M.J. Hill

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.

Leiomyoma: genetics, assisted reproduction, pregnancy and therapeutic advances

PurposeUterine leiomyomas are common, benign, reproductive tract tumors affecting a majority of reproductive aged women. They are associated with gynecologic morbidity and detrimentally affect reproductive potential. The etiology of leiomyomas is poorly understood and their diagnosis prior to treatment with Assisted Reproductive Technologies (ART) represents a management dilemma. The purpose of this paper is to review known genetic and molecular contributions to the etiologies of leiomyomas, describe their impact on ART outcomes and reproductive potential, and review alternative therapies and future directions in management.MethodsA critical review of the literature pertaining to genetic component of uterine leiomyomas, their impact on ART and pregnancy and leiomyoma therapeutics was performed.ResultsUterine leiomyomas are characterized by complex molecular mechanisms. Their location and size determines their potential detriment to ART and reproductive function and novel therapeutic modalities are being developed.ConclusionThe high prevalence of uterine leiomyomas and their potential detrimental influence on ART and reproductive function warrants continued well-designed studies to ascertain their etiology, optimal treatment and novel less morbid therapies.

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.

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.

A GnRH agonist and exogenous hormone stimulation protocol has a higher live-birth rate than a natural endogenous hormone protocol for frozen-thawed blastocyst-stage embryo transfer cycles: an analysis of 1391 cycles

OBJECTIVE To compare embryo and birth data in cryopreserved-thawed blastocyst-stage ET cycles between natural endogenous hormone cycles and exogenous hormone stimulation cycles. DESIGN Retrospective cohort analysis. SETTING Large academic assisted reproductive technology center. PATIENT(S) One thousand three hundred ninety-one patient cycles undergoing frozen-thawed blastocyst-stage ET cycles. MAIN OUTCOME MEASURE(S) Live-birth rate. INTERVENTION(S) The synthetic protocol used GnRH agonist followed by estrogen and P. The natural protocol used monitoring and post-transfer P. RESULT(S) The patients in the two protocols had similar baseline characteristics. Multiple linear regression showed the synthetic protocol to have a higher live-birth rate (odds ratio [OR], 1.46; 95% confidence interval [CI], 1.02-2.09). In patients having two embryos transferred, the synthetic stimulation protocol resulted in a higher live-birth rate per cycle start (32.3% vs. 20.4%; relative risk [RR], 1.58; 95% CI, 1.22-2.06). Similarly, patients with one or two embryos transferred who had additional cryopreserved blastocysts available also had a higher live-birth rate per cycle start (36.1% vs. 12.1; RR, 2.98; 95% CI, 1.16-7.63). CONCLUSION(S) The synthetic hormone protocol was associated with a higher live-birth rate when compared with a natural cycle protocol for frozen-thawed blastocyst-stage ET cycles. This improvement persisted when analysis was controlled for cycle cancellation. The synthetic stimulation protocol for frozen-thawed embryo cycles offers improved outcome results for patients.

Are good patient and embryo characteristics protective against the negative effect of elevated progesterone level on the day of oocyte maturation

OBJECTIVE To evaluate if an elevated progesterone (P) level on the day of human chorionic gonadotropin (hCG) administration is associated with a decrease in live-birth rate in patients with a good prognosis. DESIGN Retrospective cohort study. SETTING Large, private, assisted reproductive technology (ART) practice. PATIENT(S) One thousand six hundred twenty fresh autologous ART cycles. INTERVENTION(S) None. MAIN OUTCOME MEASURE(S) Live-birth rate. RESULT(S) A total of 934 blastocyst and 686 cleavage-stage embryo transfer (ET) cycles were evaluated. Serum P levels were not associated with markers of oocyte or embryo quality, including fertilization, embryo stage at transfer, and embryos available for cryopreservation. Patient age, stage of ET, embryo quality, the number of embryos transferred, and P level on the day of hCG administration were all significantly associated with live birth. Higher P levels were associated with decreased odds of live birth for cleavage- and blastocyst-stage embryos, poor-fair and good-quality embryos, and poor- and high-responder patients. The nonsignificance of interaction tests of P levels with embryo stage, embryo quality, patient age, and ovarian response indicated that the relationship between P level and live birth was similar regardless of these factors. CONCLUSION(S) An elevated serum P level on the day of hCG administration was negatively associated with live birth, even in ETs with a good prognosis.

A luteal estradiol protocol for anticipated poor-responder patients may improve delivery rates

OBJECTIVE To compare IVF data and outcomes between a standard protocol and a luteal phase E(2) protocol. DESIGN Retrospective cohort analysis. SETTING(S) Large academic assisted reproduction technologies center. PATIENT(S) Fifty-seven infertile patients with a history of poor response to IVF stimulation and 228 matched control patients. INTERVENTION(S) IVF with a standard protocol or a luteal phase E(2) protocol. MAIN OUTCOME MEASURE(S) Live-birth rates. RESULT(S) Patients in the luteal E(2) protocol required more days of stimulation and total gonadotropins and had higher peak E(2) levels when compared with the control group. The luteal E(2) protocol showed a greater percentage of embryos with >or=7 cells on day 3. A trend toward improved delivery rates was seen in the luteal E(2) protocol (28.1% vs. 22.4%; relative risk, 1.25, 0.78-2.03). CONCLUSION(S) A luteal E(2) protocol results in improved day 3 embryo development as demonstrated by the percent of embryos at the >or=7-cell stage. Likewise, the luteal E(2) protocol may ultimately improve pregnancy outcomes for patients with poor response to IVF stimulation.

Does a frozen embryo transfer ameliorate the effect of elevated progesterone seen in fresh transfer cycles

OBJECTIVE To compare the effect of progesterone (P) on the day of trigger in fresh assisted reproduction technology (ART) transfer cycles versus its effect on subsequent frozen embryo transfer (FET) cycles. DESIGN Retrospective cohort study. SETTING Large private ART practice. PATIENT(S) Fresh autologous and FET cycles from 2011-2013. INTERVENTION(S) None. MAIN OUTCOME MEASURE(S) Live birth. RESULT(S) A paired analysis of patients who underwent both a fresh transfer and subsequent FET cycle and an unpaired analysis of data from all fresh transfer cycles and all FET cycles were performed. We analyzed 1,216 paired and 4,124 unpaired cycles, and P was negatively associated with birth in fresh but not FET cycles in all analyses. Interaction testing of P and cycle type indicated P had a different association with birth in fresh versus FET cycles. When P was ≥ 2 ng/mL at the time of trigger, live birth was more likely in FET versus fresh cycles in the paired analysis (47% vs. 10%), in the unpaired analysis (51% vs. 14%), and in unpaired, good blastocyst only transfer subgroup (51% vs. 29%). Live birth was similar in FET cycles, with P ≥ 2 ng/mL versus P < 2 ng/mL (51% vs. 49%). Conversely, live birth was lower in fresh cycles, with P ≥ 2 ng/mL versus P <2 ng/mL (15% vs. 45%). CONCLUSION(S) Elevated P levels on the day of trigger during the initial fresh cycle were negatively associated with live birth in the fresh transfer cycles but not in subsequent FET cycles. Freezing embryos and performing a subsequent FET cycle ameliorates the effect of elevated P on live-birth rates.

GnRH antagonist rescue in high responders at risk for OHSS results in excellent assisted reproduction outcomes

Gonadotrophin-releasing hormone (GnRH) antagonist rescue is performed by replacing a GnRH agonist with a GnRH antagonist in patients with rapidly rising serum oestradiol who are at risk of ovarian hyperstimulation syndrome (OHSS) during stimulation. It results in a rapid reduction in serum oestradiol, allowing for the avoidance of cycle cancellation and the continuation of exogenous gonadotrophin administration. A total of 387 patients who underwent GnRH antagonist rescue for ovarian hyperresponse were compared with 271 patients who did not receive GnRH antagonist rescue and had oestradiol concentrations >4000 pg/ml on the day of human chorionic gonadotrophin (HCG) administration. GnRH antagonist rescue decreased the mean oestradiol concentration by 35% on the first day of use. There was no difference in oocyte maturity (82% versus 83%) or fertilization rate (69% versus 67%) between the antagonist rescue and comparison groups, respectively. The percentage of high-grade embryos on day 3 and the blastocyst development rate were also similar between groups. The live-birth rate was 41.9% in the antagonist rescue group and 36.9% in the comparison group. GnRH antagonist rescue enabled cycle completion with high live-birth rates in patients at risk for OHSS. GnRH antagonist was associated with high oocyte quality, blastocyst development and pregnancy. Gonadotrophin-releasing hormone (GnRH) antagonist rescue is a protocol to reduce the risk of ovarian hyperstimulation syndrome (OHSS) in assisted reproduction treatment. Patients who have a hyperresponse to medication during their treatment cycle have their GnRH agonist discontinued and a GnRH antagonist started in its place. This causes a rapid reduction in oestrogen concentrations and allows for the continuation of stimulation medication. We evaluated the effectiveness of this protocol by comparing patients who had GnRH antagonist rescue against high-responding patients who did not receive GnRH antagonist rescue. GnRH antagonist rescue resulted in a 35% reduction in oestrogen concentration and only a 1.5% cycle cancellation rate. There were no differences in oocyte maturity or fertilization between the two groups. There were no differences in the quality of day-3 and day-5 embryos between the two groups. The live birth rate was 41.9% in the antagonist rescue group and 36.9% in the comparison group. GnRH antagonist rescue reduced serum oestradiol concentrations and enabled cycle completion with high live-birth rates in patients at risk for OHSS. GnRH antagonist was associated with high oocyte quality, blastocyst development and pregnancy.