K. Brill

Inhibition of ovulation by an oral contraceptive containing 100 μg levonorgestrel in combination with 20 μg ethinylestradiol

Abstract Twenty-four healthy female volunteers with normal ovulatory cycles, aged between 20 and 34 years (27.5 ± 4.3), were included in a single-center, non-comparative study to investigate the effect on inhibition of ovulation of an oral contraceptive containing 20 μg ethinylestradiol in combination with 100 μg levonorgestrel. At baseline, during three treatment cycles and post-treatment, ultrasonography was used to examine the ovaries, to measure follicular size, and to measure the thickness of the endometrium. Serum levels of LH, FSH, estradiol, progesterone, total tescosterone, free testosterone, SHBG, and CBG were also measured. Compared with treatment cycle 1, an increase in residual ovarian (follicle grades 4–5) was observed in cycles 2 and 3. Mean levels of LH, FSH, 17β-estradiol and progesterone remained suppressed during treatment. No escape ovulation was observed during the treatment phase of the study and there were no pregnancies. Ovulation was noted to return rapidly in the posttreatment cycle. Subjective and objective tolerance of the present regimen was noted to be good. Results indicate that the monophasic oral contraceptive containing 100 μ devonorgestrel combined with 20 μg ethinylestradiol effectively inhibits ovulation, providing adequate suppression of ovarian activity.

A multicenter, uncontrolled clinical investigation of the contraceptive efficacy, cycle control, and safety of a new low dose oral contraceptive containing 20 μg ethinyl estradiol and 100 μg levonorgestrel over six treatment cycles

Abstract The aim of the trial was to demonstrate the contraceptive efficacy of a new low dose oral contraceptive containing 20 μg ethinyl estradiol and 100 μg levonorgestrel and to observe cycle control and safety. Data from 805 treated women resulted in 4400 treatment cycles. One pregnancy occurred while on the trial medication as a result of method failure, resulting in a Pearl index of 0.29. Cycle control was good, and cycle length as well as duration and intensity of withdrawal bleeding were not significantly changed during the trial. Intermenstrual bleeding usually occurred as spotting and decreased considerably during the treatment phase. Spotting alone was reported in 12.4% of cycles, breakthrough bleeding alone in 4.5% of cycles, and breakthrough bleeding and spotting together in 1.4% of treatment cycles. The rate of absence of withdrawal bleeding declined throughout the trial to 2.4% in cycle 6. There were no serious adverse events related to treatment, and most adverse events were those commonly observed in clinical trials with oral contraceptives. Headache, breast tension, and nausea were reported by 17.3%, 11.0%, and 7.7% of the women, respectively. There were no clinically relevant changes in laboratory parameters, blood pressure, or weight. In this trial, the new low dose oral contraceptive containing 20 μg ethinyl estradiol and 100 μg levonorgestrel was shown to be effective, safe, and well tolerated. Cycle control was found to be good and there was a low incidence of adverse events.

The influence of the dose of ethinylestradiol in oral contraceptives on follicle growth

This prospective, randomized comparative clinical study involving 416 women investigated follicle development over a period of 12 oral contraceptive treatment cycles. Women were allocated to two groups, one group (n = 207) received a preparation containing 30 micrograms ethinylestradiol and 75 micrograms gestodene daily, and the other group (n = 209) received 20 micrograms ethinylestradiol and 150 micrograms desogestrel, daily. Follicular development was monitored by transvaginal ultrasonography of the ovaries, during days 18-21 in the pretreatment cycle and in treatment cycles 1, 3, 6, 9 and 12. Follicular development was found to be twice as frequent in the group receiving 20 micrograms ethinylestradiol/desogestrel as in the group receiving 30 micrograms ethinylestradiol/gestodene. For all cycles, follicles of 10-30 mm were found in 18% of women in the desogestrel group, compared with 9.7% in the gestodene group, whilst follicles with a diameter of >30 mm were present in 5% of the desogestrel group compared with 1.9% of the gestodene group. The difference between the treatment groups with respect to follicle diameters of 10-30 mm and >30 mm was statistically significant (p < 0.05 and p < 0.001, respectively). No ruptured follicles were observed in either group throughout the study, suggesting that there was no escape ovulation, however, there was one pregnancy in the desogestrel group that could not be explained either by drug interactions or missed pills. It can be concluded that the ethinylestradiol dose in an oral contraceptive has a significant effect on follicular ovarian activity, and that reducing the dose to 20 micrograms is associated with a significant increase in follicle size.

Comparison of Serum Ethinyl Estradiol, Sex-Hormone-Binding Globulin, Corticoid-Binding Globulin and Cortisol Levels in Women Using Two Low-Dose Combined Oral Contraceptives

The study included 69 women taking a desogestrel (n = 30)- or gestodene (n = 39)-containing low-dose combined oral contraceptive for at least 3 months. Group size was calculated to detect a difference in mean values of 80% of 1 standard deviation (alpha = 0.05, beta = 0.1). Seven serum samples were obtained up to 4 h, and 1 sample 24 h, after drug intake on 1 day between the 10th and the 21st day of the cycle. The concentrations of sex-hormone-binding globulin (SHBG), corticoid-binding globulin (CBG) and cortisol were measured in a 0- to 4-hour serum pool by radioimmunoassay. Ethinyl estradiol (EE2) levels were analyzed in single and pooled samples using anti-EE2-6 beta-carboxymethyloxime-bovine serum albumin antiserum. The area under the curves (AUC) up to 4 and 24 h and Cmax and tmax were evaluated. Statistical analysis (analysis of covariance) did not reveal a dependence of values on duration of treatment or day of cycle. Both treatments resulted in almost identical values for all parameters evaluated. The mean levels of SHBG, CBG and cortisol were in the range of 186-226 nmol/l, 89-93 mg/l and 280-281 micrograms/l, respectively. Mean maximum EE2 levels of 106-129 pg/ml were found 1.6-1.8 h after pill intake and AUC0-4 h accounted for 329-374 pg.h.ml-1. The recently reported differences in serum EE2 and CBG levels between two groups of 11 women each treated with desogestrel- and gestodene-containing pills, respectively, could not be confirmed.

Clinical acceptability of monophasic gestodene

The monophasic low-dose contraceptive containing 30 micrograms of ethinyl estradiol and 75 micrograms of gestodene has been tested in numerous clinical studies to determine contraceptive reliability, cycle control, and influence on metabolism and to uncover concomitant symptoms. Clinical data have been derived from continuous phase III studies. Now that the preparation has been introduced in several countries, the opportunity to assemble comprehensive experience has been taken by initiating phase IV studies. Documentation on 600,000 therapy cycles with monophasic gestodene among 100,000 women is already available. The drop-out rate was low. A large number of women participated in the clinical studies for a long time--some up to 3 years. Study results showed that contraceptive reliability was high and cycle control was excellent. The gestodene combination was well tolerated. The frequency of concomitant symptoms was low. The monophasic gestodene meets the basic criteria essential for an oral contraceptive.

Investigation of the influence of two low-dose monophasic oral contraceptives containing 20 μg ethinylestradiol/75 μg gestodene and 30 μg ethinylestradiol/75 μg gestodene, on lipid metabolism in an open randomized trial

An open comparison at a single center was performed in volunteers (n = 58) randomly allocated to two treatment groups, one receiving tablets containing 20 micrograms ethinylestradiol (EE) + 75 micrograms gestodene, and the other 30 micrograms EE + 75 micrograms gestodene. The study consisted of three treatment-free pre-cycles, followed by thirteen 28-day treatment cycles. Analysis of results revealed that there were no statistically significant differences between the two groups with regard to the plasma levels of HDL-cholesterol and its subfractions, LDL-cholesterol and apolipoproteins. There was, however, a trend toward a more favorable effect on HDL-cholesterol in the 20 micrograms EE group, where levels increased by 3% compared with the 30 micrograms EE group, where levels decreased by 9%. There was a statistically significant difference between the adjusted mean values of total triglycerides in the two groups in favor of the 20 micrograms EE group (+21%), compared with the 30 micrograms EE group (+64%) (p = 0.029). Two serious adverse events were reported (lymphadenopathy and vertigo), but neither were considered to be causally related to either study medication. The formulation containing 75 micrograms gestodene and 20 micrograms EE was shown to be a reliable and well tolerated oral contraceptive, with a favorable lipid profile.

Protein binding of active ingredients and comparison of serum ethinyl estradiol sex hormone-binding globulin, corticosteroid-binding globulin, and cortisol levels in women using a combination of gestodene/ ethinyl estradiol (Femovan) or a combination of desogestrel/ ethinyl estradiol (Marvelon) and single-dose ethinyl estradiol bioequivalence from both oral contraceptives

Results from two clinical pharmacokinetic studies are given. The first study was an observational study in oral contraceptive users who took either a combination of gestodene and ethinyl estradiol (pill A, Femovan) or desogestrel and ethinyl estradiol (pill B, Marvelon). A total of 69 women (39 receiving pill A and 30 receiving pill B) were evaluated to determine serum ethinyl estradiol, sex hormone-binding globulin, corticosteroid-binding globulin, and cortisol levels. Samples were obtained on 1 day during the tenth to twenty-first days of pill intake. All women received the respective oral contraceptive for at least 3 months. The test power was such that an 80% difference of 1 standard deviation of each target variable would have been detected (alpha = 0.05; beta = 0.1). No statistically significant differences were found in sex hormone-binding globulin, corticosteroid-binding globulin, or cortisol serum levels between both groups. Time and height of maximum ethinyl estradiol levels were identical as was the area under the curves. Ex vivo protein-binding analysis of the progestins revealed a free portion of 0.6% for gestodene and 2.5% for 3-ketodesogestrel as the active metabolite of desogestrel. Sex hormone-binding globulin-bound portions were much higher for gestodene (75.3% +/- 9.1%) than for 3-ketodesogestrel (31.6% +/- 12%). The remaining fractions were bound to albumin. In a second study, ethinyl estradiol-bioequivalence from pills A and B was investigated in 18 women in a controlled, single-dose, randomized, crossover design. The area under the ethinyl estradiol serum levels were identical up to 4 hours after pill intake between both treatments. According to the relatively low variation in data in this group of women, a 10% difference in ethinyl estradiol-availability could have been detected. Both studies indicate that the pharmacokinetics of ethinyl estradiol were independent of the concomitantly administered progestin, that is, desogestel and gestodene.

Long-term experience with a low-dose oral contraceptive

Oral contraception has proved to be the most efficient reversible method of fertility control for over 25 years. During this period, various investigations and epidemiological studies have suggested that some risks may be involved, but, on the other hand, a number of non-contraceptive benefits have become obvious. The results of these investigations were taken into account when new formulations had to be developed, with an aim to improving hormonal fertility control with regard to its tolerance, cycle control, and impact on metabolism. Since then, the objective of research has been to contrive new hormonal contraceptives which ensure safety to the largest possible extent, from a medical point of view, for the sake of the patient, without affecting contraceptive effectiveness. The aim to reduce side-effects connected with the use of oral contraception, as well as to lower the risks possibly involved, has obviously been achieved by extensive research. Both by devising a new substance and reducing doses, the criteria of modern low-dose oral contraception have been met, as has become evident in the course of the clinical experience gathered with Femovan.