Endometrial receptivities after leuprolide suppression and gonadotropin stimulation: histology, steroid receptor concentrations, and implantation rates.

The effect of markedly supraphysiologic levels of E2 and P4 on the endometrium was assessed by examining endometrial histology, E2 and P4 receptor concentrations, and embryo implantation rates in IVF cycles with and without leuprolide use. Results suggest that 1) the high ovarian response common in leuprolide pretreated cycles can advance endometrial histology, but only up to a certain limit, 2) P4 greater than 25ng/ml or E2 greater than 200pg/ml on the day of transfer was associated with non-lagging endometria, 3) implantation rate in high response cycles is not impaired and may be increased, 4) earlier P4 supplementation in low response cycles may be beneficial, 5) extraordinarily high response (E2 greater than 5000pg/ml) may be detrimental to implantation, and 6) the optimal histology for implantation appears to be at least day 16.

Basal follicle-stimulating hormone level and age affect the chance for and outcome of pre-embryo cryopreservation.

All IVF cycles in which subsequent transfers of thawed pre-embryos occurred were studied. Both age and basal (cycle day 3) FSH level are important determinants of the chance for cryopreservation and the performance of cryopreserved pre-embryos. Although there was no age or FSH level above which pregnancy with frozen pre-embryos was not possible, the chances clearly decline. Thus, consideration to transferring larger numbers of pre-embryos fresh should be given to women in the fifth decade and those with basal FSH > 15 IU/L.

Superior analytic characteristics of an immunometric assay for gonadotropins also provides useful clinical prediction of in vitro fertilization outcomes.

OBJECTIVE: To determine whether an analytically superior gonadotropin assay, the monoclonal, two-site immunometric assay, also provided superior prediction of clinical outcomes when compared with conventional RIA methodology. DESIGN: Methods comparison study. SETTING: Tertiary academic center. PATIENTS: One hundred fifty-seven consecutive IVF patients. INTERVENTION: Comparisons of FSH and LH levels on cycle day 3 were made using paired RIA and immunometric assay procedures. The ability of day 3 LH, FSH, and their ratio in predicting IVF performance was determined using regression analyses. RESULTS: The predictive ability of FSH as assayed by immunometric assay at least equaled that obtained by RIA for both peak E2 levels and the number of mature oocytes retrieved. CONCLUSION: Results from this study indicate that gonadotropin levels as measured by immunometric assay represent an effective clinical tool in predicting IVF outcomes that may prove superior to RIA.

Experience with a novel vaginal progesterone preparation in a donor oocyte program.

OBJECTIVE: To compare the efficacy of a vaginal progesterone preparation with our standard IM preparation within a donor egg program. DESIGN: Prospective randomized trial. SETTING: Donor egg program at a university assisted reproductive therapy program (Jones Institute for Women's Health). PATIENT(S): Couples accepted into the donor egg program because of either premature ovarian failure or evidence of diminished ovarian reserve. INTERVENTION(S): Women were randomized into either a group receiving IM progesterone replacement or a group receiving vaginal progesterone replacement. Both groups underwent Estraderm patch/progesterone treatment in a mock cycle leading to an endometrial biopsy on day 26 followed by a second cycle in which ET was performed. Subjects with residual ovarian function received a GnRH agonist. In the IM treatment group, 100 mg was administered from cycle days 15 to 27. In the vaginal treatment group, Crinone 8%, a polycarbophil-based gel preparation containing 90 mg of micronized progesterone, was administered twice daily from the evening of day 14. MAIN OUTCOME MEASURE(S): Endometrial histology, serum levels of progesterone (on days 13, 17, 20, 24, and 26), the occurrence of pregnancy, implantation rate, and pregnancy outcome. RESULT(S): Fifty-four women randomized into the vaginal progesterone treatment group and 18 women in the IM treatment group achieved ET. Mean serum progesterone levels were higher in the IM treatment group than in the Crinone group. Endometrial histology was "in phase" for all subjects in both groups. Clinical pregnancies were observed in 26 of 54 women and 5 of 18 women in the Crinone and IM progesterone groups, respectively. The ongoing pregnancy rate (PR) of 31% (17/54) and implantation rate of 23% in the subjects receiving Crinone was not statistically different from the IM progesterone group's ongoing PR of 22% (4/18) and implantation rate of 18%. CONCLUSION: Vaginal progesterone replacement with the polycarbophil gel preparation was as effective as IM progesterone in producing clinical and ongoing pregnancies within our donor egg program in the dosages administered.

Crinone 8% (90 mg) given once daily for progesterone replacement therapy in donor egg cycles.

OBJECTIVE: To determine whether once-daily dosing of Crinone 8% (90-mg progesterone vaginal gel; Serono Laboratories, Inc., Norwell, MA) is sufficient for normal endometrial development and pregnancy support. DESIGN: Prospective cohort study. SETTING: Academic medical center. PATIENT(S): Eighty-six women who required complete progesterone replacement for a donor egg cycle. INTERVENTION(S): Crinone 8% (90 mg) once daily or IM progesterone (100 mg) once daily was administered from day 15 onward. Both groups underwent an endometrial biopsy on day 26 of a mock cycle, followed by a second cycle in which ET was performed. MAIN OUTCOME MEASURE(S): Endometrial development, serum progesterone levels, pregnancy rates, implantation rates, and bleeding patterns. RESULT(S): Mean (+/-SD) serum progesterone levels on day 26 were 11.3+/-6.5 ng/mL in the Crinone group and 65.2+/-12.5 ng/mL in the IM progesterone group. At histologic examination, endometrial biopsy specimens were found to be "in phase" for 100% (42/42) of women in the Crinone group and 95.5% (42/44) of women in the IM progesterone group. Although 8 of 42 patients had serum progesterone levels of <6 ng/mL, there was no correlation with endometrial development. Only 1 patient bled before the 14th day of progesterone therapy, and she went on to be delivered of twins. Clinical pregnancy, ongoing pregnancy, implantation, and miscarriage rates were not statistically different for the Crinone and IM progesterone groups: 45.6% (21/46) versus 52.3% (23/44); 39.1% (18/46) versus 40.9% (18/44); 21.5% (34/158) versus 19% (30/158), and 14.3% (3/21) versus 22% (5/23), respectively. Power was sufficient to detect a 25% difference in clinical pregnancy rates. CONCLUSION(S): Crinone 8% administered once daily appears to produce the same endometrial development and pregnancy rates as IM progesterone in women who require complete progesterone replacement, and it does not cause early bleeding.

Outcome of twin, triplet, and quadruplet in vitro fertilization pregnancies: the Norfolk experience.

OBJECTIVE: To review the maternal morbidity and neonatal morbidity and mortality associated with in vitro fertilization (IVF) multiple pregnancies. DESIGN: Retrospective analysis of data collected from office and hospital records and from questionnaires sent to patients, their obstetricians, and pediatricians. SETTING: Patients (all with private insurance carriers) enrolled in an academic IVF program (The Jones Institute for Reproductive Medicine). PATIENTS, PARTICIPANTS: All IVF pregnancies resulting in one or more gestational sacs on the initial ultrasound at 6 to 7 weeks were reviewed. MAIN OUTCOME MEASURES: The frequency and severity of obstetrical and neonatal complications and the perinatal mortality of IVF twins, triplets, and quadruplets were compared. These were also compared with non-IVF multiple pregnancies. RESULTS: From 1982 to 1990, 629 IVF pregnancies progressed beyond 20 weeks; 115 twins (18.3%), 15 triplets (2.4%), and 4 quadruplets (0.6%). There was a high incidence of antenatal complications such as abortions (30.3%, 42%, and 20%), premature labor (41.5%, 92.3%, and 75%), pregnancy-induced hypertension (17.0%, 38.6%, and 50%), and gestational diabetes mellitus (3.1%, 38.5%, and 25%) for twins, triplets, and quadruplets, respectively. The mean gestational age at delivery was 35.5 +/- 3.7, 31.8 +/- 2.7, and 31.0 +/- 1.7 weeks, respectively. There was also a proportionate progressive increase in neonatal complications. The mean weights were 2,473 +/- 745, 1,666 +/- 441 and 1,414 +/- 368 g, respectively. Twins (22.7%), 64.1% of triplets, and 75% of quadruplets needed admission to the neonatal intensive care unit and remained for an average of 12.0 +/- 2.3, 17.4 +/- 14.0, and 57.8 +/- 17.9 days, respectively. There was no difference in the mean Apgar scores or the incidence of congenital malformations in the three groups. The corrected perinatal mortality rates were 38.5, 0.0, and 0.0 per thousand live births, respectively. CONCLUSION: Triplet and quadruplet IVF pregnancies have increased obstetrical and neonatal complications compared with IVF twins. The perinatal mortality and the incidence of congenital malformations are, however, comparable in all three groups.

Significance of basal follicle-stimulating hormone levels in women with one ovary in a program of in vitro fertilization.

OBJECTIVE: To understand the impact of having a single ovary on basal follicle-stimulating hormone (FSH) level and its diagnostic and prognostic usefulness in in vitro fertilization (IVF). DESIGN: All IVF cases from July 1987 to June 1990 with known basal FSH (n = 1,272) were divided into those with one and those with two ovaries to compare outcomes based on basal FSH levels. SETTING: Tertiary care academic center with a large IVF practice. MAIN OUTCOME MEASURES: Basal FSH, age, and IVF outcomes including peak estradiol, numbers of follicles aspirated, oocytes retrieved, fertilized, and transferred, and pregnancies (clinical and ongoing). RESULTS: In women with only one ovary, basal FSH was increased, and IVF outcomes were poorer. The rise in FSH was able, in large part, to account for the diminished performance in the single ovary cases. CONCLUSIONS: Women with only one ovary have higher basal FSH levels than those with two ovaries, and this rise can be used to predict their IVF performance.

Basal follicle-stimulating hormone level is a better predictor of in vitro fertilization performance than age.

A study of 1,478 consecutive in vitro fertilization (IVF) cycles was made to determine if basal follicle-stimulating hormone (FSH) levels and age were independent predictors of IVF performance. Regression analyses indicated independent contributions of both basal FSH and age in predicting cancellation rate, peak estradiol, number of oocytes retrieved, fertilized, and transferred, and total and ongoing pregnancy rates. Miscarriage rate was unrelated to both age and basal FSH. Follicle-stimulating hormone level was a better predictor than age for all outcome variables examined and remained a significant predictor after accounting for age, etiology of infertility, and semen quality. The combined use of age and basal FSH in counseling patients improves the accuracy of prognosis, and may provide an index of functional ovarian reserve ("ovarian age").

Predictive value of pregnancy during original in vitro fertilization cycle on implantation and pregnancy in subsequent cryothaw cycles.

OBJECTIVE: To understand the homogeneity of oocyte quality within a cohort. DESIGN: All women (n = 367) that had cryopreserved pre-embryos subsequently thawed were studied. Pregnancy and implantation rates in the in vitro fertilization (IVF) and cryothaw transfers were examined. SETTING: Tertiary care academic center. RESULTS: Pregnancy in original IVF cycle predicted higher implantation rates at subsequent cryothaw transfers. Similarly, pregnancy in cryothaw cycles was associated with higher implantation and ongoing pregnancy rates at the initial IVF cycle. CONCLUSIONS: Within a cohort of oocytes, pregnancy with some of the pre-embryos in a cohort predicts pregnancy with the remaining oocytes in the cohort. Thus, oocytes within a cohort have similar pregnancy potential.

Messenger ribonucleic acid kinetics in human oocytes--effects of in vitro culture and nuclear maturational status.

OBJECTIVE: To study the effects of different nuclear maturational status (prophase I [PI] versus metaphase II [MII]) and in vitro culture on the kinetics of maternal messenger ribonucleic acid (mRNA) in human oocytes. DESIGN: Molecular biology on excess oocytes obtained from our clinical IVF program. INTERVENTIONS: The oocytes, classified as either PI or MII at collection, were used as such or cultured in vitro for an additional 24 hours. The relative levels of c-mos and cyclin-B1 were measured using semiquantitative reverse transcriptase polymerase chain reaction (RT-PCR). RESULTS: The mean levels of c-mos and cyclin-B1 transcripts were indistinguishable between the PI, MII, PI oocytes matured in vitro, PI oocytes failing to mature, and MII oocytes cultured for additional 24 hours. The variability in the levels of these transcripts increased during the vitro culture. CONCLUSIONS: The level of c-mos and cyclin-B1 transcripts were not different in PI versus MII oocytes, therefore, differences seen in the clinical outcome of PI and MII oocytes may be unrelated to levels of these gene products. C-mos and cyclin B1 mRNA were maintained in vitro, thus degradation of maternal RNA is not activated in excess during the 24-hour culture.

Endometrial estrogen and progesterone receptor and pinopode expression in stimulated cycles of oocyte donors.

OBJECTIVE: To study the effect of controlled ovarian hyperstimulation and the ovarian response on several features of endometrial morphology simultaneously. DESIGN: Prospective controlled study. SETTING: Academic infertility center. PATIENT(S): Twenty-five oocyte donors undergoing COH and 10 ovulatory controls. INTERVENTION(S): Endometrial biopsies during the luteal phase and measurement of serum E2 and progesterone levels on days 12, 13, and 18-20. MAIN OUTCOME MEASURE(S): Endometrial morphology as judged by histologic dating, pinopode expression, and estrogen and progesterone receptor content. RESULT(S): Controlled ovarian hyperstimulation caused the early expression of endometrial features as judged by histologic dating criteria, estrogen and progesterone receptor expression, and the timing of pinopode expression in many of the subjects. A significant correlation within subjects with regard to their particular result on any one measure (e.g., histologic examination) and the others (e.g., estrogen and progesterone receptors, pinopodes) was observed. Those with higher levels of progesterone the day after hCG administration exhibited the most prematurity of morphologic features. CONCLUSION(S): Many controlled ovarian hyperstimulation cycles are associated with synchronous early expression of the expected pattern of histologic features, estrogen and progesterone receptors, and pinopodes. The most predictive feature of this premature expression was the level of progesterone the day after hCG administration.

The impact of an egg donor's age and her prior fertility on recipient pregnancy outcome.

OBJECTIVE: To investigate the effect of donor's age and her prior fertility on recipient pregnancy outcome in our donor egg program. DESIGN: Retrospective cohort analysis. SETTING: Large academic infertility center. PATIENT(S): A total of 568 fresh ETs were analyzed for the effect of the egg donor's age on pregnancy outcome; a subset of these (n = 185) were analyzed for the effect of the egg donor's prior fertility on pregnancy outcome. INTERVENTION(S): Donors were paired with recipients independent of recipient's age and donor's prior fertility status. MAIN OUTCOME MEASURE(S): Recipient clinical pregnancy rates (PRs) and delivery rates for different donor age groups and for nulligravid donors versus donors with proven fertility. RESULT(S): Donors > or = 33 years old were less likely than younger donors to produce clinical pregnancies and deliveries in their recipients (43.5% versus 26.6% and 35.1% versus 22.1%, respectively). However, there was no difference in clinical PRs or delivery rates between nulligravid donors and donors with proven fertility. CONCLUSION(S): Donors > or = 33 years of age could be excluded from egg donation because of the lower pregnancy potential of their eggs. However, lack of proven fertility in a donor seems to have no negative impact on pregnancy potential.

Follicle-stimulating hormone levels on cycle day 3 are predictive of in vitro fertilization outcome.

Cycle day 3 basal levels of follicle-stimulating hormone (FSH), luteinizing hormone (LH), and estradiol (E2) were measured in 441 patients in 758 consecutive cycles to determine their predictive value for stimulation quality and pregnancy rates in vitro fertilization (IVF). Patients with low basal FSH levels (less than 15 mIU/ml) had higher pregnancy rates per attempt than those with moderate levels (15 to 24.9 mIU/ml), both of which were higher than those with high FSH levels (greater than 25 mIU/ml). Basal LH and E2 values did not improve the predictive value beyond that provided by FSH. Ongoing pregnancy rates per attempt in the low, moderate, and high FSH groups were 17.0%, 9.3%, and 3.6%, respectively (P less than 0.01). The three groups differed significantly in the percentage of patients having two ovaries, the mean number of follicles aspirated per retrieval, the mean number of preovulatory oocytes obtained, and peak E2 values (P less than 0.01). Cycle day 3 FSH levels are predictive of pregnancy outcome and stimulation characteristics in IVF, and may be useful in counseling patients.

Histochemical localization of endometrial insulin-like growth factor binding protein-1 and -3 during the luteal phase in controlled ovarian hyperstimulation cycles: a controlled study.

OBJECTIVE: To determine if controlled ovarian hyperstimulation (COH) affects the endometrial expression of IGFBP-1 and IGFBP-3. DESIGN: Prospective, controlled study. SETTING: Tertiary infertility clinic. PATIENT(S): Eighteen oocyte donors undergoing COH cycles and 17 natural cycle controls. INTERVENTION(S): Controlled ovarian hyperstimulation, endometrial biopsies. MAIN OUTCOME MEASURE(S): Immunohistochemical scoring of endometrial IGFBP-1 and -3 expression, morphological endometrial dating, and serum estradiol (E(2)), LH, and progesterone (P(4)) concentrations. RESULT(S): No statistically significant difference was observed between natural and stimulated cycles in change in IGFBP-1 or -3 over standardized cycle days throughout the window of embryo implantation (days 17-24). The IGFBP-1 and -3 expression was zero or near zero for both the natural and COH cycles until day 12-13. Both IGFBPs showed increased production throughout the secretory phase. Advanced endometrial histology (>/=1 day) in glands and stroma was noted in COH cycles. Significant positive correlations of E(2) and P(4) were noted with IGFBP-1 and -3 but not with advanced endometrial morphology in the COH cycles. CONCLUSION(S): The COH cycles have no significantly increased endometrial IGFBP-1 or -3 expression throughout the implantation phase of the luteal cycle compared with normal menstrual cycles. Both IGFBPs were absent in the proliferative phase and increased throughout the secretory portion of the embryo implantation window.

Detection of endometrial pinopodes by light microscopy.

OBJECTIVE: To study the value of light microscopy (LM) in the assessment of endometrial pinopodes. DESIGN: Comparative histologic study. SETTING: Outpatient infertility clinic in an academic teaching institution. PATIENT(S): Eighteen oocyte donors undergoing controlled ovarian hyperstimulation. INTERVENTION(S): Endometrial biopsies on days 14-24 of the cycle. MAIN OUTCOME MEASURE(S): Assessment of pinopodes by scanning electron microscopy (SEM) and of endometrial surface projections by LM. RESULT(S): The luminal surface was identified by LM in 36 of 38 endometrial specimens obtained. Although apical projections could be recognized in all, they were few, moderate, and abundant in 20, 12, and 4 cases, respectively. Pinopodes were detected by SEM in all 4 samples with abundant projections, but in only 14 of 32 samples with lesser quantities of these surface features. No predictive value could be ascribed to apical projections viewed by LM for the developmental stage of pinopodes as defined by SEM. CONCLUSION(S): The LM of routine endometrial specimens can serve as a preliminary tool in the evaluation of surface morphology. Although abundant apical projections by LM are compatible with the presence of pinopodes by SEM, the latter modality remains as the definitive method in cases with few or moderate projections and for the evaluation of the stage of pinopode development.

Evaluation of outpatient hysteroscopy, saline infusion hysterosonography, and hysterosalpingography in infertile women: a prospective, randomized study.

OBJECTIVE: To compare the diagnostic accuracy, pain scores, and procedure length of outpatient hysteroscopy (OHS), hysterosalpingography (HSG), and saline infusion hysterosonography (SIS) for evaluation of the uterine cavity of infertile women. DESIGN: Prospective, randomized, investigator-blind study. SETTING: Tertiary infertility clinic. PATIENT(S): Forty-six consecutive infertile women. INTERVENTION(S): Outpatient HSG, OHS, and SIS, followed by operative hysteroscopy (HS). MAIN OUTCOME MEASURE(S): Uterine abnormalities, procedure length, and subjective pain. RESULT(S): Fifty-nine percent of infertile subjects were found to have an abnormality on at least one of three outpatient uterine evaluations. When compared with the case of definitive operative HS, 60% of abnormalities were correctly classified by HSG, 72% by OHS, and 52% by SIS (P: NS). When comparing all combinations of 2 outpatient screening tests to operative hysteroscopy, 68% were correctly classified by HSG/OHS, 58% by HSG/SIS, and 64% by OHS/SIS (P: NS). The average time length for the OHS was 9.1 min., which was significantly greater than for both HSG (average, 5.3 min) and SIS (average, 6.1 min.) (P<.0001 for both). HSG and SIS were not statistically different regarding procedure time length. The average pain score (0-10) for SIS was 2.7, compared with 5.8 and 5.3 for HSG and OHS, respectively. Both HSG and OHS mean pain scores were significantly greater than the SIS mean. CONCLUSION(S): OHS, SIS, and HSG were statistically equivalent regarding evaluation of uterine cavity pathology in infertile women.

Endometrial glycodelin-A expression in the luteal phase of stimulated ovarian cycles.

OBJECTIVE: To determine if controlled ovarian hyperstimulation (COH) affects the endometrial expression of glycodelin-A (GdA). DESIGN: Prospective, controlled study. SETTING: Tertiary infertility clinic. PATIENT(S): Fifteen oocyte donors undergoing COH cycles and 19 natural-cycle control patients. INTERVENTION(S): COH, endometrial biopsies. MAIN OUTCOME MEASURE(S): Immunohistochemical scoring of endometrial GdA expression, morphologic endometrial dating, and serum E2, LH, and P4 concentrations. RESULT(S): GdA was detected in all subjects throughout the implantation window period. Immunolocalization was demonstrated in the endometrial glands and not in the stroma or on the surface. A significantly increased proportion of GdA-staining endometrial cells were noted in COH cycle patients as compared with natural-cycling control patients throughout the window of embryo implantation. Both cycle types demonstrated increasing GdA expression throughout the late luteal phase. A significant positive correlation was noted between GdA expression and serum E2 levels (r = 0.5, P<.001) in natural cycles and advanced histology in COH cycles (r = 0.63, P=.01). Neither LH nor P4 were correlated with endometrial GdA expression. CONCLUSION(S): COH cycles have a significantly increased endometrial GdA expression throughout the implantation phase of the luteal cycle when compared with normal menstrual cycles. The increased expression may affect implantation during COH cycles.

The gonadotropin-releasing hormone agonist stimulation test--a sensitive predictor of performance in the flare-up in vitro fertilization cycle.

OBJECTIVE: To evaluate the initial versus early pattern of estradiol (E2) change after administration of a gonadotropin-releasing hormone agonist (GnRH-a), i.e., the GnRH-a stimulation test versus E2 pattern, respectively, as predictors of ovarian response and pregnancy in in vitro fertilization (IVF) patients stimulated with a flare-up protocol. DESIGN: Prospective study in a consecutive group of patients. SETTING: Tertiary care, institutional setting. PATIENTS: Two hundred twenty-eight patients entered and completed the study. The only patients excluded from study were those anticipated to have polycystic ovarian disease, those with a single ovary, or those with an ovarian cyst(s). INTERVENTIONS: Patients were stimulated with a GnRH-a flare-up protocol beginning on menstrual day 2. MAIN OUTCOME: Evaluation of the GnRH-a stimulation test and the E2 pattern as predictors of the number of mature oocytes retrieved and pregnancy. RESULTS: The GnRH-a stimulation test but not the E2 pattern was predictive of the number of mature oocytes retrieved (r = 0.53, P less than 1 X 10(-5) and pregnancy (chi 2 = 8.5, P = 0.04). The E2 pattern was predictive of the duration and number of ampules of gonadotropin required for stimulation. CONCLUSION: The GnRH-a stimulation test is a sensitive predictor of performance in the flare-up IVF cycle.

Sperm morphology as diagnosed by strict criteria: probing the impact of teratozoospermia on fertilization rate and pregnancy outcome in a large in vitro fertilization population.

OBJECTIVE: To investigate the predictive value of sperm morphology assessed by strict criteria on IVF outcome. DESIGN: Retrospective analysis of all IVF cycles (January 1987 to December 1992). MAIN OUTCOME MEASURES: All patients were assigned to one of three groups based on sperm morphology: P-pattern (< 4% normal forms), G-pattern (4% to 14% normal forms), and N-pattern (> 14% normal forms). Morphology pattern was related to other semen characteristics and IVF outcome. RESULTS: Despite corrective measures at oocyte insemination, the fertilization rate was significantly different among the three morphology groups, P < G < N. N-pattern sperm produced a mean fertilization rate over 85% regardless of low motility or concentration. In a cohort study, P-pattern cycles produced a lower implantation rate and lower ongoing pregnancy rate, independent of the lower fertilization rate. CONCLUSIONS: Strict morphology is an excellent biomarker of sperm fertilizing capacity, independent of motility and concentration. P-pattern sperm may denote a poorer prognosis for establishing a pregnancy, even after a satisfactory fertilization rate is achieved.

Cessation of gonadotropin-releasing hormone agonist therapy combined with high-dose gonadotropin stimulation yields favorable pregnancy results in low responders.

OBJECTIVE: To evaluate the pregnancy results of an ovarian hyperstimulation protocol for IVF-ET that combines GnRH agonist down-regulation, cessation of GnRH agonist therapy with the onset of menstruation, and high-dose gonadotropin administration in low responders. DESIGN: Prospective analysis. SETTING: Academic IVF program. PATIENT(S): One hundred eighty-two low responders undergoing 224 IVF-ET cycles. INTERVENTION(S): Down-regulation was obtained with the administration of leuprolide acetate beginning in the midluteal phase and ending with the onset of menses. Daily administration of 6 ampules of FSH alone or in combination with hMG was initiated on cycle day 3. MAIN OUTCOME MEASURE(S): Stimulation characteristics and pregnancy rates (PRs) were compared between fresh cycles in which pure FSH alone was used and 35 cycles in which a combination of FSH and hMG was administered. RESULT(S): The clinical PR per transfer, the ongoing PR per transfer, and the implantation rate were 32%, 24%, and 9%, respectively. No differences were noted between cycles in which pure FSH alone was used in comparison with cycles in which a combination of FSH and hMG was administered. CONCLUSION(S): Short-term ovarian suppression begun in the luteal phase and discontinued with the onset of menses followed by high-dose stimulation with gonadotropins yields favorable pregnancy results in low responders.