Vivian Chi Yan Lee

A randomized, controlled, pilot trial on the effect of dehydroepiandrosterone on ovarian response markers, ovarian response, and in vitro fertilization outcomes in poor responders

OBJECTIVE To evaluate whether pretreatment dehydroepiandrosterone (DHEA) supplementation improves ovarian response markers, ovarian response to standard low-dose gonadotropin stimulation, and in vitro fertilization (IVF) outcomes in poor responders. DESIGN Randomized, double-blind, placebo-controlled pilot study. SETTING Tertiary reproductive medicine unit. PATIENT(S) Thirty-two women with anticipated poor ovarian response. INTERVENTION(S) Randomization into DHEA group (n=16) receiving GNC (25 mg three times a day) or placebo (n=16) starting from at least 12 weeks before the scheduled IVF treatment according to a computer-generated randomization list. MAIN OUTCOME MEASURE(S) Measurement of monthly ovarian response markers, including antral follicle count (AFC), serum antimüllerian hormone (AMH), and follicle-stimulating hormone (FSH) levels; comparison of ovarian response to a standard dose of gonadotropin stimulation at week 8 and IVF outcomes; and AFC after 12 weeks (primary outcome). RESULT(S) The DHEA supplementation resulted in statistically significantly higher serum DHEA-S, free androgen index, and follicular DHEA-S levels. No statistically significant differences in the ovarian response markers (AFC, AMH, or FSH), the ovarian response to standard-dose gonadotropin stimulation, or IVF outcomes were found between the two groups. CONCLUSION(S) No statistically significant improvement in ovarian response markers, ovarian response to standard dose gonadotropin stimulation, or IVF outcomes was found in poor responders receiving pretreatment DHEA. CLINICAL TRIAL REGISTRATION NUMBER HKCTR-1149 (www.hkclinicaltrials.com) and NCT01915186 (www.ClinicalTrials.org).

Role of Baseline Antral Follicle Count and Anti-Mullerian Hormone in Prediction of Cumulative Live Birth in the First In Vitro Fertilisation Cycle: A Retrospective Cohort Analysis

Objective This retrospective study determined for the first time the role of baseline antral follicle count (AFC) and serum anti-Mullerian hormone (AMH) level in the first in-vitro fertilisation (IVF) cycle in predicting cumulative live birth from one stimulation cycle. Methods We studied 1,156 women (median age 35 years) undergoing the first IVF cycle. Baseline AFC and AMH level on the day before ovarian stimulation were analysed. The main outcome measure was cumulative live birth in the fresh plus all the frozen embryo transfers after the same stimulation cycle. Results Serum AMH was significantly correlated with AFC. Both AMH and AFC showed significant correlation with age and ovarian response in the stimulated cycle and total number of transferrable embryos. Baseline AFC and serum AMH were significantly higher in subjects attaining a live birth than those who did not in the fresh stimulated cycle, as well as those attaining cumulative live birth. There was a significant trend of higher cumulative live birth rate in women with higher AMH or AFC. However, logistic regression revealed that both AMH and AFC were not significant predictors of cumulative live birth after adjusting for age and number of embryos available for transfer. Considering only one single predictor, the areas under the ROC curves for AMH (0.646, 95% CI 0.616–0.675) and age (0.648, 95% CI 0.618–0.677) were slightly higher than that for AFC (0.617, 95% CI 0.587–0.647) in predicting cumulative live birth. However, a model combining AMH (with or without AFC) and age of the women only classified an addition of less than 2% of subjects correctly compared to the model with age alone. Conclusion Baseline AFC and serum AMH have only modest predictive performance on the occurrence of cumulative live birth, and may not give additional value on top of the womens age.

A Randomized Double-Blinded Placebo-Controlled Trial on the Effect of Dehydroepiandrosterone for 16 Weeks on Ovarian Response Markers in Women with Primary Ovarian Insufficiency

CONTEXT Preliminary reports have shown encouraging effects of dehydroepiandrosterone (DHEA) in women with poor ovarian reserve undergoing assisted reproduction and primary ovarian insufficiency (POI), although data from randomized controlled trials are limited. The present study assesses the effect of DHEA on ovarian response markers in women with POI. OBJECTIVE The objective of the study was to evaluate whether DHEA for 16 wk would improve ovarian response markers in women with POI. DESIGN This was a randomized, double-blinded, placebo-controlled study. SETTING The study was conducted at a tertiary reproductive unit. PATIENTS Twenty-two women with unexplained POI participated in the study. INTERVENTIONS Eligible subjects were randomized into the DHEA group (n = 10), who received DHEA (LiveWell, 25 mg three times a day), or the placebo group (n = 12), who received placebo for 16 wk according to a computer-generated randomization list. Ovarian response markers included serum anti-mullerian hormone (AMH), FSH levels, and antral follicle count (AFC) as well as follicles of 10 mm or greater in diameter, and hormonal profiles were measured at 4-wk intervals until 4 wk after completion of treatment. Any returns of menses and side effects from treatment were recorded. MAIN OUTCOME MEASURES The primary outcome was serum AMH level. RESULTS No significant change in serum AMH and FSH levels had been detected throughout the study. AFC and ovarian volume were significantly higher at wk 12 and 20, respectively, in the DHEA group. Significantly more women having at least one follicle of 10 mm or greater at wk 12, 16, and 20 were found in the DHEA group. Serum testosterone and DHEA sulfate levels along with higher estradiol levels were significantly higher in the DHEA group. CONCLUSION This randomized, double-blinded, placebo-controlled trial found higher AFC and ovarian volume at wk 12 and 20, respectively, in the DHEA group, although there were no significant changes in serum AMH and FSH levels. Further trials using a longer duration of DHEA should be considered to evaluate the long-term effect of DHEA in women with POI.

Misoprostol With or Without Letrozole Pretreatment for Termination of Pregnancy: A Randomized Controlled Trial

OBJECTIVE: To compare the success rate and side effects of letrozole and misoprostol versus misoprostol alone for medical termination of early pregnancy. METHODS: Patients requesting termination of pregnancy up to 63 days of gestation were randomized into two groups. The letrozole group received letrozole 10 mg daily for 3 days followed by 800 micrograms of vaginal misoprostol, while the placebo group received placebo for 3 days followed by the same dosage of misoprostol. The complete abortion rate and the side effects profiles of the two groups were compared. The primary outcome measure was the complete abortion rate. RESULTS: A total of 168 women were recruited. The complete abortion rate of the letrozole group was significantly higher than that of the placebo group (86.9% compared with 72.6%, relative risk [RR] 1.20, 95% confidence interval [CI] 1.03–1.40). The complete abortion rate in gestations up to 49 days was significantly higher in the letrozole group than in the placebo group (93.3% compared with 78.7%, RR 1.19, 95% CI 1.002–1.40), while the corresponding rates for gestation between 50 and 63 days were not significantly different between the two groups. There were significantly fewer women complaining of vomiting in the letrozole group than those in the placebo group (8.3% compared with 19.0%, P=.043, RR 2.29, 95% CI 1.005–5.27). CONCLUSION: The use of letrozole and misoprostol is associated with a higher complete abortion rate. CLINICAL TRIAL REGISTRATION: HKClinicalTrials.com, http://www.hkclinicaltrials.com, HKCTR-349. LEVEL OF EVIDENCE: I

Impact of positive hepatitis B surface antigen on the outcome of IVF treatment

There has been controversy about the effect of hepatitis B virus (HBV) infection on pregnancy outcome after IVF treatment. A total of 1676 couples undergoing their first IVF cycle were included in this study. The prevalence of HBV infection in the female partners of the subfertile population seeking treatment with assisted reproductive technology was 7.8-9.6% during the study period. The ongoing pregnancy rate was not significantly different between couples with HBV-seropositive wives and seronegative ones (26.7% versus 30.2%). The ongoing pregnancy rate and the live-birth rate of couples with both partners being HBV surface antigen positive was not significantly different from couples with discordant HBV serostatus and those couples with both partners being HBV surface antigen negative (23% versus 29% versus 30%, respectively; 23% versus 27% versus 27%, respectively). The percentage of normal sperm morphology in HBV-seropositive husbands was significantly lower than that of seronegative counterparts (5.0% versus 10.0%, P=0.009). In conclusion, there was no adverse effect of HBV infection on the assisted reproduction outcomes. This study was the first report on the live-birth rate of hepatitis B (HBV) seropositive couples, revealing the effect on the pregnancy outcome of IVF. The prevalence of HBV infection in the female partners of subfertile population seeking treatment with ART was 7.8-9.6%. Both the ongoing pregnancy rate and live-birth rate were not significantly different among couples with both partners being positive for HBV surface antigen, couples with discordant HBV serostatus and those couples with both partners being negative for HBV surface antigen. The percentage of normal sperm morphology in HBV-seropositive husbands was significantly lower than that of seronegative counterparts.

Sequential use of letrozole and gonadotrophin in women with poor ovarian reserve: a randomized controlled trial

Sequential use of letrozole and human menopausal gonadotrophin (HMG) was compared with HMG only in poor ovarian responders undergoing IVF. Patients (n=53) with less than four oocytes retrieved in previous IVF cycles or less than five antral follicles were randomized to either letrozole for 5days followed by HMG or HMG alone. The letrozole group had lower dosage of HMG (P<0.001), shorter duration of HMG (P<0.001) and fewer oocytes (P=0.001) when compared with controls. Live-birth rate was comparable with a lower miscarriage rate in the letrozole group (P=0.038). Serum FSH concentrations were comparable in both groups except on day 8, while oestradiol concentrations were all lower in the letrozole group from day 4 (all P<0.001). Follicular fluid concentrations of testosterone, androstenedione, FSH and anti-Müllerian hormone were higher in the letrozole group (P=0.009, P=0.001, P=0.046 and P=0.034, respectively). Compared with HMG alone, sequential use of letrozole and HMG in poor responders resulted in significantly lower total dosage and shorter duration of HMG, a comparable live-birth rate, a significantly lower miscarriage rate and a more favourable hormonal environment of follicular fluid. The management of poor ovarian responders or women with poor ovarian reserve in IVF is controversial. The use of letrozole has been studied; however, results are inconsistent. This randomized trial studied the sequential use of letrozole and gonadotrophin compared with gonadotrophin alone in poor responders undergoing IVF. The sequential use of letrozole and gonadotrophin led to a significantly lower dosage and shorter duration of gonadotrophin use, significantly fewer oocytes, comparable live-birth rate, a significantly lower miscarriage rate and a more favourable hormonal environment at a lower cost.

Effect of preovulatory progesterone elevation and duration of progesterone elevation on the pregnancy rate of frozen–thawed embryo transfer in natural cycles

OBJECTIVE To assess the incidence of P elevation (PE) in natural cycles and evaluate its effect on frozen-thawed embryo transfer cycles performed in natural cycles (FET-NC). STUDY DESIGN Retrospective analysis. SETTING A tertiary assisted reproductive unit. PATIENT(S) Subfertile woman who did not conceive in their stimulated IVF cycle and underwent the first FET-NC cycle. INTERVENTION(S) Achieved serum samples were assayed for P concentrations from the day of LH surge up to 3 days before the surge. The cutoff level of PE was defined as 5 nmol/L. MAIN OUTCOME MEASURE(S) Clinical and ongoing pregnancy rates. RESULT(S) The incidence of PE in natural cycles was 173 of 610 (28.4%). There were no significant differences in both clinical and ongoing pregnancy rates (39.0% vs. 37.3% and 32.5% vs. 31.7%) between those with vs. without PE on the day of LH surge. If PE lasted for 2 days or more, there was a significant reduction in the clinical pregnancy rate (39.4% vs. 20.7%). Using multivariate logistic regression, womens age, PE for 2 days or more, and the number of top-quality embryos were the significant factors for clinical pregnancy rates in FET-NC. CONCLUSION(S) The incidence of PE in FET-NC was similar to that in stimulated cycles. Progesterone elevation for 2 days or more before the LH surge impaired the clinical pregnancy rate of FET-NC, whereas PE on the day of LH surge only did not have such an adverse effect.

A pilot study on the use of letrozole with either misoprostol or mifepristone for termination of pregnancy up to 63 days.

BACKGROUND Letrozole is a third-generation selective aromatase inhibitor. Animal data suggested that it might be useful in medical abortion. We performed two pilot studies to assess the feasibility of using letrozole in combination with either mifepristone or misoprostol for termination of pregnancy up to 63 days. STUDY DESIGN We recruited 40 subjects who requested legal termination of pregnancies up to 63 days. Medical abortion was performed with letrozole 7.5 mg daily for 2 days followed by 800 mcg vaginal misoprostol in 20 subjects and letrozole 7.5 mg combined with 200 mg mifepristone in another 20 subjects. RESULTS The mean induction-to-abortion interval of the regimen of letrozole and misoprostol was 9.1 h (median 7.9 h, range 2.7-23.6 h). The complete abortion rate was 80% (95% CI: 56.3-94.3%). For those with gestation of ≤ 49 days, the complete abortion rate was 87.5% (14/16; 95% CI: 61.7-98.5%). The mean induction-to-abortion interval of letrozole combined with mifepristone was 90.1 h (median 93.4 h, range 66.0-121.2 h). The complete abortion rate was 71.4% (95% CI: 47.8-88.7%). CONCLUSION These preliminary results suggest that a regimen of letrozole and misoprostol may be useful in medical abortion, but the combination with mifepristone is less effective and takes longer. Randomized studies comparing letrozole and misoprostol to misoprostol alone are warranted.

Luteal phase support does not improve the clinical pregnancy rate of natural cycle frozen-thawed embryo transfer: a retrospective analysis

OBJECTIVE To evaluate pregnancy outcomes with and without use of luteal phase support (LPS) in frozen-thawed embryo transfer (FET) performed in natural cycles (NC). STUDY DESIGN Retrospective analysis. Before 1st July 2009, two doses of 1500 IU intramuscular human chorionic gonadotrophin were given on the day of FET and 6 days after the transfer. Such practice was stopped after 1st July 2009. The pregnancy outcomes of NC FET with and without LPS were compared. RESULTS A total of 408 NC FET cycles were analysed. Demographic data, embryo quality, clinical pregnancy rates and miscarriage rates were comparable with and without LPS. By univariate logistic regression, the only significant factors predicting the clinical pregnancy rate were the womens age, the number of embryos transferred, the number of top quality embryos before and after cryopreservation, and the average number of blastomeres after thawing. Only the womens age (OR 0.944, 95%C.I. 0.893-0.998, p=0.044) remained to be a significant predictor of clinical pregnancy rate by multivariate logistic regression. CONCLUSION The pregnancy outcomes of NC FET were similar with or without LPS. The womens age was the significant factor affecting the clinical pregnancy rate. A randomised trial should be carried out to confirm the results.

A pilot study on the use of a 7-day course of letrozole followed by misoprostol for the termination of early pregnancy up to 63 days

BACKGROUND Our previous randomized controlled study showed that the complete abortion rate in termination of pregnancy up to 63 days with the combined use of letrozole for 3 days followed by vaginal misoprostol was significantly higher than that of misoprostol alone. A positive correlation was observed between the basal estradiol level and the failure rate. We performed this pilot study to assess if a longer course of letrozole followed by misoprostol would improve the estradiol suppression and the complete abortion rate of pregnancy up to 63 days. STUDY DESIGN Twenty subjects requesting legal termination of pregnancies up to 63 days were recruited. Medical abortion was offered with letrozole 10 mg daily for 7 days followed by vaginal misoprostol 800 mcg on the 7th day. RESULTS Median induction-to-abortion interval was 7.5 h (range, 4.75-10.75 h). Overall complete abortion rate was 95%. All subjects with gestation ≤49 days (12/12) as well as 87.5% of subjects with gestation between 50 and 63 days (7/8) had complete abortion. No major adverse event were reported and over 88% of women would like to have medical termination as an option should it be required in the future. CONCLUSION This pilot study showed that a 7-day course of letrozole followed by vaginal misoprostol was associated with a very high complete abortion rate (95%) which is comparable to the standard regimen with sequential use of mifepristone and misoprostol in medical termination of early pregnancy up to 63 days.