Ethinylestradiol/drospirenone flexible extended regimen improves endometriosis-associated pain, gynaecologic outcomes
A flexible extended regimen of ethinylestradiol and drospirenone improved endometriosis-associated pelvic pain and gynaecologic symptoms, according to a new study.
“[A flexible extended regimen] may provide a new alternative for managing endometriosis … [as it] effectively alleviated all [endometriosis-associated pelvic pain] variables, improved gynaecologic findings, and reduced the size of endometriomas,” said the researchers.
A total of 312 women with endometriosis (mean age 35.2 years) were evaluated for 52 weeks (24-week double-blind treatment phase and 28-week open-label extension phase). Participants were randomized to receive a flexible extended regimen of ethinylestradiol 20 µg and drospirenone 3 mg (n=130, 1 tablet daily for 120 days), placebo (n=129, 1 tablet daily for 120 days), or dienogest (n=53; 2 mg daily for 52 weeks).
Flexible extended regimen and placebo recipients had a 4-day tablet-free interval either after 120 days or after ≥3 consecutive days of spotting and/or bleeding on days 25–120. Placebo participants were switched to a flexible extended regimen during the extension phase. [Fertil Steril 2017;doi:10.1016/j.fertnstert.2017.07.1165]
At week 24, compared with placebo, the flexible extended regimen reduced the most severe endometriosis-associated pelvic pain (mean difference in Visual Analogue Scale score, -26.3 mm; p<0.0001) and significantly improved indurations in cul de sac (from 63.1 to 85.6 percent vs from 71.9 to 74.8 percent), uterine mobility (from 70.8 to 81.7 percent vs from 71.1 to 72.1 percent), and pelvic tenderness (from 57.7 to 85.6 percent vs from 63.3 to 64.9 percent).
There was also a reduction in the number of endometriomas with the flexible extended regimen vs placebo from baseline to week 24 (from 2.0 to 1.2 vs from 1.3 to 1.4), as well as in endometrioma mean size (from 29.87 to 24.33 mm vs from 28.86 to 28.84 mm), proportion of patients with serum E2 levels ≥27.2 pg/mL (from 95.4 to 11.5 percent vs from 94.5 to 92.8 percent), and endometrial thickness (from 10.7 to 4.2 mm vs from 10.9 to 8.6 mm).
The flexible extended regimen could have inhibited follicular maturation and ovulation and had a thinning effect on the endometrium, hence the reduced serum E2 levels and endometrial thickness, said the researchers.
Despite the higher incidence of treatment-emergent adverse events (TEAEs) with the flexible extended regimen vs placebo during the treatment phase (78.5 percent vs 67.2 percent), the rates became similar at week 52 (91.5 percent vs 91.4 percent).
Genital hemorrhage was a TEAE specifically attributed to the flexible extended regimen at weeks 24 and 52. “The commonly observed TEAEs considered specific to [the flexible extended regimen] were related to the reproductive system and coagulation factors and nausea. These TEAEs are well known adverse effects of [oestrogen/progestin] combination products,” said the researchers.
The American Congress of Obstetricians and Gynaecologists recommends an extended cycle of combined oral contraceptives as initial treatment for endometriosis. [Am Fam Physician 2011;83:84-85] “Extended [oestrogen/progestin] regimens may … [reduce] the number of withdrawal bleeds … [and] suppress ovarian function more reliably than [the established] 28-day cyclic regimens, with greater improvement of symptoms associated with menstruation,” said the researchers.
Evidence shows that an extended regimen does not change the steady-state pharmacokinetics of ethinylestradiol or drospirenone [J Fam Plann Reprod Health Care 2013;39:e1-13] and is beneficial for contraception and for reducing the frequency of menstrual periods which consequently reduces dysmenorrhoea, a typical symptom of endometriosis-related pain. [J Fam Plann Reprod Health Care 2012;38:73-101]
Additionally, monotherapy with progestins has been tied to a high frequency of irregular vaginal bleeding, which could lead to treatment withdrawal and eventual failure, as well as worsening quality of life (QoL). [Int J Womens Health 2011;3:175-184]
“[As] the variable pain considerably affects QoL … therapy must be suitable for long-term use and associated with a low incidence of adverse drug reactions that [may] further deteriorate QoL,” said the researchers.