Does the presence of coexisting diseases modulate the effectiveness of a low-dose estrogen/progestin, ethinylestradiol/drospirenone combination tablet in dysmenorrhea? Reanalysis of two randomized studies in Japanese women

Abstract

Background: The purpose of this study was to investigate the effectiveness of a combination of ethinylestradiol (EE) and 0.02 mg/drospirenone (DRSP) 3 mg in Japanese women with dysmenorrhea and in particular to determine whether or not the presence of specific coexisting organic diseases (eg, endometriosis, uterine fibroids, uterine adenomyosis) has an impact on treatment.

Methods and results: Four hundred and ten patients with dysmenorrhea aged 20 years or older (315 without coexisting organic disease, 28 with endometriosis, 37 with uterine fibroids, and 46 with uterine adenomyosis [some patients had multiple coexisting organic diseases]) were enrolled and treated with EE/DRSP in either a 16-week comparator study or a 52-week long-term safety study. Evaluations included changes in total dysmenorrhea score, visual analog scale for dysmenorrhea, severity of symptoms, hormone levels, endometrial thickness, and safety outcomes. In both studies, the total dysmenorrhea score was significantly (P<0.001) decreased from baseline during treatment with EE/DRSP. Time-dependent changes in visual analog score for dysmenorrhea and alleviation of symptoms, such as lower abdominal pain, low back pain (lumbago), headache, and nausea/vomiting, were similar in all patient groups with and without any specific coexisting organic diseases. These improvements with EE/DRSP were observed for both short-term (16 weeks) and long-term (52 weeks) use. These effects were associated with suppressed increases in serum estradiol and progesterone levels and decreased endometrial thickness. The safety profile of EE/DRSP was similar in all patients, irrespective of the presence of coexisting organic diseases.

Conclusion: EE/DRSP may be prescribed for patients with dysmenorrhea irrespective of the presence of any specific coexisting organic diseases.

Keywords: drospirenone; dysmenorrhea; ethinylestradiol; oral contraceptive; organic disease.

Figure 1

Time-dependent changes in total dysmenorrhea score in patients with dysmenorrhea. Notes: For (A) and (B) ***P<0.001 for changes in total dysmenorrhea score from baseline to individual time points. In the Comparative study, EE/DRSP was also significantly different to placebo at each time point. After administration refers to a follow-up visit after last treatment administration. Abbreviation: EE/DRSP, ethinylestradiol/drospirenone.

Figure 2

Time-dependent changes in VAS in patients with dysmenorrhea (A and B). Notes: **P<0.01 and ***P<0.001 for changes in VAS score from baseline to individual time points. No comparison was conducted between EE/DRSP and placebo. After administration refers to a follow-up visit after last treatment administration. (B) © 2010. Iji Publishing Co., Ltd. Adapted with permission from Momoeda M, Mizunuma H, Taketani Y. [Long term efficacy and safety of drospirenone/ethinylestradiol combination (YAZ) tablets for patients with dysmenorrhea: Shinryo to Shinyaku]. Med Consult and New Remedies. 2010;47:1003–1015. Japanese. Abbreviations: EE/DRSP, ethinylestradiol/drospirenone; VAS, visual analog scale.

Figure 3

Time-dependent changes in VAS in patients with dysmenorrhea with and without coexisting organic diseases. Notes: The data are from the Long-term study and are presented as the mean and SD. The numbers of patients at each time point are shown in the table below the figure (some patients had more than one coexisting organic disease). Abbreviations: SD, standard deviation; VAS, visual analog scale.

Figure 4

Changes in the severity of dysmenorrheic symptoms during menstruation in patients with dysmenorrhea. Notes: The data are presented as the proportion of patients with different symptom severities at baseline and individual time points. For (A), A indicates EE/DRSP-treated patients (baseline, n=61/cycle 4, n=51) and B indicates placebo-treated patients (baseline, n=58/cycle 4, n=46). For (B), A indicates patients without organic disease (baseline, n=273/cycle 13, n=188); B indicates patients with endometriosis (baseline, n=24/cycle 13, n=15); C indicates patients with uterine fibroids (baseline, n=27/cycle 13, n=19), and D indicates patients with uterine adenomyosis (baseline, n=35/cycle 13, n=25). (B) © 2010. Shindan to Chiryo Sha, Inc. Reproduced with permission from Momoeda M, Mizunuma H, Taketani Y. [Treatment of functional and organic dysmenorrhea: Efficacy and safety of drospirenone/ethinylestradiol combination tablet: Sanka to Fujinka]. Obstet Gynecol. 2010;77:977–988. Japanese. Abbreviation: EE/DRSP, ethinylestradiol/drospirenone.

Figure 5

Changes in endometrial thickness (A) in patients with dysmenorrhea and (B) stratified by coexisting organic diseases. Notes: Data are from the Comparative study. For (A), placebo (baseline, n=58/cycle 4, n=47) and EE/DRSP (baseline, n=61/cycle 4, n=50). For (B), without organic disease (baseline, n=42/cycle 4, n=32), endometriosis (both baseline and cycle 4, n=4), uterine fibrosis (both baseline and cycle 4, n=4), and uterine adenomyosis (baseline, n=11/cycle 4, n=10). For (A) ^###P<0.001 between EE/DRSP and placebo for endometrial thickness; ***P<0.001 for changes in endometrial thickness with EE/DRSP from baseline to cycle 4. Abbreviation: EE/DRSP, ethinylestradiol/drospirenone.