Eric D. Levens

CDB-2914 for Uterine Leiomyomata Treatment: A Randomized Controlled Trial

OBJECTIVE: To evaluate whether 3-month administration of CDB-2914, a selective progesterone receptor modulator, reduces leiomyoma size and symptoms. METHODS: Premenopausal women with symptomatic uterine leiomyomata were randomly assigned to CDB-2914 at 10 mg (T1) or 20 mg (T2) daily or to placebo (PLC) for 3 cycles or 90–102 days if no menses occurred. The primary outcome was leiomyoma volume change determined by magnetic resonance imaging at study entry and within 2 weeks of hysterectomy. Secondary outcomes included the proportion of amenorrhea, change in hemoglobin and hematocrit, ovulation inhibition, and quality-of-life assessment. RESULTS: Twenty-two patients were allocated, and 18 completed the trial. Age and body mass index were similar among groups. Leiomyoma volume was significantly reduced with CDB-2914 administration (PLC 6%; CDB-2914 –29%; P=.01), decreasing 36% and 21% in the T1 and T2 groups, respectively. During treatment, hemoglobin was unchanged, and the median estradiol was greater than 50 pg/mL in all groups. CDB-2914 eliminated menstrual bleeding and inhibited ovulation (% ovulatory cycles: CDB-2914, 20%; PLC, 83%; P=.001). CDB-2914 improved the concern scores of the uterine leiomyoma symptom quality-of-life subscale (P=.04). One CDB-2914 woman developed endometrial cystic hyperplasia without evidence of atypia. No serious adverse events were reported. CONCLUSION: Compared with PLC, CDB-2914 significantly reduced leiomyoma volume after three cycles, or 90–102 days. CDB-2914 treatment resulted in improvements in the concern subscale of the Uterine Fibroid Symptom Quality of Life assessment. In this small study, CDB-2914 was well-tolerated without serious adverse events. Thus, there may be a role for CDB-2914 in the treatment of leiomyomata. Clinical Trial Registration: ClinicalTrials.gov,www.clinicaltrials.gov, NCT00290251 LEVEL OF EVIDENCE: I

Endometrial effects of a single early luteal dose of the selective progesterone receptor modulator CDB-2914

OBJECTIVE To test potential contraceptive mechanisms of the selective P receptor modulator CDB-2914 in the early luteal phase. DESIGN Prospective randomized clinical trial. SETTING Clinical research center. PATIENT(S) Fifty-six women with regular cycles. INTERVENTION(S) Women received a single dose of CDB-2914 (10, 50, or 100 mg) or placebo given after ovulation and within 2 days of the LH surge. Four to 6 days later, a transvaginal ultrasound scan measured endometrial thickness, and an endometrial biopsy specimen was obtained. MAIN OUTCOME MEASURE(S) The endometrium was evaluated by thickness and by immunohistochemical analysis for P-dependent markers; safety laboratory tests were performed, and E(2) and P levels were obtained. RESULT(S) CDB-2914 caused a significant dose-dependent decrease in endometrial thickness, an increase in glandular P receptors, and a decrease in peripheral node addressins. Estradiol and P levels and menstrual cycle timing were not altered. No adverse effects were observed. CONCLUSION(S) The alteration in endometrial thickness and P-dependent markers of implantation in the absence of changes in hormone levels and cycle length suggests that CDB-2914 may have contraceptive properties.

The use of recombinant luteinizing hormone in patients undergoing assisted reproductive techniques with advanced reproductive age: a systematic review and meta-analysis

OBJECTIVE To evaluate the effect of recombinant LH in assisted reproduction technology (ART) cycles in patients of advanced reproductive age. DESIGN A systematic review and meta-analysis. SETTING Published randomized controlled clinical trials comparing recombinant LH plus recombinant FSH versus recombinant FSH only in patients of advanced reproductive age. PATIENT(S) Patients 35 years and older undergoing assisted reproduction. INTERVENTION(S) Recombinant LH plus recombinant FSH controlled ovarian hyperstimulation (COH) versus recombinant FSH stimulation only in assisted reproduction cycles. MAIN OUTCOME MEASURE(S) Implantation and clinical pregnancy. RESULT(S) Seven trials were identified that met inclusion criteria and comprised 902 assisted reproduction technology cycles. No differences in serum E(2) on the day of hCG administration were reported in any trials. Two trials reported lower oocyte yield and one trial reported lower metaphase II oocyte yield in the recombinant LH-supplemented group. One trial reported higher fertilization rates in the recombinant LH-supplemented group. In a fixed effect model, implantation was higher in the recombinant LH-supplemented group (odds ratio 1.36, 95% confidence interval 1.05-1.78). Similarly, clinical pregnancy was increased in the recombinant LH-supplemented group (odds ratio 1.37, 95% confidence interval 1.03-1.83). CONCLUSION(S) The addition of recombinant LH to ART cycles may improve implantation and clinical pregnancy in patients of advanced reproductive age.

Trophectoderm grade predicts outcomes of single-blastocyst transfers

OBJECTIVE To estimate the effect of the embryo stage, trophectoderm (TE) morphology grade, and inner cell mass (ICM) morphology grade on live birth in single-blastocyst transfers. DESIGN Retrospective cohort study. SETTING Large private assisted reproductive technologies (ART) practice. PATIENT(S) Fresh autologous ART cycles. INTERVENTION(S) None. MAIN OUTCOME MEASURE(S) Live birth. RESULT(S) A total of 694 single-blastocyst transfers met the inclusion criteria. Univariate regression analysis showed embryo stage and TE score to be correlated with implantation and live birth. Live birth rates were 57%, 40%, and 25% for TE grades A, B, and C, respectively. There was no significant association between ICM grade and implantation or live birth. Live birth rates were 53%, 52%, and 0% for ICM grades A, B, and C respectively. Multiple logistic regression analysis showed that only patient age and TE grade were significantly associated with implantation and live birth, whereas ICM grade was not significantly associated with outcome. The TE score had the strongest correlation with live birth. CONCLUSION(S) TE grading, but not ICM grading, significantly correlated with implantation and live birth for single-blastocyst transfers.

Blastocyst development rate impacts outcome in cryopreserved blastocyst transfer cycles

OBJECTIVE To assess cycle outcome among day 5 and day 6 cryopreserved frozen-thawed blastocyst embryo transfers (FBET). DESIGN Retrospective cohort study. SETTING Military-based assisted reproduction technology (ART) center. PATIENT(S) One hundred seventy-two nondonor, programmed cryopreserved embryo cycles. INTERVENTION(S) Fully expanded blastocysts on day 5 were cryopreserved on day 5, and those achieving this state on day 6 were cryopreserved on day 6. Leuprolide acetate was given for ovulation inhibition, and endometrial supplementation was by oral and vaginal estradiol. Progesterone in oil was administered, and blastocyst transfer occurred in the morning of the sixth day of progesterone. MAIN OUTCOME MEASURE(S) Implantation, pregnancy, and live-birth rates. RESULT(S) Fresh and frozen cycle characteristics were similar between groups. Day-5 FBET had statistically significantly higher implantation rates (32.2% vs. 19.2%), which remained significant even when adjusting for covariates (odds ratio: 1.91; 95% confidence interval, 1.00, 3.67). Live-birth rates trended toward improvement after adjusting for covariates (odds ratio: 1.18; 95% confidence interval, 0.61, 2.30). CONCLUSION(S) Cryopreserved day-5 blastocysts have higher implantation rates and trend toward improved pregnancy outcomes compared with cryopreserved day-6 blastocysts. This suggests that embryo development rate may, in part, predict implantation and subsequent FBET outcomes, although embryos not achieving the blastocyst stage until day 6 still demonstrate acceptable outcomes.

Contribution of male age to outcomes in assisted reproductive technologies

OBJECTIVE To evaluate the relationship between male age and pregnancy outcome in donor oocyte assisted reproductive technology cycles. DESIGN Retrospective cohort. SETTING Private IVF center. PATIENT(S) A total of 1,392 donor cycles from 1,083 female recipients and their male partners. INTERVENTION(S) Oocyte donor cycles. MAIN OUTCOME MEASURE(S) Live birth. RESULT(S) Increasing male age was associated with semen parameters including volume and motility; however, male age was not observed to have a statistically significant association with likelihood of live birth in donor cycles after adjustment for female recipient age. CONCLUSION(S) When treatment cycle number and female recipient age were taken into account, male age had no significant association with pregnancy outcomes in assisted reproductive technology donor cycles in this study population.

Progesterone luteal support after ovulation induction and intrauterine insemination: a systematic review and meta-analysis

OBJECTIVE To evaluate the effect of luteal phase P support after ovulation induction IUI. DESIGN A systematic review and meta-analysis. SETTING Not applicable. PATIENT(S) Undergoing ovulation induction IUI. INTERVENTION(S) Any form of exogenous P in ovulation induction IUI cycles. MAIN OUTCOME MEASURE(S) Clinical pregnancy and live birth. RESULT(S) Five trials were identified that met inclusion criteria and comprised 1,298 patients undergoing 1,938 cycles. Clinical pregnancy (odds ratio [OR] 1.47, 95% confidence interval [CI] 1.15-1.98) and live birth (OR 2.11, 95% CI 1.21-3.67) were more likely in P-supplemented patients. These findings persisted in analyses evaluating per IUI cycle, per patient, and first cycle only data. In subgroup analysis, patients receiving gonadotropins for ovulation induction had the most increase in clinical pregnancy with P support (OR 1.77, 95% CI 1.20-2.6). Conversely, patients receiving clomiphene citrate (CC) for ovulation induction showed no difference in clinical pregnancy with P support (OR 0.89, 95% CI 0.47-1.67). CONCLUSION(S) Progesterone luteal phase support may be of benefit to patients undergoing ovulation induction with gonadotropins in IUI cycles. Progesterone support did not benefit patients undergoing ovulation induction with CC, suggesting a potential difference in endogenous luteal phase function depending on the method of ovulation induction.

Selective venous sampling for androgen‐producing ovarian pathology

Objective  Multiple diagnostic modalities may be needed to establish the source of excessive androgen production in women. The role of selective venous catheterization in this process has not been established fully.

Does exogenous LH in ovarian stimulation improve assisted reproduction success? An appraisal of the literature

A review of the scientific literature on the use of exogenous LH in assisted reproductive technology was performed by searching the MEDLINE, PubMed and Cochrane online databases. Scientific evidence was reviewed comparing recombinant FSH-only protocols to protocols supplemented with exogenous LH activity: human menopausal gonadotrophin (HMG), recombinant LH and mid-follicular human chorionic gonadotrophin (HCG). Studies were further compared based on pituitary suppression with gonadotrophin- releasing hormone (GnRH) antagonist and agonist protocols. Primary focus was given to randomized controlled trials and meta-analyses. Data from hypogonadotrophic hypogonadal patients demonstrated the importance of LH activity for success of assisted reproduction treatment. However, the majority of normogonadotrophic patients had adequate endogenous LH to successfully drive ovarian steroidogenesis and oocyte maturation. Exogenous LH supplementation was consistently associated with higher peak oestradiol concentrations. The use of HMG in long GnRH agonist cycles was associated with a 3–4% increase in live birth rate. There was insufficient evidence to make definitive conclusions on the need for exogenous LH activity in GnRH antagonist cycles or the benefit of recombinant LH and HCG protocols. Poor responders and patients 35 years of age and older may benefit from exogenous LH.

Magnetic resonance imaging and transvaginal ultrasound for determining fibroid burden: implications for research and clinical care

OBJECTIVES To compare magnetic resonance and ultrasound imaging for uterine fibroid measurement. STUDY DESIGN Eighteen women undergoing hysterectomy for symptomatic fibroids underwent preoperative pelvic ultrasound and magnetic resonance imaging. Resected fibroids were correlated with the images. Weighted kappa agreement statistics and Spearman correlations for patient characteristics were calculated. RESULTS Magnetic resonance imaging identified 121 of 151 pathologically confirmed fibroids, yielding 91% positive predictive value (95% confidence interval [CI], 85-95) and 80% sensitivity (95% CI, 73-86). Positive predictive value and sensitivity for ultrasound were 97% (95% CI, 89-100) and 40% (95% CI, 32-48), respectively. Mean diameter-equivalent discrepancies between imaging and pathologic measurements were 0.51 +/- 0.68 cm for magnetic resonance imaging and 0.76 +/- 0.88 cm for ultrasound. kappa statistics comparing imaging to pathology showed better agreement for magnetic resonance than ultrasound (kappa = 0.60 vs 0.36). The number of fibroids detected by magnetic resonance imaging predicted measurement errors (r = 0.76; P = .0002). CONCLUSION Superior sensitivity and minimal measurement discrepancies suggest magnetic resonance imaging may be preferentially used for fibroid assessment in clinical research.