Effect on ovarian activity and ovulation inhibition of different oral dosages of levonorgestrel.

OBJECTIVES: To investigate the effect of different oral dosages of levonorgestrel (LNG) on ovarian activity and to identify the lowest dosage at which no ovulation occurred. Secondary objectives were to assess return of ovulation after stopping treatment, bleeding pattern, pharmacokinetic (PK) parameters and safety and tolerability. STUDY DESIGN: A parallel-group study with adaptive design was performed in 90 healthy women with proven ovulatory cycles. Investigated dosages were LNG 0.095, 0.115 and 0.135 mg per day. Measurements of follicular growth and estradiol (E2) and progesterone concentrations were performed every 3 (±1) days during a 56-day treatment and a post-treatment period. Follicle-stimulating hormone and luteinizing hormone concentrations and multiple-dose PK parameters were determined during treatment. RESULTS: Two normal ovulations occurred in the LNG 0.095 mg group, none in the higher dose groups. Most subjects had active follicle-like structures without ovulation (Hoogland-Skouby scores 4). Ovarian activity was more suppressed in the highest dose group than in the other groups. Mean E2 concentrations were 241, 219 and 180 pmol/L during treatment with 0.095, 0.115 and 0.135 mg per day, respectively. PK results showed dose-proportionality. Most subjects ovulated during the post-treatment period. CONCLUSION: LNG 0.115 mg per day was the lowest effective dosage for consistent ovulation inhibition. All investigated dosages were safe and well-tolerated, and mean E2 concentrations were sufficient for prevention of hypoestrogenic side effects. IMPLICATIONS: Marketed progestogen-only pills (POP) containing 0.03 mg LNG do not consistently inhibit ovulation. Increasing the dosage to 0.115 mg or 0.135 mg per day, resulting in consistent ovulation inhibition, may improve the contraceptive efficacy of the LNG-POP.

Ovulation inhibition with a new vaginal ring containing trimegestone.

OBJECTIVES: The primary objective was to determine the lowest trimegestone (TMG) dose, administered via a vaginal ring, that effectively inhibited ovulation. STUDY DESIGN: Single-centre, open-label, single-dose, parallel-group clinical trial with adaptive design. Eighty healthy female volunteers with proven ovulatory cycles were allocated to treatment with a vaginal ring during 28 days, with an average daily release rate of either 46 µg, 94 µg, 147 µg, or 184 µg TMG (20 women/group). Ultrasound measurements of follicular growth and endometrial thickness, and blood sampling for follicle-stimulating hormone, luteinizing hormone, estradiol and progesterone determinations were performed every 3rd (±1) day from treatment day 4 (±1) until day 28 (±1), and in a follow-up phase after ring removal, until study day 39 (±1). Trimegestone concentrations were measured at each visit in the treatment phase. RESULTS: Mean age and body mass index were 28.8 years and 23.15 kg/m2. One subject in the lowest dose group (46 µg/day) ovulated, no ovulations were seen in the higher dose groups. The degree of ovarian suppression increased with the dose. Median estradiol levels were 119, 36.5, 33.2 and 27.2 pg/mL in the 46, 94, 147 and 184 µg/day groups, respectively. Ovarian activity was resumed in the follow-up phase. Plasma TMG levels gradually declined over the treatment period and showed dose proportionality. The study treatment was safe and well tolerated. CONCLUSION: The release rate of 94 µg TMG per day was the lowest effective dose for ovulation inhibition. The study results justify further development of the TMG-ring as progestogen-only contraceptive. IMPLICATIONS: The vaginal ring releasing TMG seems to be an effective new progestogen-only contraceptive preparation, having the advantage of once-a-month vaginal insertion.

Reduced hemostatic effects with drospirenone-based oral contraceptives containing estetrol vs. ethinyl estradiol.

OBJECTIVE: The effects of estetrol (E4), a natural fetal estrogen, combined with drospirenone (DRSP) were evaluated on plasma levels of sex hormone-binding globulin (SHBG), angiotensinogen and 12 hemostasis markers. STUDY DESIGN: Combinations of 3 mg DRSP with 5 or 10 mg E4 were compared with YAZ® (20 mcg ethinyl estradiol and 3 mg DRSP; EE/DRSP) in parallel groups of 15-18 healthy young women. Main outcome was the relative change from pretreatment to the end (day 24±1) of the third treatment cycle. RESULTS: All E4 combinations showed low estrogen impact compared to EE/DRSP. Effects on SHBG and angiotensinogen of 10 mg E4 combined with DRSP were 15%-20% that of EE/DRSP. Both E4/DRSP combinations reduced D-dimer level and the 5 mg E4/DRSP combination also decreased fragment 1+2. CONCLUSIONS: The reduction in coagulation markers suggests an anticoagulant effect from DRSP. The indications of a low thrombosis risk for E4 preparations should be validated in larger studies. IMPLICATION STATEMENT.

Maintenance of ovulation inhibition with a new progestogen-only pill containing drospirenone after scheduled 24-h delays in pill intake.

OBJECTIVES: Traditional progestogen-only pills (POPs) have stringent daily timing and missed pill rules that might affect contraceptive reliability. A new-generation oestrogen-free pill has been developed, containing 4-mg drospirenone with a unique regimen of 24 active treatment days followed by four placebo tablets. A previous study showed that this new drospirenone-only pill effectively inhibited ovulation. Clinical efficacy, however, can be affected by compliance, and delayed or forgotten pill intake often occurs in daily life. The aim of this study was to investigate if inhibition of ovulation was maintained after four scheduled 24-h delays in tablet intake. STUDY DESIGN: One hundred thirty healthy women with proven ovulatory cycles were randomized, and 127 were treated with the drospirenone-only pill during two cycles. In treatment Group A (n=62), 24-h delays in tablet intake were scheduled on days 3, 6, 11 and 22 during Cycle 2 and, in treatment Group B (n=65) during Cycle 1, respectively. Ovulation was defined as disappearance or persistence of a large follicle and progesterone levels higher than 5 ng/mL for at least 5 consecutive days. RESULTS: The overall ovulation rate was 0.8%; only one subject in Group A fulfilled the ovulation criteria in Cycle 2. Follicular diameters in the regular-intake and the delayed-intake cycles were similar. CONCLUSION: Despite the 4-day hormone-free period and multiple intentional 24-h delays in tablet intake, ovulation inhibition was maintained. This property distinguishes this new-generation oestrogen-free pill from traditional POPs by allowing the same "safety window" or flexibility in intake as combined oral contraceptives without compromising contraceptive reliability. IMPLICATIONS: Delayed or forgotten pill intake is very common. Ovulation inhibition by the new-generation oestrogen-free pill, containing 4-mg drospirenone for 24 days followed by a 4-day treatment-free period, was maintained despite four 24-h delays in tablet intake, so the impact of delayed intake on contraceptive reliability will be low.

Inhibition of ovulation by administration of estetrol in combination with drospirenone or levonorgestrel: Results of a phase II dose-finding pilot study.

OBJECTIVES: The aim of the study was to evaluate the efficacy of different dosages of estetrol (E4) combined with one of two progestins in suppressing the pituitary-ovarian axis and ovulation in healthy premenopausal women. METHODS: This was an open, parallel, phase II, dose-finding, pilot study performed in healthy women aged 18 to 35 years with a documented ovulatory cycle before treatment. For three consecutive cycles in a 24/4-day regimen, participants received 5 mg or 10 mg E4/3 mg drospirenone (DRSP); 5 mg, 10 mg or 20 mg E4/150 µg levonorgestrel; or 20 µg ethinylestradiol (EE)/3 mg DRSP as comparator. Pituitary-ovarian axis activity and the occurrence of ovulation were evaluated by monitoring follicular size, serum levels of follicle-stimulating hormone, luteinising hormone, estradiol and progesterone during treatment cycles 1 and 3. Endometrial thickness was evaluated throughout the trial, and the return of ovulation was evaluated after the last intake of medication. RESULTS: A total of 109 women were included in the trial. No ovulation occurred in any treatment group. Ovarian activity inhibition seemed proportional to the E4 dosage: the highest suppression was observed in the 20 mg E4 group and was very similar to that observed with EE/DRSP. Endometrial thickness was suppressed to the same extent in all groups. Post-treatment ovulation occurred in all participants between 17 and 21 days after the last active treatment. The study combinations were well tolerated and safe. CONCLUSIONS: Combined with a progestin, E4 adequately suppresses ovarian activity, particularly when given at a dosage above 10 mg/day.

A randomised study comparing the effect on ovarian activity of a progestogen-only pill (POP) containing desogestrel and a new POP containing drospirenone in a 24/4 regimen.

OBJECTIVES: Progestogen-only pills (POPs) are safer with respect to cardiovascular risks than contraceptives containing estrogens. Despite the increased contraceptive efficacy of a desogestrel-only pill compared with a traditional POP, POPs are still not widely used due to an unpredictable bleeding pattern. A new POP containing 4 mg drospirenone has been developed with a 24/4 intake regimen which may improve the bleeding pattern. The objectives of this study were to investigate ovulation inhibition with the new drospirenone-only pill in comparison with the desogestrel-only pill and, in addition, to assess the effects on cervical mucus permeability and bleeding. METHODS: Sixty-four healthy volunteers with proven ovulatory cycles were randomised and treated with either the drospirenone-only or the desogestrel-only pill during two 28-day cycles. Follicular diameter, endometrial thickness, and serum estradiol (E2) and progesterone concentrations were measured and Hoogland scores were determined. Additionally, cervical mucus scores, bleeding and return of ovulation were assessed. RESULTS: Both treatments effectively inhibited ovulation. Follicular diameter, E2 levels and Hoogland scores were equal, demonstrating efficient ovarian suppression. One subject in each group had a Hoogland score of 6, but the criteria for normal luteal activity were not fulfilled. In both groups, ovulation did not occur before day 9 of the post-treatment cycle. Cervical mucus permeability was suppressed in both groups. The median number of bleeding and spotting days was lower in the drospirenone group. CONCLUSIONS: The new drospirenone-only pill inhibited ovulation as effectively as the desogestrel-only pill despite the 4-day hormone-free interval.

Effects of a monophasic combined oral contraceptive containing nomegestrol acetate and 17 beta-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)/17 beta-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 microg; 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.

Polycystic ovaries, as defined by the 2003 Rotterdam consensus criteria, are found to be very common in young healthy women.

BACKGROUND: The criteria for polycystic ovaries (PCO) as defined by the 2003 Rotterdam consensus are based on the follicle number and ovarian volume, which decrease with age. A study was performed to assess the influence of age on the PCO prevalence. In addition, the relation between follicle number and ovulation day was studied. METHODS: Assessments were done in a spontaneous menstrual cycle in 171 healthy volunteers. The ovulation day and cycle duration were recorded. Transvaginal ultrasonography was performed between cycle day 6 and 9 to determine the follicle number and ovarian volume. RESULTS: In the age groups between 18 and 22, 23 and 27, 28 and 32, 33 and 37, and 38 and 40 years, the prevalence of PCO was 83-84%, 66-84%, 42-79%, 19-33%, and 0-33%, respectively. Most PCO subjects had ovulatory cycles. The follicle number and ovarian volume decreased with age. There was a positive correlation between the follicle number and the ovulation day. CONCLUSIONS: PCO were found to be very common in young women. The follicle number and ovarian volume decreased with age, and therefore also the PCO prevalence decreased with age. We believe the PCO criteria should be reconsidered and adapted to the woman's age. Ovulation occurred later with increasing follicle number.

One, two or three: how many directions are useful in transvaginal ultrasound measurement of ovarian follicles?

OBJECTIVE: To investigate whether it is necessary to measure an ovarian follicle in three directions using transvaginal ultrasonography. METHODS: In 36 healthy female volunteers transvaginal ultrasonography was performed every other day during a spontaneous menstrual cycle. The diameter of the largest follicle in each ovary was measured in two directions in the sagittal plane, and in two directions in the coronal plane. In total, 304 follicular measurements were performed. The largest follicular diameter was compared to the mean diameter of two and three directions, respectively. The mean diameter of two directions was compared to that of three directions. RESULTS: The mean difference between measurement in one and two directions was 1.2 mm (standard deviation (S.D.) = 1.1 mm), between measurement in one and three directions 1.2 mm (S.D. = 1.0 mm), and between measurement in two and three directions -0.03 mm (S.D. = 0.3 mm). The mean difference and the standard deviation of the difference increased with the follicular diameter. CONCLUSIONS: In non-stimulated menstrual cycles, follicle measurement in only one direction is less accurate than measurement in two and three directions, and may result in clinically relevant differences. However, measurement in three directions gives no additional information compared to measurement in two directions.

Follicular growth during contraceptive pill or vaginal ring treatment depends on the day of ovulation in the pretreatment cycle.

BACKGROUND: The aim of this study was to investigate whether the day of ovulation and the duration of a pretreatment cycle were related to the degree of follicular growth during subsequent contraceptive treatment. METHODS: This randomized, open-label study was performed in 40 healthy female volunteers, who were randomized by a computer-generated list after stratification for the ovulation day in a pretreatment cycle. They received two cycles of NuvaRing (21 subjects) or a combined oral contraceptive (COC) containing 30 microg ethinylestradiol and 150 microg levonorgestrel (19 subjects). Follicular diameter and serum hormone concentrations (FSH, LH, 17beta-estradiol, progesterone) were measured every third day. Data from treatment day 20 onwards were used for analysis. RESULTS: In the NuvaRing users, subjects with short cycles and early ovulations in the pretreatment cycle developed larger follicles during treatment than subjects with longer cycles and late ovulations. In the COC users, subjects with early ovulations in the pretreatment cycle developed larger follicles during treatment. CONCLUSIONS: The degree of follicular growth during treatment with a combined hormonal contraceptive is influenced by the duration of the pretreatment cycle and particularly by the duration of the follicular phase.

Ovarian function with the contraceptive vaginal ring or an oral contraceptive: a randomized study.

BACKGROUND: The effects on ovarian function of the combined contraceptive vaginal ring NuvaRing and a combined oral contraceptive (COC) were compared. METHODS: This randomized, open-label study was performed in 40 healthy female volunteers, who were randomized by a computer-generated list after stratification for the ovulation day in a pretreatment cycle. They received two cycles of NuvaRing (21 subjects) or a COC (30 microg ethinylestradiol and 150 microg levonorgestrel, 19 subjects). NuvaRing was started on cycle day 5, COC on cycle day 1. Follicular diameter, endometrial thickness and FSH, LH, 17beta-estradiol (E2) and progesterone concentrations were determined. RESULTS: The median maximum follicular diameter (maxFD) was < or =11 mm during treatment. In the first treatment cycle the maxFD was lower in the COC than in the NuvaRing group, due to the different starting procedures. MaxFD were not different in the second treatment cycle. In both groups, E2 and progesterone levels remained low during treatment. Ovulations did not occur. CONCLUSIONS: In both groups, ovarian activity was adequately suppressed. Due to the different starting procedures, lower ovarian activity was observed in the COC group in the first treatment cycle. In the second cycle, ovarian suppression was comparable with NuvaRing and COC treatment.

Single dose pharmacokinetics and effects on follicular growth and serum hormones of a long-acting recombinant FSH preparation (FSH-CTP) in healthy pituitary-suppressed females.

BACKGROUND: A long-acting FSH preparation has been developed by site-directed mutagenesis and gene transfer techniques. METHODS: In this open-label trial, we investigated the pharmacokinetic and pharmacodynamic properties of FSH-CTP (corifollitropin alpha, Org 36286) in healthy female volunteers. Twenty-four subjects were treated with a high-dose oral contraceptive (OC) to suppress pituitary function. A single dose of 15, 30 or 60 micro g FSH-CTP was injected (s.c., eight subjects per dose group) and seven of these 24 subjects were subsequently treated with a single dose of 120 micro g. RESULTS: Maximum serum FSH-CTP concentrations (0.42, 0.66, 1.49 and 3.27 ng/ml after administration of 15, 30, 60 and 120 micro g Org 36286 respectively) were reached between 36 and 48 h after injection and t(1/2) varied between 60 and 75 h. Dose proportionality was shown across the studied dose range, whereas t(max) and t(1/2) were dose independent. In most subjects follicular growth was observed; the number and maximum diameter of the follicles increased with the dose. Follicles with a diameter vertical line 8.0 mm were observed only in the 60 and 120 micro g dose groups, diameters between 12.0 and 15.9 mm occurred only in the 120 micro g group. Serum LH and 17beta-oestradiol levels remained low due to profound pituitary suppression whereas inhibin-B levels increased with dose. Maximum mean inhibin-B levels were 30.4, 322.7 and 1059.3 pg/ml in the 30, 60 and 120 micro g dose group respectively. The preparation was safe and well tolerated, and no FSH-CTP antibody formation was observed. CONCLUSIONS: The pharmacokinetics of FSH-CTP were shown to be proportional with the dose. The elimination half-life was approximately two times longer than that of rFSH. A single dose of FSH-CTP was shown to be safe and able to induce multiple follicular growth accompanied by a dose-dependent rise in serum inhibin-B concentrations.