Letrozole is superior to clomiphene in infertile women with polycystic ovary syndrome and leads to higher ovulation and live birth rates. Berberine, a major active component of Chinese herbal medicine Rhizoma coptidis and found in Cortex Phellodendri and Cortex Berberidis in the rest of the world, has similar but even more profound metabolic effects than metformin. Our hypothesis was that a combination of letrozole and berberine would result in a higher live birth rate than letrozole or berberine alone in infertile women with polycystic ovary syndrome.
In this multicentre, randomised, double-blind, placebo-controlled trial in 19 participating centres in mainland China, we compared the effect of three interventions for up to six menstrual cycles: letrozole plus berberine placebo (letrozole group), berberine plus letrozole placebo (berberine group), or the combination of letrozole and berberine (combination group). The randomisation (1:1:1) was done through a web-based computer program operated by an independent data center in the China Academy of Chinese Medical Sciences. Participants, investigators, doctors, laboratory technicians, and data analysers were masked to the assignments. Eligible women (age 20–40 years) had polycystic ovary syndrome, as defined by the Rotterdam criteria, had at least one open Fallopian tube and normal uterine cavity, and had at least 1 year of infertility. Berberine or berberine placebo were administrated orally at a daily dose of 1·5 g for 6 months. Patients received an initial dose of 2·5 mg of letrozole or placebo on days 3–7 of the first three treatment cycles. This dose was increased to 5 mg letrozole or placebo on days 3–7 of the last three treatment cycles if not pregnant. Couples were instructed to have regular intercourse two to three times a week until becoming pregnant. The primary outcome was live birth rate after intervention for up to six menstrual cycles. We used either a χ2 test or Fisher's exact test a two-sided significance level of 0·05 to test differences between groups. Data were analysed according to the intention-to-treat principle. This study was approved by an Ethics Committee (2009LL-001) at First Affiliated Hospital in Heilongjiang University of Chinese Medicine. This trial is registered at Chinese Clinical Trials Registration, identifier ChiCTR-TRC-09000376, and at ClinicalTrials.gov, number NCT01116167. All participants provided written informed consent.
We enrolled 644 participants. The live birth rates were comparable between the letrozole group (78 [36%] of 215 births) and the combination group (74 [34%] of 215 birth) after treatment (odds ratio [OR] 0·92, 95% CI 0·62–1·37; p=0·687), whereas live birth rates in the berberine group (44 [22%] of 214 births) were lower than in the letrozole group (OR 2·02, 95% CI 1·32–3·10; p=0·001) and the combination group (OR 1·86, 95% CI 1·21–2·86; p=0·004). Conception, pregnancy, and ovulation rates were similar in the letrozole (46%, 39%, and 59%, respectively) and combination groups (49%, 38%, and 61%, respectively), and these were higher than in the berberine group. There was one twin birth in the letrozole group and three twin births in the combination group, but none in the berberine group (29%, 22%, and 6%, respecitively). Berberine was associated with constipation and nausea whereas letrozole was associated with fatigue and hot flashes.
For ovulation and live births, the combination of letrozole and berberine did not improve outcomes compared with letrozole alone, but letrozole and the combination of letrozole and berberine improved fertility in women with polycystic ovary syndrome compared with berberine alone. Some limitations include the early study termination because of the expiration of the study drug berberine or placebo, not all participants had pelvic sonograms to assess for polycystic ovaries, and some participants had regular cycles. The major strength of this study is that it was a large multicentre, double-blind trial with close monitoring of adverse events and serious adverse events and tracking of live birth in line with our recent Harbin consensus.
National Public Welfare Projects for Chinese Medicine (200807021) of China, the National Key Discipline of Chinese Medicine in Gynecology during the year of 2009–14, the Heilongjiang Province Foundation for Outstanding Youths (JC200804), the Intervention for Polycystic Ovary Syndrome Based on Traditional Chinese Medicine Theory—‘TianGui Shi Xu’ (2011TD006), and the National Clinical Trial Base in Chinese Medicine during the year of 2009–14 in First Affiliated Hospital, Heilongjiang University of Chinese Medicine.
Declaration of interests
All authors report financial support to their institutions from the National Public Welfare Projects for Chinese Medicine of China and the National Key Discipline of Chinese Medicine in Gynecology during the year of 2009–14. X-KW reports other research grants for this trial from the Heilongjiang Province Foundation for Outstanding Youths and the Intervention for Polycystic Ovary Syndrome Based on Traditional Chinese Medicine Theory—‘TianGui Shi Xu’. ES-V reports a travel grant from Longjiang Scholarship from Heilongjiang Province. X-KW, EHYN, J-PL, and ES-V are members of the Steering Committee and received conference travel expenses and lecture fees from National Key Discipline of China. YX and YW are members of the Scientific Advisory Board, and have received payment from National Key Discipline and TCM Trial Base of China.
We thank the participants and the staff of participating centres for their contribution to the trial. This work was a post-doctoral dissertation of Xiao-Ke Wu MD