therefore, it will most likely not affect its contraceptive efficacy.     

A pharmacokinetic study with a low-dose oral contraceptive containing 20 microg ethinylestradiol plus 100 microg levonorgestrel.

This study investigated the pharmacokinetics of a dose-reduced oral contraceptive containing 20 microg ethinylestradiol (EE) + 100 microg levonorgestrel (LNG) in 18 young, healthy females. Serum levels of EE and LNG were determined after single and repeated daily oral administration over three treatment cycles, each consisting of 21 treatment days followed by a 7-day treatment-free period. Additionally, the time courses of sex hormone-binding globulin (SHBG), corticoid-binding globulin (CBG) and total and free testosterone serum levels were analyzed. Both active ingredients were rapidly absorbed and maximum concentrations in serum were reached between, on average, 1 and 2 h after single and multiple administrations, respectively. Concentrations of EE increased during repeated daily administration. An approximate two-fold accumulation was calculated based on the comparison of EE area under the curve (AUC) (0-24 h) values determined after the first and the last tablet administration within a treatment cycle. LNG serum concentrations also increased during repeated daily administration, reaching steady-state levels after about 11 days. Based on the comparison of AUC (0-24 h) values determined after the first and the last tablet administration, LNG accumulated approximately by a factor of 3 within a treatment cycle. Steady-state pharmacokinetics of LNG were similar at the end of the first and the third treatment cycles, indicating no further accumulation of LNG beyond a treatment cycle under long-term use of this combined oral contraceptive. The clearance and volume of distribution of LNG decreased and the terminal half-life increased after repeated daily administration, compared with single administration. These effects have also been reported for other LNG/EE combinations. SHBG serum concentrations increased during repeated daily intake by, on average, 1.5-1.6-fold, and for CBG, an average increase of 1.4-1.8-fold was found. Although free testosterone concentrations declined during repeated daily administration by about 40%, total testosterone remained relatively unchanged at a low level. In conclusion, the pharmacokinetics of EE and LNG determined in the present study were in good agreement with those previously reported for 30 microg EE + 150 microg LNG, taking the 33% dose reduction into account.     

Comparison of two oral contraceptives containing either drospirenone or cyproterone acetate in the treatment of hirsutism.

Combined oral contraceptives (COCs) are considered the first-line treatment for women with hirsutism. They diminish androgen release from the ovary and decrease plasma free testosterone levels by increasing sex hormone-binding globulin (SHBG) concentrations. COCs containing cyproterone acetate (CPA) and drospirenone (DRSP) have been proved effective for the treatment of acne and facial hirsutism. This study prospectively compared the clinical and biochemical efficacy of 3 mg DRSP/30 microg ethinyl estradiol (EE) and 2 mg CPA/35 microg EE combinations in a total of 91 patients with hirsutism. Individuals randomly received a cyclic combination of either DRSP/EE (n=48) or CPA/EE (n=43) for 12 months. Basal serum total testosterone, free testosterone, androstenedione, dehydroepiandrosterone sulfate and SHBG levels, as well as Ferriman-Gallwey scores, were determined before and after treatment. Both COCs achieved a similar effect on clinical hirsutism scores, in addition to serum androgen and SHBG levels, after completion of therapy. The percentage reductions in total hirsutism score (median % (min-max)) during therapy were 0.70 (0-0.58) vs. 0.57 (0.10-1.00) at 6 months (p = 0.028) and 0.80 (0-0.42) vs. 0.81 (0-0.75) at 12 months (p = 0.6) in the DRSP/EE and CPA/EE groups, respectively. In conclusion, the DRSP/EE combination is at least as effective as the CPA/EE combination in improving hirsutism scores.     

Transfer of drospirenone to breast milk after a single oral administration of 3 mg drospirenone + 30 microg ethinylestradiol to healthy lactating women.

Drospirenone (DRSP) is a synthetic progestogen which has been developed in combination with ethinylestradiol (EE) for use as an oral contraceptive (Yasmin, Schering AG, Berlin, Germany). The pharmacokinetic characteristics of DRSP were evaluated in serum and breast milk from lactating women who received a single oral dose of 3 mg DRSP + 30 microg EE, to determine the fraction of the dose of DRSP which transfers to breast milk. Nine healthy, lactating women were included into the present study and pharmacokinetic data were obtained from six participants. The maximum DRSP concentrations (data given as mean +/- standard deviation) were reached on average 2.5+/-1.2 and 2.8+/-1.3 h in serum and breast milk, respectively after oral administration of 3 mg DRSP + 30 microg EE, and amounted on average to 30.8+/-14.4 and 13.5+/-11.7 ng DRSP/ml in serum and breast milk. The mean breast milk versus serum concentration ratios of DRSP increased from 0.16 to 0.57 within 2 h after dosing and decreased to 0.16 after 24 h. The average ratio of AUC0-48 h, values in breast milk versus serum was 0.23+/-0.09. The mean DRSP concentration in breast milk over the 24-h period after dosing was 3.7+/-1.9 ng/ml. The amount of DRSP measured to be transferred into breast milk in the six women participating in the present study was, on average, 635 ng (range 256.2-1357.9 ng) within 24 h, corresponding to about 0.02% of the maternal dose. Based on the average concentration of the drug in breast milk over 24 h and assuming a daily ingestion of approximately 800 ml breast milk, the daily dose that reaches an infant via breast milk is estimated to be approximately 3 microg DRSP. The subjective and objective tolerances of 3 mg DRSP + 30 microg EE were good, with no adverse events reported.     

Effect of an oral contraceptive containing drospirenone on the renin-angiotensin-aldosterone system in healthy female volunteers.

Drospirenone is a new synthetic progestogen with both progestational, antimineralocorticoid and antiandrogenic properties. In combination with ethinylestradiol, it is being developed as an oral contraceptive which will contain 30 micrograms ethinylestradiol and 3 mg drospirenone (Yasmin, Schering AG, Germany). The effects of drospirenone alone, and in combination with ethinylestradiol, upon the renin-angiotensin-aldosterone system (RAAS) have been evaluated in healthy female volunteers. RAAS activity was assessed by measurement of plasma renin substrate (PRS) concentration (otherwise known as angiotensinogen), plasma renin activity (PRA), and plasma aldosterone (P-Aldo) concentration. An antimineralocorticoid effect was observed when volunteers received drospirenone alone at doses in the range 0.5-3.0 mg/day for one cycle. The effect was dose-dependent for P-Aldo but was not dose-dependent for PRA. When ethinylestradiol (30 micrograms) was combined with either 2 mg or 3 mg drospirenone and given to volunteers for three cycles, an increase in PRS was observed with both preparations, which was indicative of estrogenic stimulation, and increases in PRA and P-Aldo were shown which were indicative of an antimineralocorticoid effect of drospirenone. Increases in PRA and P-Aldo were significantly higher with the preparation containing 3 mg drospirenone in cycle 1 but not in cycle 3. The effect of the preparation containing 30 micrograms ethinylestradiol/3 mg drospirenone upon RAS activity was also compared with that of a commercially available preparation also containing 30 micrograms ethinylestradiol but combined with 150 micrograms desogestrel (Marvelon). Over a period of 13 cycles, increases in PRS were seen with both treatments, the effect being slightly more pronounced with 30 micrograms ethinylestradiol/150 micrograms desogestrel. A markedly greater increase in PRA was seen following treatment with 30 micrograms ethinylestradiol/3 mg drospirenone, and, in cycle 3, this difference was statistically significant. In contrast, P-Aldo was increased markedly with 30 micrograms ethinylestradiol/3 mg drospirenone in all measured cycles, whereas, in the 30 micrograms ethinylestradiol/150 micrograms desogestrel group, changes were minimal. The increases in PRA and P-Aldo are interpreted as endogenous counter-regulation against the antimineralocorticoid activity of drospirenone. PRS increases under all combinations are an expression of estrogenic stimulation. Measurement of body weight and blood pressure in the studies with combined ethinylestradiol and drospirenone revealed that drospirenone was associated with either stable body weight or with a slight loss in body weight, while blood pressure remained largely unchanged. Overall, the results indicate that 30 micrograms ethinylestradiol/3 mg drospirenone has a distinct antimineralocorticoid effect.     

Transfer of drospirenone to breast milk after a single oral administration of 3 mg drospirenone + 30 μg ethinylestradiol to healthy lactating women

Drospirenone (DRSP) is a synthetic progestogen which has been developed in combination with ethinylestradiol (EE) for use as an oral contraceptive (Yasmin^®, Schering AG, Berlin, Germany). The pharmacokinetic characteristics of DRSP were evaluated in serum and breast milk from lactating women who received a single oral dose of 3 mg DRSP + 30 μg EE, to determine the fraction of the dose of DRSP which transfers to breast milk. Nine healthy, lactating women were included into the present study and pharmacokinetic data were obtained from six participants. The maximum DRSP concentrations (data given as mean ± standard deviation) were reached on average 2.5 ± 1.2 and 2.8 ± 1.3 h in serum and breast milk, respectively after oral administration of 3 mg DRSP + 30 μg EE, and amounted on average to 30.8 ± 14.4 and 13.5 ± 11.7 ng DRSP/ml in serum and breast milk. The mean breast milk versus serum concentration ratios of DRSP increased from 0.16 to 0.57 within 2 h after dosing and decreased to 0.16 after 24 h. The average ratio of AUC_{0-48 h} values in breast milk versus serum was 0.23 ± 0.09. The mean DRSP concentration in breast milk over the 24-h period after dosing was 3.7 ± 1.9 ng/ml. The amount of DRSP measured to be transferred into breast milk in the six women participating in the present study was, on average, 635 ng (range 256.2–1357.9 ng) within 24 h, corresponding to about 0.02% of the maternal dose. Based on the average concentration of the drug in breast milk over 24 h and assuming a daily ingestion of approximately 800 ml breast milk, the daily dose that reaches an infant via breast milk is estimated to be approximately 3 μg DRSP. The subjective and objective tolerances of 3 mg DRSP + 30 μg EE were good, with no adverse events reported.     

Effect of an oral contraceptive containing drospirenone on the renin-angiotensin-aldosterone system in healthy female volunteers

Drospirenone is a new synthetic progestogen with both progestational, antimineralocorticoid and antiandrogenic properties. In combination with ethinylestradiol, it is being developed as an oral contraceptive which will contain 30 μg ethinylestradiol and 3 mg drospirenone (Yasmin®, Schering AG, Germany). The effects of drospirenone alone, and in combination with ethinylestradiol, upon the renin–angiotensin–aldosterone system (RAAS) have been evaluated in healthy female volunteers. RAAS activity was assessed by measurement of plasma renin substrate (PRS) concentration (otherwise known as angiotensinogen), plasma renin activity (PRA), and plasma aldosterone (P-Aldo) concentration. An antimineralocorticoid effect was observed when volunteers received drospirenone alone at doses in the range 0.5–3.0 mg/day for one cycle. The effect was dose-dependent for P-Aldo but was not dose-dependent for PRA. When ethinylestradiol (30 μg) was combined with either 2 mg or 3 mg drospirenone and given to volunteers for three cycles, an increase in PRS was observed with both preparations, which was indicative of estrogenic stimulation, and increases in PRA and P-Aldo were shown which were indicative of an antimineralocorticoid effect of drospirenone. Increases in PRA and P-Aldo were significantly higher with the preparation containing 3 mg drospirenone in cycle 1 but not in cycle 3. The effect of the preparation containing 30 μg ethinylestradiol/3 mg drospirenone upon RAS activity was also compared with that of a commercially available preparation also containing 30 μg ethinylestradiol but combined with 150 μg desogestrel (Marvelon®). Over a period of 13 cycles, increases in PRS were seen with both treatments, the effect being slightly more pronounced with 30 μg ethinylestradiol/150 μg desogestrel. A markedly greater increase in PRA was seen following treatment with 30 μg ethinylestradiol/3 mg drospirenone, and, in cycle 3, this difference was statistically significant. In contrast, P-Aldo was increased markedly with 30 μg ethinylestradiol/3 mg drospirenone in all measured cycles, whereas, in the 30 μg ethinylestradiol/150 μg desogestrel group, changes were minimal. The increases in PRA and P-Aldo are interpreted as endogenous counter-regulation against the antimineralocorticoid activity of drospirenone. PRS increases under all combinations are an expression of estrogenic stimulation. Measurement of body weight and blood pressure in the studies with combined ethinyl-estradiol and drospirenone revealed that drospirenone was associated with either stable body weight or with a slight loss in body weight, while blood pressure remained largely unchanged. Overall, the results indicate that 30 μg ethinylestradiol/3 mg drospirenone has a distinct antimineralocorticoid effect.     

Efficacy and tolerability of a monophasic oral contraceptive containing ethinylestradiol and drospirenone.

OBJECTIVE: To assess the contraceptive reliability, cycle control and tolerability of a new monophasic oral contraceptive containing 30 g ethinylestradiol plus 3 mg drospirenone (Yasmin, Schering AG, Berlin, Germany), it was compared with an established oral contraceptive containing 30 g ethinylestradiol plus 150 g desogestrel (Marvelon, NV Organon, Oss, The Netherlands). METHODS: A randomized, open-label, 13-cycle study was performed at 80 European centers. Contraceptive reliability, cycle control, blood pressure, body weight, the incidence of adverse events and skin condition were assessed during 13 cycles of oral contraceptive use, and at follow-up. Subjects recorded body weight on three consecutive days pretreatment and weekly thereafter. RESULTS: Of 2069 women who started the study and received the trial preparations in a ratio of 4:1 (ethinylestradiol/drospirenone, n = 1657; ethinylestradiol/desogestrel, n = 412), 1615 completed the 13 cycles plus follow-up, providing data for over 23,000 evaluable cycles. Eleven pregnancies occurred during treatment, only one of which (in the ethinylestradiol/drospirenone group) could not be ascribed to user failure or interaction with other factors. Both preparations provided effective contraception and cycle control. Pre-existing acne and seborrhea were improved and blood pressure was essentially unchanged. The two treatments differed in their effect on body weight, the difference being statistically significant. In the ethinylestradiol/drospirenone group, there was a distinct decrease over the whole treatment phase, while a subtle and less distinct decrease was documented in the ethinylestradiol/desogestrel group. CONCLUSIONS: The combination of 30 g ethinylestradiol/3 mg drospirenone provides effective oral contraception, excellent cycle control, good tolerability and a level of weight loss that may have a significant beneficial effect on compliance in women with a tendency to weight gain due to water retention.     

Efficacy and tolerability of a monophasic combined oral contraceptive containing nomegestrol acetate and 17β-oestradiol in a 24/4 regimen,in comparison to an oral contraceptive containing ethinylestradiol and drospirenone in a 21/7 regimen

ABSTRACT

Objectives The primary objective was to assess the efficacy, cycle control and tolerability of a monophasic combined oral contraceptive (COC) containing nomegestrol acetate (NOMAC) and 17β-oestradiol (E2). Effects on acne were evaluated as a secondary objective. Results were compared to those of a COC containing drospirenone (DRSP) and ethinylestradiol (EE).

Methods Women (aged 18–50 years) were randomised to receive NOMAC/E2 (2.5 mg/1.5 mg) in a 24/4-day regimen (n = 1591) or DRSP/EE (3 mg/30 μg) in a 21/7-day regimen (n = 535) for 13 cycles.

Results Estimated Pearl Indices for NOMAC/E2 and DRSP/EE were 0.38 and 0.81 in women aged ≤ 35 years and 0.31 and 0.66 for all women (18–50 years), respectively. Scheduled withdrawal bleedings were shorter and lighter among users of NOMAC/E2 and were sometimes absent altogether. Intracyclic bleeding/spotting was infrequent in both groups, and decreased over time. Type and frequency of adverse events were similar to those typically reported for COCs.

Conclusions These data show that NOMAC/E2 provides high contraceptive efficacy with acceptable cycle control as well as an overall adverse event profile similar to that of DRSP/EE.     

Efficacy and tolerability of a monophasic oral contraceptive containing ethinylestradiol and drospirenone

Objective To assess the contraceptive reliability, cycle control and tolerability of a new monophasic oral contraceptive containing 30 g ethinylestradiol plus 3 mg drospirenone (Yasmin, Schering AG, Berlin, Germany), it was compared with an established oral contraceptive containing 30 g ethinylestradiol plus 150 g desogestrel (Marvelon, NV Organon, Oss, The Netherlands).

Methods A randomized, open-label, 13–cycle study was performed at 80 European centers. Contraceptive reliability, cycle control, blood pressure, body weight, the incidence of adverse events and skin condition were assessed during 13 cycles of oral contraceptive use, and at follow-up. Subjects recorded body weight on three consecutive days pretreatment and weekly thereafter.

Results Of 2069 women who started the study and received the trial preparations in a ratio of 4:1 (ethinylestradiol/drospirenone, n = 1657; ethinylestradiol/desogestrel, n = 412), 1615 completed the 13 cycles plus follow-up, providing data for over 23 000 evaluable cycles. Eleven pregnancies occurred during treatment, only one of which (in the ethinylestradiol/ drospirenone group) could not be ascribed to user failure or interaction with other factors. Both preparations provided effective contraception and cycle control. Pre-existing acne and seborrhea were improved and blood pressure was essentially unchanged. The two treatments differed in their effect on body weight, the difference being statistically significant. In the ethinylestradiol/drospirenone group, there was a distinct decrease over the whole treatment phase, while a subtle and less distinct decrease was documented in the ethinylestradiol/desogestrel group.

Conclusions The combination of 30 g ethinylestradiol/3 mg drospirenone provides effective oral contraception, excellent cycle control, good tolerability and a level of weight loss that may have a significant beneficial effect on compliance in women with a tendency to weight gain due to water retention.     

A comparative investigation of contraceptive reliability, cycle control and tolerance of two monophasic oral contraceptives containing either drospirenone or desogestrel.

OBJECTIVE: To assess the contraceptive reliability, cycle control and tolerance of a new monophasic oral contraceptive (Yasmin) containing 30 microg ethinylestradiol and 3 mg drospirenone and compare it with a preparation containing an equal dose of ethinylestradiol combined with 150 microg desogestrel (Marvelon). METHODS: A multicenter, open-label, randomized study was carried out in 26 European centers. Contraceptive efficacy, cycle control and tolerance (including body weight, blood pressure and heart rate) were assessed over 26 cycles, plus a 3-month follow-up period. RESULTS: Of 900 women who were randomized, 887 started treatment and 627 completed the 26 cycles plus follow-up (310 in the ethinylestradiol/drospirenone group and 317 in the ethinylestradiol/desogestrel group). Both study preparations were found to be effective with regard to contraceptive reliability and cycle control was good. There were six pregnancies (three in each group), but none were considered to have been the result of method failures. The subjective and objective tolerances were good in both groups. A statistically significant difference was found in body weight changes between the two groups. While there was an increase in mean body weight in the ethinylestradiol/desogestrel group from cycle 5 onward, the mean body weight per cycle in the ethinylestradiol/drospirenone group was slightly below the baseline value throughout the study. The incidence ofpremenstrual symptoms was higher in the ethinylestradiol/drospirenone group than in the ethinylestradiol/desogestrel group during the 6 months prior to the study, but lower during treatment. The rates ofdysmenorrhea were identical under both treatments but the symptoms were more often mild and less often severe in the ethinylestradiol/drospirenone group. CONCLUSION: The combination of 30 microg ethinylestradiol combined with 3 mg drospirenone provides effective oral contraception and good cycle control, and is well tolerated. Ethinylestradiol/drospirenone had a more favorable effect on body weight than ethinylestradiol/desogestrel, with the mean body weight remaining lower than baseline for the majority of the women.     

Effects of a monophasic combined oral contraceptive containing nomegestrol acetate and 17β-oestradiol on ovarian function in comparison to a monophasic combined oral contraceptive containing drospirenone and ethinylestradiol

Objective?To compare the effects on ovarian activity of two oral contraceptives containing nomegestrol acetate (NOMAC)/17β-oestradiol (E2) or drospirenone (DRSP)/ethinylestradiol (EE).

Methods?In this open-label, randomised, six-cycle study, 32 subjects using NOMAC/E2 (2.5–1.5?mg; 24/4-day regimen) were compared to 16 subjects using DRSP/EE (3 mg–30?μg; 21/7-day regimen). Measurements included serum oestradiol, progesterone, follicle stimulating hormone (FSH) and luteinising hormone (LH), and ultrasonography of follicular diameter.

Results?No ovulations occurred during treatment. Progesterone was fully suppressed, with mean maximum values?<2 nmol/l in both groups over all cycles. For NOMAC/E2, mean maximum follicular diameter decreased from 19.3?mm before treatment to between 6.9 and 8.2?mm during treatment, with no subject having a follicular diameter ≥15?mm. For DRSP/EE, a decrease from 19.6 to between 7.4 and 10.8?mm was observed, with two subjects (12.5%) having a maximum follicle diameter ≥15?mm. These findings were consistent with observed FSH reductions; full suppression of LH surges was observed in both groups. Post-treatment return of ovulation in both groups occurred on average 21 days after the last active tablet intake.

Conclusions?NOMAC/E2 achieves consistent ovulation inhibition, with suppressive effects on the ovaries at least similar to those of DRSP/EE.     

Effects of a monophasic combined oral contraceptive containing nomegestrol acetate and 17β-oestradiol in comparison to one containing levonorgestrel and ethinylestradiol on markers of endocrine function

ABSTRACT

Objectives To compare the effects of two monophasic combined oral contraceptives, containing either nomegestrol acetate/17β-oestradiol (NOMAC/E2) or levonorgestrel/ ethinylestradiol (LNG/EE) on endocrine function, androgens, and sex hormone-binding globulin (SHBG).

Methods Randomised, open-label, multi-centre trial involving 121 healthy women, aged 18–50 years old. Participants received NOMAC/E2 (2.5 mg/1.5 mg) in a 24/4-day regimen (n = 60) or LNG/EE (150 μg/30 μg) in a 21/7-day regimen (n = 61) for six cycles. The primary outcome was the change from baseline to cycle 6 in markers of adrenal and thyroid function, androgens, and SHBG.

Results Total cortisol, corticosteroid-binding globulin (CBG), and thyroxine-binding globulin (TBG) increased from baseline in both groups, with significantly greater increases in the LNG/EE group. No relevant changes from baseline or differences between the groups were observed for thyroid-stimulating hormone (TSH) and free thyroxine (T₄). Androgens and androgen precursors decreased from baseline in both groups, with significantly greater decreases in the LNG/EE group (except for free testosterone). A greater increase in SHBG was observed with NOMAC/E2 than with LNG/EE.

Conclusions NOMAC/E2 has significantly less influence on markers of adrenal and thyroid function and androgens than LNG/EE. The clinical relevance of these findings requires further study.     

Individualization of low-dose oral contraceptives. Pharmacological principles and practical indications for oral contraceptives

The contraceptive pill has been a revolution of the last 40 years. In Italy, however, it is much less widely used than in other countries. Explanations for this phenomenon range from religious implications and customs to misinformation and word-of-mouth communication of negative experiences. The oral contraceptive pill is often used to correct menstrual disorders, leading to poor results and side-effects. Recent advances in oral contraception have led to a substantial reduction in doses and side-effects. Low-dose pills contain minimal doses of progesterones and estrogens and ensure good control of the menstrual cycle. Although reduction of ethinyl estradiol (EE) concentrations has reduced the incidence of negative systemic side effects such as water retention, edema and swollen breasts, the low estrogen dose may be associated with spotting and hypomenorrhea or amenorrhea in the long term, as well as dyspareunia due to reduced vaginal trophism, which may induce women to suspend use of the drug. It is also true that only one type of estrogen is used in the pill, albeit at different doses, whereas the progesterone may differ and in many cases is the cause of common side-effects. The choice of progesterone therefore involves not only its effect on the endometrium in synergy with estrogen, but also possible residual androgenic activity which may have negative metabolic repercussions. Indeed, addition of a progesterone, especially androgen-derived, attenuates the positive metabolic effects of estrogen. Two new monophasic oral contraceptives were recently released. They contain 30 microg (Yasmin) or 20 muicrog (Yasminelle) EE and a new progesterone, drospirenone, derived from spirolactone, which has antiandrogenic and antimineralcorticoid activity similar to endogenous progesterone. Like progesterone, the drospirenone molecule is an aldosterone antagonist and has a natriuretic effect that opposes the sodium retention effect of EE. It may, therefore, help to prevent the water retention, weight gain and arterial hypertension often associated with oral contraceptive use. Recent comparative studies recorded weight loss that stabilized after 6 months of treatment with drospirenone/EE. Overweight women may therefore benefit from the formulation with 20 microg EE, whereas the formulation with at least 30 microg EE should be more appropriate for underweight women. Women with slight to moderate acne, the formulation with 30 microg EE has been found to be as effective as 2 mg cyproterone acetate combined with 35 micrig EE (Diane). Menstrual cycle characteristics, however, remain the main factor determining the choice of formulation. Randomised control studies comparing the new formulation with others containing second or third generation progesterones have found similar efficacy in cycle control and incidence of spotting. From this point of view, it is not advisable to prescribe more than 30 microg EE (Yasmin or Yasminelle) for women with normal menstrual cycles, whereas in cases of hypomenorrhea and/or amenorrhea at least this dose of EE plus drospirenone may be used. Women with hypermenorrhea run the risk of spotting if an inappropriate drug is chosen. A solution is to use 30 microg EE/drospirenone from day 5 of the cycle. To control so-called minor side-effects, the dose of EE must be appropriate. In women with premenstrual tension a dose of at least 30 microg EE associated with drospirenone reduces or even prevents symptoms. On the other hand, in cases of chronic headache or headache as a side-effect of oral contraceptive use, a lower dose of estrogen is beneficial, and doses below 20 microg may be used. Although the progesterone component is not considered to affect headache, good results have been obtained with drospirenone, the antimineralcorticoid effects of which reduce blood pressure and improve symptoms. Formulations with 20 microg EE and drospirenone are particularly indicated in women with pre-existing mastodynia, fibrocystic breast manifestations or who develop mastodynia as a side-effect of oral contraceptive use. Since high plasma concentrations of androgens have been recorded in these women, a progesterone with antiandrogen and antiedema activity can be beneficial. Finally, it is worth recalling that monophasic pills with low estrogen doses, such as the formulations mentioned above, ensure good mood control, reducing the depressive symptoms often associated with oral contraceptive use. In conclusion, formulations containing drospirenone are a valid alternative to conventional oral contraceptives for the personalisation of these drugs.     

Effect of an oral contraceptive containing drospirenone and ethinylestradiol on general well-being and fluid-related symptoms.

Oral contraception is the most widely used reversible contraceptive method. Continuous research over the past decades has led to a range of highly reliable, effective and safe oral contraceptives. Newly developed progestogens may also provide additional non-contraceptive health-related benefits that differentiate the products from each other. Women desiring contraception may thus choose from a wide range of oral contraceptives according to their individual needs. A variety of physical and emotional changes have been linked to hormonal fluctuations during the menstrual cycle. To date, only very few studies have been performed on the impact of fluid retention-related symptoms on well-being and few data are hence available on suggested methods of measurement. This open, multicenter, uncontrolled study evaluated the effects of a combined preparation containing 3 mg drospirenone and 30 microg ethinylestradiol (Yasmin, Schering AG, Berlin, Germany) on general well-being and fluid-related symptoms in women experiencing psychological, behavioral and somatic premenstrual symptoms. The study was conducted over six 28-day cycles, with 336 subjects enrolled. A significant beneficial effect on psychological general well-being, as measured by the Psychological General Well-Being Index (PGWBI), was evident by cycle 3 and maintained at cycle 6. There was a significant reduction in both the incidence and severity of somatic symptoms associated with the menstrual cycle (abdominal bloating and breast tension) during treatment. Assessment by the investigator showed that 80% of subjects had improved on study treatment and 75% of subjects considered themselves satisfied with the study treatment. There was good agreement between the clinician and subject in their assessment of the treatment. Cycle control was very good and body weight remained stable or decreased slightly during the study. In conclusion, 3 mg drospirenone in combination with 30 microg ethinylestradiol has been shown to have a beneficial effect on psychological general well-being, as measured by the PGWBI. Reductions in the incidence and severity of somatic symptoms associated with the menstrual cycle were also observed, suggesting a beneficial effect due to the antimineralocorticoid nature of drospirenone. To our knowledge, this is the first study on oral contraceptives which has used the PGWBI in this population. As quality of life is one of the least explored segments in oral contraceptive users, more studies should investigate the impact of oral contraceptives on quality of life and general well-being in this overall healthy population.     

Effect of an oral contraceptive containing drospirenone and ethinylestradiol on general well-being and fluid-related symptoms

Oral contraception is the most widely used reversible contraceptive method. Continuous research over the past decades has led to a range of highly reliable, effective and safe oral contraceptives. Newly developed progestogens may also provide additional non-contraceptive health-related benefits that differentiate the products from each other. Women desiring contraception may thus choose from a wide range of oral contraceptives according to their individual needs. A variety of physical and emotional changes have been linked to hormonal fluctuations during the menstrual cycle. To date, only very few studies have been performed on the impact of fluid retention-related symptoms on well-being and few data are hence available on suggested methods of measurement. This open, multicenter, uncontrolled study evaluated the effects of a combined preparation containing 3 mg drospirenone and 30 μg ethinylestradiol (Yasmin^®, Schering AG, Berlin, Germany) on general well-being and fluid-related symptoms in women experiencing psychological, behavioral and somatic premenstrual symptoms. The study was conducted over six 28-day cycles, with 336 subjects enrolled. A significant beneficial effect on psychological general well-being, as measured by the Psychological General Well-Being Index (PGWBI), was evident by cycle 3 and maintained at cycle 6. There was a significant reduction in both the incidence and severity of somatic symptoms associated with the menstrual cycle (abdominal bloating and breast tension) during treatment. Assessment by the investigator showed that 80% of subjects had improved on study treatment and 75% of subjects considered themselves satisfied with the study treatment. There was good agreement between the clinician and subject in their assessment of the treatment. Cycle control was very good and body weight remained stable or decreased slightly during the study. In conclusion, 3 mg drospirenone in combination with 30 μg ethinylestradiol has been shown to have a beneficial effect on psychological general well-being, as measured by the PGWBI. Reductions in the incidence and severity of somatic symptoms associated with the menstrual cycle were also observed, suggesting a beneficial effect due to the antimineralocorticoid nature of drospirenone. To our knowledge, this is the first study on oral contraceptives which has used the PGWBI in this population. As quality of life is one of the least explored segments in oral contraceptive users, more studies should investigate the impact of oral contraceptives on quality of life and general well-being in this overall healthy population.     

Effects of two combined oral contraceptives containing ethinyl estradiol 30 μg combined with either gestodene or drospirenone on hemostatic parameters,lipid profiles and blood pressure

Objective  The aim of this study is to compare the effect of ethinyl estradiol 0.03 mg/gestodene 0.075 mg (EE/GSD) with ethinylestradiol 0.03 mg/drospirenone 3 mg (EE/DRSP) administered according to conventional 21/7 regimen on body mass index (BMI), blood pressure (BP), lipid metabolism and hemostatic parameters. Method  In this study, 160 healthy women were randomized to EE/GSD mg or EE/DRSP for 12 months. Mean differences in BMI, high density lipoprotein-cholesterol (HDL-C) and low density lipoprotein-cholesterol (LDL-C), total cholesterol (TC) levels and BP compared to baseline were assessed. Results  One hundred and forty-five (89%) of the women completed all 12 treatment cycles. The subjects randomly assigned into two treatment groups. Group EE/GSD (n = 71) and group EE/DRSP (n = 72). In group B, BMI values were significantly lower than baseline at the sixth cycle. DRSP/EE had more favorable effects on BP than GSD/EE with the mean systolic and diastolic BPs remaining lower in the DRSP/EE group. The difference between the two preparations was not statistically significant at the end of the study. TC levels remained similar in both groups throughout the study period. In both groups LDL-C levels decreased, triglyceride and HDL-C levels significantly increased from baseline levels. These changes result in increasing HDL-C/LDL-C ratio, demonstrating anti-atherogenic effect. Menstrual cycle patterns and the incidence of adverse events were similar between groups. The duration of withdrawal bleeding decreased during the study for both groups and was similar. Conclusion  The EE/DRSP regimen provides good cycle control with reliable contraceptive efficacy and low incidence of adverse events. Compared with the EE/GSD preparation, the EE/DRSP preparation demonstrated a more favorable effect on BMI and BP with the mean BMI and mean BP remaining lower than baseline mean. The new formulation may be especially beneficial for women susceptible to body weight gain and rise in BP.     

Effectiveness and acceptability of progestogens in combined oral contraceptives - a systematic review

BACKGROUND: The progestogen component of oral contraceptives (OCs) has undergone changes since it was recognized that their chemical structure can influence the spectrum of minor adverse and beneficial effects. METHODS: The objective of this review was to evaluate currently available low-dose OCs containing ethinylestradiol and different progestogens in terms of contraceptive effectiveness, cycle control, side effects and continuation rates. The Cochrane Controlled Trials Register, MEDLINE and EMBASE databases were searched. Randomized trials reporting clinical outcomes were considered for inclusion and were assessed for methodological quality and validity. RESULTS: Twenty-two trials were included in the review. Eighteen were sponsored by pharmaceutical companies and in only 5 there was an attempt for blinding. Most comparisons between different interventions included one to three trials, involving usually less than 500 women. Discontinuation was less with second-generation progestogens compared to first-generation (RR 0.79; 95% CI 0.69-0.91). Cycle control appeared to be better with second-compared to first-generation progestogens for both, mono-and triphasic preparations (RR 0.69; 95% CI 0.52-0.91) and (RR 0.61; 95% CI 0.43-0.85), respectively. Intermenstrual bleeding was less with third- compared to second-generation pills (RR 0.71; 95% CI 0.55-0.91).Contraceptive effectiveness of gestodene (GSD) was comparable to that of levonorgestrel (LNG), and had similar pattern of spotting, breakthrough bleeding and absence of withdrawal bleeding). Drospirenone (DRSP) was similar compared to desogestrel (DSG) regarding contraceptive effectiveness, cycle control and side effects. CONCLUSION: The third- and second-generation progestogens are preferred over first generation in all indices of acceptability. Current evidence suggests that GSD is comparable to LNG in terms of contraceptive effectiveness and for most cycle control indices. GSD is also comparable to DSG. DRSP is comparable to DSG. Future research should focus on independently conducted well designed randomized trials comparing particularly the third- with second-generation progestogens.