Hongying Kuang

Effect of Acupuncture and Clomiphene in Chinese Women With Polycystic Ovary Syndrome: A Randomized Clinical Trial

Importance Acupuncture is used to induce ovulation in some women with polycystic ovary syndrome, without supporting clinical evidence. Objective To assess whether active acupuncture, either alone or combined with clomiphene, increases the likelihood of live births among women with polycystic ovary syndrome. Design, Setting, and Participants A double-blind (clomiphene vs placebo), single-blind (active vs control acupuncture) factorial trial was conducted at 21 sites (27 hospitals) in mainland China between July 6, 2012, and November 18, 2014, with 10 months of pregnancy follow-up until October 7, 2015. Chinese women with polycystic ovary syndrome were randomized in a 1:1:1:1 ratio to 4 groups. Interventions Active or control acupuncture administered twice a week for 30 minutes per treatment and clomiphene or placebo administered for 5 days per cycle, for up to 4 cycles. The active acupuncture group received deep needle insertion with combined manual and low-frequency electrical stimulation; the control acupuncture group received superficial needle insertion, no manual stimulation, and mock electricity. Main Outcomes and Measures The primary outcome was live birth. Secondary outcomes included adverse events. Results Among the 1000 randomized women (mean [SD] age, 27.9 [3.3] years; mean [SD] body mass index, 24.2 [4.3]), 250 were randomized to each group; a total of 926 women (92.6%) completed the trial. Live births occurred in 69 of 235 women (29.4%) in the active acupuncture plus clomiphene group, 66 of 236 (28.0%) in the control acupuncture plus clomiphene group, 31 of 223 (13.9%) in the active acupuncture plus placebo group, and 39 of 232 (16.8%) in the control acupuncture plus placebo group. There was no significant interaction between active acupuncture and clomiphene (P = .39), so main effects were evaluated. The live birth rate was significantly higher in the women treated with clomiphene than with placebo (135 of 471 [28.7%] vs 70 of 455 [15.4%], respectively; difference, 13.3%; 95% CI, 8.0% to 18.5%) and not significantly different between women treated with active vs control acupuncture (100 of 458 [21.8%] vs 105 of 468 [22.4%], respectively; difference, −0.6%; 95% CI, −5.9% to 4.7%). Diarrhea and bruising were more common in patients receiving active acupuncture than control acupuncture (diarrhea: 25 of 500 [5.0%] vs 8 of 500 [1.6%], respectively; difference, 3.4%; 95% CI, 1.2% to 5.6%; bruising: 37 of 500 [7.4%] vs 9 of 500 [1.8%], respectively; difference, 5.6%; 95% CI, 3.0% to 8.2%). Conclusions and Relevance Among Chinese women with polycystic ovary syndrome, the use of acupuncture with or without clomiphene, compared with control acupuncture and placebo, did not increase live births. This finding does not support acupuncture as an infertility treatment in such women. Trial Registration clinicaltrials.gov Identifier: NCT01573858

Acupuncture and Clomiphene Citrate for Live Birth in Polycystic Ovary Syndrome: Study Design of a Randomized Controlled Trial

Acupuncture is an alternative therapy to induce ovulation in women with polycystic ovary syndrome (PCOS), but there is no study reporting the live birth rate following ovulation induction by acupuncture or its potential as an adjuvant treatment to clomiphene citrate (CC). We assess the efficacy of acupuncture with or without CC in achieving live births among 1000 PCOS women in Mainland China. This paper reports the methodology of an ongoing multicenter randomized controlled trial. The randomization scheme is coordinated through the central mechanism and stratified by the participating sites. Participants will be randomized into one of the four treatment arms: (A) true acupuncture and CC, (B) control acupuncture and CC, (C) true acupuncture and placebo CC, and (D) control acupuncture and placebo CC. To ensure the quality and integrity of the trial we have developed a unique multinational team of investigators and Data and Safety Monitoring Board. Up to the end of April 2013, 326 subjects were recruited. In conclusion, the success of this trial will allow us to evaluate the additional benefit of acupuncture beyond the first line medicine for fertility treatment in PCOS women in an unbiased manner.

Assessment of multiple intrauterine gestations from ovarian stimulation (AMIGOS) trial: baseline characteristics

OBJECTIVE To identify baseline characteristics of women with unexplained infertility to determine whether treatment with an aromatase inhibitor will result in a lower rate of multiple gestations than current standard ovulation induction medications. DESIGN Randomized, prospective clinical trial. SETTING Multicenter university-based clinical practices. PATIENT(S) A total of 900 couples with unexplained infertility. INTERVENTION(S) Collection of baseline demographics, blood samples, and ultrasonographic assessments. MAIN OUTCOME MEASURE(S) Demographic, laboratory, imaging, and survey characteristics. RESULT(S) Demographic characteristics of women receiving clomiphene citrate (CC), letrozole, or gonadotropins for ovarian stimulation were very consistent. Their mean age was 32.2 ± 4.4 years and infertility duration was 34.7 ± 25.7 months, with 59% primary infertility. More than one-third of the women were current or past smokers. The mean body mass index (BMI) was 27 and mean antimüllerian hormone level was 2.6; only 11 women (1.3%) had antral follicle counts of <5. Similar observations were identified for hormonal profiles, ultrasound characterization of the ovaries, semen parameters, and quality of life assessments in both male and female partners. CONCLUSION(S) The cause of infertility in the couples recruited to this treatment trial is elusive, as the women were regularly ovulating and had evidence of good ovarian reserve both by basal FSH, antimüllerian hormone levels, and antral follicle counts; the male partners had normal semen parameters. The three treatment groups have common baseline characteristics, thereby providing comparable patient populations for testing the hypothesis that use of letrozole for ovarian stimulation can reduce the rates of multiples from that observed with gonadotropin and CC treatment. CLINICAL TRIAL REGISTRATION NUMBER NCT 01044862.

The effect of complementary and alternative medicine on subfertile women with in vitro fertilization.

About 10–15% of couples have difficulty conceiving at some point in their reproductive lives and thus have to seek specialist fertility care. One of the most commonly used treatment options is in vitro fertilization (IVF) and its related expansions. Despite many recent technological advances, the average IVF live birth rate per single initiated cycle is still only 30%. Consequently, there is a need to find new therapies to promote the efficiency of the procedure. Many patients have turned to complementary and alternative medical (CAM) treatments as an adjuvant therapy to improve their chances of success when they undergo IVF treatment. At present, several CAM methods have been used in infertile couples with IVF, which has achieved obvious effects. However, biologically plausible mechanisms of the action of CAM for IVF have not been systematically reviewed. This review briefly summarizes the current progress of the impact of CAM on the outcomes of IVF and introduces the mechanisms.

Effect of berberine on insulin resistance in women with polycystic ovary syndrome: study protocol for a randomized multicenter controlled trial

BackgroundInsulin resistance and hyperinsulinemia play a key role in the pathogenesis of polycystic ovary syndrome (PCOS), which is characterized by hyperandrogenism, ovulatory dysfunction, and presence of polycystic ovaries on pelvic scanning. Insulin resistance is significantly associated with the long-term risks of metabolic syndrome and cardiovascular disease. Berberine has effects on insulin resistance but its use in women with PCOS has not been fully investigated. In this paper, we present a research design evaluating the effects of berberine on insulin resistance in women with PCOS.Methods/designThis is a multicenter, randomized, placebo-controlled and double-blind trial. A total of 120 patients will be enrolled in this study and will be randomized into two groups. Berberine or placebo will be taken orally for 12 weeks. The primary outcome is the whole body insulin action assessed with the hyperinsulinemic-euglycemic clamp.DiscussionWe postulate that women with PCOS will have improved insulin resistance following berberine administration.Trial registrationThis study is registered at ClinicalTrials.gov, NCT01138930.

Letrozole, berberine, or their combination for anovulatory infertility in women with polycystic ovary syndrome: study design of a double-blind randomised controlled trial

Introduction Letrozole is being used as an alternative to clomiphene citrate in women with polycystic ovary syndrome (PCOS) requiring ovulation induction. Berberine, a major active component of Chinese herbal medicine rhizoma coptidis, has been used to improve insulin resistance to facilitate ovulation induction in women with PCOS but there is no study reporting the live birth or its potential as a complementary treatment to letrozole. We aim to determine the efficacy of letrozole with or without berberine in achieving live births among 660 infertile women with PCOS in Mainland China. Methods and analysis This study is a multicentre randomised, double-blind trial. The randomisation scheme is coordinated through the central mechanism and stratified by the participating site. Participants are randomised into one of the three treatment arms: (1) letrozole and berberine, (2) letrozole and berberine placebo, or (3) letrozole placebo and berberine. Berberine is administered three times a day (1.5 g/day) for up to 24 weeks, starting on day 1 after a spontaneous period or a withdrawal bleeding. Either letrozole or letrozole placebo 2.5 mg is given daily from day 3 to day 7 of the first three cycles and the dose is increased to 5 mg/day in the last three cycles, if not pregnant. The primary hypothesis is that the combination of berberine and letrozole results in a significantly higher live birth rate than letrozole or berberine alone. Ethics and dissemination The study was approved by the ethics committee of the First Affiliated Hospital of Heilongjiang University of Chinese Medicine. Study findings will be disseminated through peer-reviewed publications and conference presentations. Trial registration ClinicalTrials.gov identifier: NCT01116167.

Identification and replication of prediction models for ovulation, pregnancy and live birth in infertile women with polycystic ovary syndrome

STUDY QUESTION Can we build and validate predictive models for ovulation and pregnancy outcomes in infertile women with polycystic ovary syndrome (PCOS)? SUMMARY ANSWER We were able to develop and validate a predictive model for pregnancy outcomes in women with PCOS using simple clinical and biochemical criteria particularly duration of attempting conception, which was the most consistent predictor among all considered factors for pregnancy outcomes. WHAT IS KNOWN ALREADY Predictive models for ovulation and pregnancy outcomes in infertile women with polycystic ovary syndrome have been reported, but such models require validation. STUDY DESIGN, SIZE, AND DURATION This is a secondary analysis of the data from the Pregnancy in Polycystic Ovary Syndrome I and II (PPCOS-I and -II) trials. Both trials were double-blind, randomized clinical trials that included 626 and 750 infertile women with PCOS, respectively. PPCOS-I participants were randomized to either clomiphene citrate (CC), metformin, or their combination, and PPCOS-II participants to either letrozole or CC for up to five treatment cycles. PARTICIPANTS/MATERIALS, SETTING, AND METHODS Linear logistic regression models were fitted using treatment, BMI, and other published variables as predictors of ovulation, conception, clinical pregnancy, and live birth as the outcome one at a time. We first evaluated previously reported significant predictors, and then constructed new prediction models. Receiver operating characteristic (ROC) curves were constructed and the area under the curves (AUCs) was calculated to compare performance using different models and data. Chi-square tests were used to examine the goodness-of-fit and prediction power of logistic regression model. MAIN RESULTS AND THE ROLE OF CHANCE Predictive factors were similar between PPCOS-I and II, but the two participant samples differed statistically significantly but the differences were clinically minor on key baseline characteristics and hormone levels. Women in PPCOS-II had an overall more severe PCOS phenotype than women in PPCOS-I. The clinically minor but statistically significant differences may be due to the large sample sizes. Younger age, lower baseline free androgen index and insulin, shorter duration of attempting conception, and higher baseline sex hormone-binding globulin significantly predicted at least one pregnancy outcome. The ROC curves (with AUCs of 0.66-0.76) and calibration plots and chi-square tests indicated stable predictive power of the identified variables (P-values ≥0.07 for all goodness-of-fit and validation tests). LIMITATIONS, REASONS FOR CAUTION This is a secondary analysis. Although our primary objective was to confirm previously reported results and identify new predictors of ovulation and pregnancy outcomes among PPCOS-II participants, our approach is exploratory and warrants further replication. WIDER IMPLICATIONS OF THE FINDINGS We have largely confirmed the predictors that were identified in the PPCOS-I trial. However, we have also revealed new predictors, particularly the role of smoking. While a history of ever smoking was not a significant predictor for live birth, a closer look at current, quit, and never smoking revealed that current smoking was a significant risk factor. STUDY FUNDING/COMPETING INTERESTS The Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Grants U10 HD27049, U10 HD38992, U10HD055925, U10 HD39005, U10 HD33172, U10 HD38998, U10 HD055936, U10 HD055942, and U10 HD055944; and U54-HD29834. Heilongjiang University of Chinese Medicine Grants 051277 and B201005. R.S.L. reports receiving consulting fees from Euroscreen, AstraZeneca, Clarus Therapeutics, and Takeda, and grant support from Ferring, Astra Zeneca, and Toba. K.R.H. reports receiving grant support from Roche Diagnostics and Ferring Pharmascience. G.C. reports receiving Honorarium and grant support from Abbvie Pharmaceuticals and Bayer Pharmaceuticals. M.P.D. holds equity from Advanced Reproductive Care Inc. and DS Biotech, receives fees from Advanced Reproductive Care Inc., Actamax, Auxogyn, ZSX Medical, Halt Medical, and Neomed, and receives grant support from Boehringer-Ingelheim, Abbott, and BioSante, Ferring Pharmaceuticals, and EMD Serono. H.Z. receives research support from the Chinese 1000-scholar plan. Others report no disclosures other than NIH grant support. TRIAL REGISTRATION NUMBER PPCOS-I and -II were respectively registered at Clinicaltrials.gov: NCT00719186 and NCT00719186.

Predictors of participant retention in infertility treatment trials

OBJECTIVE To identify variables associated with retention (or dropout) in infertility clinical trials. Retention of subjects in randomized controlled clinical trials (RCTs) has received considerable attention, but there have been few consistent findings. DESIGN Secondary analysis of data from RCTs. SETTING Academic medical centers. PATIENT(S) Women with polycystic ovary syndrome (PCOS) or couples with unexplained infertility, aged 18-40 years. INTERVENTION(S) This study is not an intervention study, but the patients in the original RCTs were treated with any or combination of metformin, clomiphene citrate (CC), letrozole, and gonadotropins. MAIN OUTCOME MEASURE(S) Successful retention versus dropout during the RCTs. RESULT(S) Race, ethnicity, body mass index (BMI), insurance coverage, history of smoking, and history of alcohol use were significantly associated with retention whether they were considered in bivariate analyses or a multivariable logistic model. Specifically, white race, higher income, having graduate degrees, normal weight, better insurance coverage, nonsmokers, and those who reported current use of alcohol at the start of the trial, had higher retention rates. CONCLUSION(S) We identified several additive and persistent predictors of retention that can be used to guide the conduct of RCTs and improve the retention rate. Given the limitation of our association analysis, methodologically sound and theoretically grounded research are warranted so that high quality data can be collected to improve our understanding on the causes of dropout. CLINICAL TRIAL REGISTRATION NUMBER NCT00068861 (PPCOS-I), NCT00719186 (PPCOS-II), and NCT01044862 (AMIGOS).

Major depression, antidepressant use, and male and female fertility

OBJECTIVE To determine if maternal major depression (MD), antidepressant use, or paternal MD are associated with pregnancy outcomes after non-IVF fertility treatments. DESIGN Cohort study. SETTING Clinics. PATIENT(S) Participants in two randomized trials: PPCOS II (clomiphene citrate versus letrozole for polycystic ovary syndrome), and AMIGOS (gonadotropins versus clomiphene citrate versus letrozole for unexplained infertility). INTERVENTION(S) Female and male partners completed the Patient Health Questionnaire (PHQ-9). Female medication use was collected. PHQ-9 score ≥10 was used to define currently active MD. MAIN OUTCOME MEASURE(S) Primary outcome: live birth. SECONDARY OUTCOMES pregnancy, first-trimester miscarriage. Poisson regression models were used to determine relative risks after adjusting for age, race, income, months trying to conceive, smoking, and study (PPCOS II versus AMIGOS). RESULT(S) Data for 1,650 women and 1,608 men were included. Among women not using an antidepressant, the presence of currently active MD was not associated with poorer fertility outcomes (live birth, miscarriage), but rather was associated with a slightly increased likelihood of pregnancy. Maternal antidepressant use (n = 90) was associated with increased risk of miscarriage, and male partners with currently active MD were less likely to achieve conception. CONCLUSION(S) Currently active MD in the female partner does not negatively affect non-IVF treatment outcomes; however, currently active MD in the male partner may lower the likelihood of pregnancy. Maternal antidepressant use is associated with first-trimester pregnancy loss, which may depend upon the type of antidepressant. CLINICAL TRIAL REGISTRATION NUMBERS NCT00719186 and NCT01044862.

Chinese Obstetrics & Gynecology journal club: a randomised controlled trial

Objectives To assess whether a journal club model could improve comprehension and written and spoken medical English in a population of Chinese medical professionals. Setting and participants The study population consisted of 52 medical professionals who were residents or postgraduate master or PhD students in the Department of Obstetrics and Gynecology, Heilongjiang University of Chinese Medicine, China. Intervention After a three-part baseline examination to assess medical English comprehension, participants were randomised to either (1) an intensive journal club treatment arm or (2) a self-study group. At the conclusion of the 8-week intervention participants (n=52) were re-tested with new questions. Outcome measures The primary outcome was the change in score on a multiple choice examination. Secondary outcomes included change in scores on written and oral examinations which were modelled on the Test of English as a Foreign Language (TOEFL). Results Both groups had improved scores on the multiple choice examination without a statistically significant difference between them (90% power). However, there was a statistically significant difference between the groups in mean improvement in scores for both written (95% CI 1.1 to 5.0; p=0.003) and spoken English (95% CI 0.06 to 3.7; p=0.04) favouring the journal club intervention. Conclusions Interacting with colleagues and an English-speaking facilitator in a journal club improved both written and spoken medical English in Chinese medical professionals. Journal clubs may be suitable for use as a self-sustainable teaching model to improve fluency in medical English in foreign medical professionals. Trial registration number NCT01844609.