Poor Cycle Control Research Articles

A new progestin-only pill (POP): the impact of drospirenone-only pill 4 mg 24 + 4 on coagulation markers and bleeding patterns

Purpose Progestin-only pills (POPs), compared to combined, are not associated with an increased risk of venous thromboembolism, but are associated with a poor cycle control. The aim of this study was to evaluate the impact of a new POP [4 mg drospirenone (DRSP) for 24 days with a 4-day hormone-free interval] on some coagulation markers (both procoagulant and fibrinolytic) and to describe its impact on bleeding patterns. Materials and methods This is a prospective trial, based on serum evaluation of following coagulation markers and tests: Factor (F) X, F VIII, F V, INR, aPTT, Protein S and antithrombin III. A ‘bleeding diary’ was used to categorise women as having (1) unscheduled bleeding, (2) scheduled bleeding and (3) amenorrhoea. Thirty patients were followed for six 28-day intake cycles, with a follow-up at the end of the 3rd and 6th cycles. Results There was a significant decrease of F X (p = 0.03) (-5.7% at cycle 6). No significant changes have been observed for F VII, F V and INR. A significant increase in aPTT (p = 0.01 at 3 cycles), Protein S (p = 0.0006 at 3 cycles) and antithrombin III (p < 0.0001 at 3 cycles) was recorded. This non-deteriorating coagulation impact was associated with a significant and progressive reduction of days of scheduled and unscheduled bleeding in users between cycles 4 and 6 (from 1.3 ± 0.2 days at cycle 4 to 0.8 ± 0.1 days at cycle 6 and from 2.6 ± 0.4 days at cycle 4 to 0.6 ± 0.2 days at cycle 6, respectively, p < 0.0001). Conclusions DRSP 24 + 4 use was associated with a non-deteriorating effect on coagulation markers and a significant progressive reduction of days of scheduled and unscheduled bleeding.

Bleeding profile of women with cardiovascular risk factors using a drospirenone only pill with 4 mg over nine cycles compared to desogestrel 0.075 mg

Objective Progestin-only pills are associated with irregular bleeding patterns, including amenorrhea. Desogestrel (DSG) 75 mcg, a pill that inhibits ovulation, shows poor cycle control that may harm acceptability and compliance. A Drospirenone (DRSP)-only pill was developed with 24 & 4 days of active & placebo days every 28-day cycle to improve cycle control. Study Design A phase III study in healthy women aged 18 to 45 years was performed to compare the bleeding profile of women taking a DRSP versus DSG over nine cycles. 249 women were older > 35 years: 173 using DRSP and 73 DSG. 259 women had a BMI > 25 kg/m2: 189 using DRSP and 70 DSG and 340 women were smokers: 237 using DRSP and 103 DSG. The amount of unscheduled bleeding/spotting days was analyzed in each of these sub-groups and compared statistically. Results Age: During cycles 2-4, the mean number of unscheduled bleeding days and spotting was 8.1 (SD10.53) for DRSP and 20.1 (19.41) for DSG; p = .0089. BMI > 25 kg/m2: During cycles 2-4 the mean number of unscheduled bleeding days and spotting was 7.8 (SD 12.18) for DRSP and 17.7 for DSG (SD 19.39); p = .0001. Smokers: During cycles 2-4, the mean number of unscheduled bleeding days and spotting was 9.6 (SD 11.69) for DRSP and 17.4 for DSG (SD 17.47); p = .0016. Conclusions These analyses show the improvement in the bleeding profile of women with specific cardiovascular risk factors using the DRSP only oral contraceptive product compared to DSG. Implications An improvement in the bleeding profile of women with specific cardiovascular risk factors like age > 35 years, BMI > 25kg/m2, and smokers using the DRSP only oral contraceptive product is described. Herby a higher contraceptive efficacy in these patients that additionally benefit from estrogen-free contraceptive methods is expected.

Overall and bleeding-related discontinuation rates of a new oral contraceptive containing 4 mg drospirenone only in a 24/4 regimen and comparison to 0.075 mg desogestrel

Objectives Progestin-only pills do not increase the risk of venous thromboembolism, stroke, and myocardial infarction but are associated with poor cycle control. A novel estrogen-free pill containing only drospirenone (DRSP) to improve bleeding patterns and tolerability and reduce discontinuation rates has been introduced into the market. The present study aims to describe the improvement in the acceptability of this DRSP-only pill, e.g. regarding the bleeding profile and the reduction in discontinuation rates due to unacceptable bleeding compared to desogestrel (DSG). Study design Double-blind, double-dummy prospective phase III study in healthy women aged 18–45 years evaluating a total of 858 women with 6691 DRSP and 332 women with 2487 DSG treatment cycles. Results Overall, 82 (9.6%) women in the DRSP group and 44 (13.3%) women in the DSG group experienced treatment-emergent adverse events (TEAEs) leading to premature termination of the trial meaning that 32% more women in the DRSP group finished the trial in comparison to the DSG group (based on the AUC of Kaplan–Meier’s curves). Discontinuation rates due to abnormal bleeding were 3.7% for DRSP and 7.3% for DSG users. This is a 55.7% lower discontinuation rate in the DRSP group compared to the DSG group. Conclusions This report describes the improvement in acceptability and bleeding profile of women using the new DRSP-only oral contraceptive compared to DSG, providing a better quality of life and adherence to the contraceptive method as demonstrated by lower discontinuation rates of women using the estrogen-free DRSP-only pill.

Estradiol Valerate and Dienogest: A Novel Four-Phasic Oral Contraceptive Pill Effective for Pregnancy Prevention and Treatment of Heavy Menstrual Bleeding

Estradiol valerate and dienogest have been combined to create a novel four-phasic oral contraceptive pill effective for both pregnancy prevention and treatment of heavy menstrual bleeding. This formulation represents the only oral contraceptive pill available in the USA containing an estrogen component that is biologically active as the endogenous estrogen 17β-estradiol. This medication was developed out of efforts to replace the most common estrogen in contraceptive pills, ethinyl estradiol, which is known to be a potent inducer of hepatic protein synthesis. Estradiol valerate has been available since the 1970s in oral and injectable forms indicated for the treatment of menopausal climacteric symptoms. Dienogest has been used in other oral contraceptive pills for over 10 years. Previous attempts to develop an oral contraceptive pill with natural estradiol or estradiol valerate were unsuccessful due to poor cycle control. A novel dynamic-dosing regimen was devised to improve the bleeding pattern. This medication has been shown in several clinical trials to have good contraceptive efficacy and cycle control. Recent studies have also demonstrated that this medication is effective for the treatment of heavy menstrual bleeding. However, compared with other oral contraceptive pills, this medication is associated with a higher frequency of absent withdrawal bleeding. Furthermore, the dynamic dosing regimen requires relatively complex instructions for users who miss pills.

Ovulation inhibition with four variations of a four-phasic estradiol valerate/dienogest combined oral contraceptive: results of two prospective, randomized, open-label studies

Background Attempts to improve the tolerability of combined oral contraceptives (COCs) have included the substitution of ethinylestradiol (EE) with 17β-estradiol (E2). However, this has proved unsatisfactory, specifically in terms of cycle control. To improve upon the poor cycle control seen previously, E2 [in the form of estradiol valerate (E2V); 1 mg of E2V contains 0.76 mg of E2] was combined with dienogest (DNG) in a novel four-phasic regimen. In the current studies, the ovulation-inhibition potency of four variations of this regimen was assessed. Study Design Two randomized, open-label, Phase II studies were performed. The first study compared two regimens (Regimens 1A and 2A) with similar dosages of DNG but different lengths of application. Having established in Study 1 that the length of application of Regimen 2A was most suitable, but that the dosages of DNG were too low for effective ovulation inhibition, a second study, which compared two regimens (Regimens 2B and 2C) with similar lengths of application but with increased dosages of DNG, was undertaken. The primary efficacy variable in both studies was the proportion of women with a Hoogland score of 5 or 6 during Cycle 2. Results The full analysis set comprised 192 and 203 women in Studies 1 and 2, respectively. In Study 1, 10 women (10.9%) in Regimen 1A and 6 women (6.4%) in Regimen 2A had a Hoogland score of 5 or 6. In Study 2, three women (3.1%) in Regimen 2B and one woman (1.0%) in Regimen 2C had a Hoogland score of 5 or 6. There were no safety concerns with any of the regimens. Conclusion The results of these studies identified a four-phasic COC preparation comprising E2V/DNG that provides efficient ovulation inhibition. It is expected that this regimen will lead to an innovative COC containing E2 instead of EE.

Comparison profiles of cycle control, side effects and sexual satisfaction of three hormonal contraceptives

Objective The objective of this study was to compare cycle control, tolerability and sexual well-being with the use of three hormonal contraceptives. Methods In this prospective randomized study, the effects of two combined oral contraceptives [20 μg of ethinylestradiol (EE)/100 μg of levonorgestrel and 15 μg of EE/60 μg of gestodene] were compared with those of the vaginal ring (15 μg of EE/120 μg of etonogestrel). One-year data from 280 women were obtained. We investigated the pattern of menstrual cycle and the incidence of weight gain, nausea, headache, breast tenderness, irritability, depression and vaginal dryness. Moreover, desire and sexual satisfaction were evaluated. Finally, the cumulative rate of discontinuation in the three groups was estimated. Conclusion The analysis of adverse events revealed two crucial points for acceptability, compliance and continuation: poor cycle control and disturbance of sexual intercourse due to vaginal dryness and loss of desire.

Cycle control, quality of life and acne with two low-dose oral contraceptives containing 20 $mu;g ethinylestradiol

Objectives Poor cycle control and tolerability can be reasons for irregular pill intake. This study compared the tolerability of two low-dose oral contraceptives and their effect on cycle control. Methods In this open, group-comparative, randomized multicenter trial in Germany and the Netherlands, women received either 20 μg ethinylestradiol plus 150 μg desogestrel (20EE/DSG; n = 500) or 20 μg ethinylestradiol plus 100 μg levonorgestrel (20EE/LNG; n = 498) for six treatment cycles. Cycle control, dysmenorrhea and premenstrual syndrome (PMS) were assessed using diary cards. Tolerability was assessed using the self-administered questionnaires Psychological General Well-Being Index (PGWBI) and the Profile of Mood States (POMS). Acne was assessed by objective (acne counts) and subjective (no, moderate, mild, severe) acne scoring of the facial area at baseline and treatment cycles 1, 3 and 6. Results A total of 404 (78.1%) and 384 (75.3%) women in the 20EE/DSG and 20EE/LNG groups, respectively, completed the trial. The occurrence rate of irregular bleeding and spotting was statistically significantly higher with 20EE/LNG than with 20EE/DSG (0.18 vs. 0.13; p < 0.05). The mean number of bleeding-spotting days per cycle was statistically significantly higher with 20EE/LNG than with 20EE/DSG (0.63 vs. 0.48; p < 0.05). Early withdrawal bleeding was more frequent with 20EE/LNG (0.15 vs. 0.08; p < 0.005), whereas continued withdrawal bleeding was more frequent with 20EE/DSG (0.32 vs. 0.45; p < 0.001); absence of withdrawal bleeding was comparable (0.06 vs. 0.04, respectively). Thirteen subjects in the 20EE/LNG group and three in the 20EE/DSG group discontinued due to unacceptable bleeding (p < 0.05). Dysmenorrhea and PMS decreased comparably in both groups. There were no differences between groups for the mean total scores of PGWBI or POMS at all time-points. Fewer acne lesions were counted with 20EE/DSG vs. 20EE/LNG after six cycles (p < 0.05). The subjective acne scores supported this finding. Conclusions 20EE/DSG provided better cycle control than 20EE/LNG with less treatment discontinuation due to unacceptable bleeding. There were no apparent differences between the two groups regarding tolerability and quality of life. There was less acne with 20EE/DSG.

Cycle control, quality of life and acne with two low-dose oral contraceptives containing 20 μg ethinylestradiol

Objectives Poor cycle control and tolerability can be reasons for irregular pill intake. This study compared the tolerability of two low-dose oral contraceptives and their effect on cycle control. Methods In this open, group-comparative, randomized multicenter trial in Germany and the Netherlands, women received either 20 μg ethinylestradiol plus 150 μg desogestrel (20EE/DSG; n = 500) or 20 μg ethinylestradiol plus 100 μg levonorgestrel (20EE/LNG; n = 498) for six treatment cycles. Cycle control, dysmenorrhea and premenstrual syndrome (PMS) were assessed using diary cards. Tolerability was assessed using the self-administered questionnaires Psychological General Well-Being Index (PGWBI) and the Profile of Mood States (POMS). Acne was assessed by objective (acne counts) and subjective (no, moderate, mild, severe) acne scoring of the facial area at baseline and treatment cycles 1, 3 and 6. Results A total of 404 (78.1%) and 384 (75.3%) women in the 20EE/DSG and 20EE/LNG groups, respectively, completed the trial. The occurrence rate of irregular bleeding and spotting was statistically significantly higher with 20EE/LNG than with 20EE/DSG (0.18 vs. 0.13; p < 0.05). The mean number of bleeding-spotting days per cycle was statistically significantly higher with 20EE/LNG than with 20EE/DSG (0.63 vs. 0.48; p < 0.05). Early withdrawal bleeding was more frequent with 20EE/LNG (0.15 vs. 0.08; p < 0.005), whereas continued withdrawal bleeding was more frequent with 20EE/DSG (0.32 vs. 0.45; p < 0.001); absence of withdrawal bleeding was comparable (0.06 vs. 0.04, respectively). Thirteen subjects in the 20EE/LNG group and three in the 20EE/DSG group discontinued due to unacceptable bleeding (p < 0.05). Dysmenorrhea and PMS decreased comparably in both groups. There were no differences between groups for the mean total scores of PGWBI or POMS at all time-points. Fewer acne lesions were counted with 20EE/DSG vs. 20EE/LNG after six cycles (p < 0.05). The subjective acne scores supported this finding. Conclusions 20EE/DSG provided better cycle control than 20EE/LNG with less treatment discontinuation due to unacceptable bleeding. There were no apparent differences between the two groups regarding tolerability and quality of life. There was less acne with 20EE/DSG.

Quality use of medicines: The young 'pill’ user with poor cycle control

This review - the last in the present "Quality Use of Medicine" series - will again seek to demonstrate the applicability of the P-drug process in making a rational medicines choice in a typical family practice case. The patient in this instance is a woman in her early twenties, seeking contraceptive advice. Although she has been using a combined oral contraceptive (for argument's sake, Mercilon) for six months, she now indicates that she "would like to try something new". She mentions that she has read that monthly bleeding can be avoided by extending the traditional 21-day pill taking interval and would like to know more about this. A friend has recommended a new pill called "Yasmin", because she has heard it can help a woman lose weight. After careful probing she reveals that the actual reason for her visit is that she has experienced frequent breakthrough bleeding, which she describes as making her feel as though she is "bleeding more often than not". This has led to dissatisfaction with her contraceptive and her search for a method which will help her escape the nuisance of poor cycle control. First, though, a quick aside strictly speaking what she is swallowing is a tablet (made by compressing granules),not a pill (rolled and then cut), but the literature on the "Pill" generally refers to "pill-taking", so that convention will be retained.

Endometrial responses to hormone replacement therapy: the bleeding pattern

Little information is available concerning the response of the endometrium to exogenous sex steroid therapy, particularly in the post-menopausal state. In this study we examined the variability of the bleeding pattern in 103 post-menopausal women receiving cyclical sequential combined hormone replacement therapy (HRT) over 6 months. All patients kept menstrual diary cards to record the onset, duration and subjective assessment of the severity of bleeding. We defined a cycle as starting from the commencement of treatment till the day of onset of bleeding. Two groups were identified amongst 99 women who experienced bleeding: those with a mean cycle length of 29 or more days (late bleeders, n = 50) and those with shorter mean cycle length (early bleeders, n = 49). The former were characterized by less variability in cycle length and bleeding that was of shorter duration. Four women experienced no bleeding. There were no significant differences between the two groups in age, year since the menopause, weight, height, body mass index (BMI), parity, or in the previous use of HRT. The only significant difference was in their smoking habits. This suggests a possible link of a hypo-oestrogenic state to poor cycle control.

Medical aspects of oral contraceptive discontinuation.

Oral contraceptive (OC) compliance is adversely affected by three medical factors: side effects, poor cycle control, and patients' fears of serious diseases. Most physicians recognize these factors but fail to understand their true impact on continuation rates. In one study, half of current OC users who changed brands and half of former OC users cited unwanted side effects as their reason for discontinuation. Moreover, a substantial number of women discontinue OCs without consulting their physicians. Among the so-called nuisance side effects cited by patients, the most prominent are bleeding irregularities. In new patients just beginning OC therapy, bleeding irregularities such as breakthrough bleeding and amenorrhea can lead to a very high discontinuation rate; as many as 50% of new users discontinue OCs before the end of the first year because of such side effects. OC discontinuation rates among other patient populations vary. The problem has not been studied extensively, but existing data show the problem is a large one. One study involving 550 women of various ages and years of OC use confirmed that cycle control problems led many women to discontinue OC use--often resulting in an unplanned pregnancy. Six percent of the women in this study discontinued OC use because of poor cycle control, and 23% of this group experienced subsequent unwanted pregnancies. In contrast, clinical tolerance with the new progestins such as gestodene is good; in one study 86% of patients had normal bleeding patterns. The principal consequences of poor cycle control are loss of confidence in the OC and the physician, increased anxiety, disruption of sexual relations, additional physician calls and visits, pregnancy tests, discontinuation, and noncompliance. The perception that European women have regarding the pill is that it is a reliable method that does not interfere with sexual activities. However, doubts about the safety of OCs influence compliance with the method. While concerns regarding blood clots have diminished, the fear of cancer is still a concern for many women. The androgenic side effects of weight gain, acne,and breast tenderness are particularly troubling for adolescents, who are sensitive to changes in body image. In one recent study, 20% to 25% of women stopped taking OCs because of weight gain or acne, and another 25% stopped because of fear of cancer. The medical component of improving compliance is the physician's choice of OC. Formulations with low, effective doses of hormones and the fewest side effects should be selected. Cycle control and the side-effect profile are improved with the new progestins.(ABSTRACT TRUNCATED AT 400 WORDS)

A RANDOMIZED DOUBLE‐BLIND TRIAL OF TWO LOW DOSE COMBINED ORAL CONTRACEPTIVES

Fifty-five women using Loestrin-20 (20 microgram ethinyl oestradiol and 1 mg norethisterone acetate) as an oral contraceptive have been compared with a like number using Microgynon-30 (30 microgram ethinyl oestradiol and 150 microgram levonorgestrel) in a randomized, double-blind trial. Despite the small sample size, the main finding in the trial is clear-cut; Loestrin-20 provides poor cycle control and is thus less acceptable as an oral contraceptive than Microgynon-30. Although there is also a suggestion that Loestrin-20 may be less effective than Microgynon-30, the difference in the accidental pregnancy rates is not statistically significant.

An appraisal of the clinical effect of three different oral contraceptive agents and their influence on transaminase activity.

165 women in a clinical trial used 3 different oral contraceptives (OCs) Aconcen (3 mg chlormadinone acetate and .1 mg ethinyl estradiol-3-methyl ether) Volidan (4 mg megastrol acetate and .05 mg ethinyl estradiol) and Wy 3707 (1 mg 13-ethyl-17-alpha-ethynyl-hydroxygon-4-en-4-one and .05 mg ethinyl estradiol) during 1442 cycles to study side reaction rates. Volidan gave poor cycle control but tended to cause less weight increase than the other 2 drugs. 25% of the women felt that their libido diminished during the therapy but 76% experienced increased enjoyment of sexual intercourse. 550 serum glutamic oxalacetic transaminase (SGOT) and serum glutamic pyruvic transaminase (SGPT) determinations were made. 18.6% of the women had abnormal SGPT values at least once. In spite of the fact that Wy 3707 contained the least amount of active substances the frequency and level of transaminases was higher than with the 2 other drugs. The frequency of elevated values was at a minimum during the first part of the menstrual cycle and there was a trend toward a diminishing frequency of elevated values with an increase in duration of treatment.