The use of high-dose human menopausal gonadotropin in an in vitro fertilization program

Sixty-three normal ovulatory women suffering from obstructive tubal disease not corrected by previous surgery were enrolled in an in vitro fertilization (IVF) program. To achieve a large number of mature follicles, a relatively high dose of human menopausal gonadotropin (hMG) was administered (19 +/- 4 ampules/cycle). Monitoring consisted of daily follicular ultrasonography and serum estradiol measurements. Human chorionic gonadotropin (10,000 IU) was administered when more than two large follicles (1.6 to 1.8 cm in diameter) were visualized. Fifty-five laparoscopies for oocyte retrieval were performed. A mean of 4.3 follicles per woman were aspirated, and 3.2 oocytes per woman were recovered. The oocytes were preincubated for 8 or 24 hours according to the morphologic degree of mucification and dispersal of the oocyte-corona-cumulus complex. Seventy-seven percent of the oocytes were fertilized and were transferred into the uterus 38 to 40 hours after insemination. Fifty-two women received one to eight embryos (mean, 3.5 +/- 1.9), and 9 (17%) conceived. This regimen of high-dose hMG precludes the need for serum or urine luteinizing hormone monitoring, because the occurrence of spontaneous ovulation is low. It is valuable in increasing the number of fertilizable oocytes, the percentage of women undergoing embryo transfer, and compensates with multiple oocyte transfer for the high embryonic loss involved in IVF.     

Clomiphene-HMG ovarian stimulation in human in vitro fertilization and embryo transfer

In a program for in vitro fertilization and embryo transfer, laparoscopies for oocyte aspiration were performed in 40 cycles in 36 normally menstruating women with irreparable tubal diseases (IVF patients) who received clomiphene citrate (CC) and human menopausal gonadotropin (hMG). An intramuscular injection of human chorionic gonadotropin (hCG) was given to all patients after completion of follicular maturation. Fourteen cycles in 13 spontaneously ovulating women (control patients), also stimulated with CC and hMG, were adequately monitored to identify the appearance of the spontaneous luteinizing hormone (LH) surge. The follicular maturation was followed by daily ovarian ultrasonographic examination and serum estradiol estimations. Just before the LH surge the diameter of the leading follicle was 20.2 +/- 0.7 (mean +/- S.E.) mm and the serum estradiol concentration per follicle was 384.1 +/- 16.3pg/ml in the control patients. In the IVF patients the former was 20.6 +/- 0.3mm and the latter was 305.8 +/- 13.3pg/ml prior to hCG administration. When the relationship of follicular size to the rates of oocytes recovery, maturation, fertilization and cleavage was examined, larger follicles (3ml less than or equal to follicular fluid volume) showed good results. Of the 152 oocytes that were recovered from these IVF patients, 96 (63.2%) were fertilized and 79 (52.0%) cleaved. Three pregnancies resulted from 35 embryo transfers.     

Combination clomiphene citrate/human menopausal gonadotropin stimulation protocols for in vitro fertilization-embryo transfer

Various protocols have been utilized for stimulation of multiple ovarian follicles in patients undergoing in vitro fertilization-embryo transfer (IVF-ET). Previous studies have suggested that the combination of clomiphene citrate (CC) and human menopausal gonadotropins (hMG) is superior to either CC or hMG alone in terms of follicular development, oocyte recovery, and embryo transfer. However, no significant increase in viable pregnancy rates has been reported with any of the protocols. This report examines five different CC/hMG protocols. While differences were seen in terms of serum estradiol response and fertilization rates of mature oocytes among the various protocols, no significant differences were found in terms of follicular development, oocyte recovery, embryo transfer, or pregnancy. The pregnancy rate in IVF-ET appears unaffected by variations in the dose and timing of CC and hMG in a combination protocol.     

A preliminary study on in vitro fertilization and embryo transfer

Forty-two women with infertility were enrolled in an in vitro fertilization and embryo transfer (IVF/ET) program, from July, 1986 to February, 1988, at the First Affiliated Hospital, Human Medical University. CC/hMG/hCG and hMG/hCG regimens for ovulation induction were used for 35 and 7 patients. Monitoring methods consisted of daily follicular ultrasonography and serum estradiol measurements. Human chorionic gonadotropin 10,000IU was administered when the leading follicle reached 18mm in diameter and serum E2 level was equal to or more than 1,480 pmol/L (400 pg/ml). Twenty-one laparoscopies and nineteen laparotomies for oocyte retrieval were performed. The IVF/ET results using CC/hMG/hCG for ovarian stimulation were as follows: an average of 6.1 follicles were aspirated and 3.5 oocytes recovered for one case. The recovery rate and fertilization rate was 57.0% and 60.1% respectively. In twenty-five women one to five embryos were transferred and a clinical pregnancy occurred in one who received three embryos. Laparotomy for oocyte retrieval showed that more oocytes could be obtained than laparoscopy. The purity of CO2 used for laparoscopy was considered to affect the IVF results.     

A prospective comparative study on IVF outcomes with either purified FSH or human menopausal gonadotrophin in downregulated normogonadotrophic women

OBJECTIVE: In compare the use of purified follicle-stimulating hormone with that of a preparation containing follicle-stimulating hormone and luteinizing hormone in infertile females undergoing IVF. DESIGN: Open-labelled prospective controlled single-center study. SETTING: Nile Badrawy IVF unit. PARTICIPANTS: 153 infertile females undergoing their first cycle of IVF divided into 2 groups. Interventions: Ovarian stimulation was done with either highly purified FSH for group 1 (n = 75) or human menopausal gonadotrophin group 2 (n = 78) after pituitary desensitization commenced in the midluteal phase of the preceding cycle. Monitoring was performed by ultrasound transvaginal oocyte retrieval followed by IVF and transfer of three embryos. OUTCOMES: Number of oocytes >18 mm at day of hCG, fertilization rate, embryo transfer rate, clinical pregnancy rate and incidence of ovarian hyperstimulation syndrome. RESULTS: The response to ovarian hyperstimulation was similar in both groups. The number of follicles >18 mm achieved at day of hCG was 12.3 +/- 0.9 (mean +/- SEM) following stimulation with 38.3 +/- 0.9 ampoules of Fostimon The Menogon-treated group needed 39.1 +/- 0.8 ampoules to produce 11.6 +/- 0.7 follicles. Fertilization rate (2PN/cell) was 58.6 vs. 64.2% in the Fostimon and Menogon group, respectively (p > 0.05). The number of embryos transferred per woman was 3.1 +/- 0.1 in the Fostimon group and 3.6 +/- 0.1 in the Menogon group. The pregnancy rate per woman was 33.3 vs. 25.6% in the Fostimon- and Menogon-treated groups, respectively (p > 0.05). Miscarriage rate was 16 vs 20%, respectively. However, the incidence of multiple pregnancies was significantly higher in the Fostimon-treated group (32%) vs. 10% only in the Menogon-treated group (p < 0.01). CONCLUSION: Purified FSH yields similar clinical outcome to hMG in terms of oocytes retrieved and clinical pregnancies in a standard IVF regimen.     

Comparative trial of luteinizing hormone-releasing hormone analog/human menopausal gonadotropin and clomiphene citrate/human menopausal gonadotropin in an assisted conception program

To establish the usefulness of a new drug regimen in an assisted conception program, a trial was performed comparing clomiphene citrate (CC) plus human menopausal gonadotropins (hMG) with a new regimen of intranasal luteinizing hormone-releasing hormone (LH-RH) analog plus hMG. One hundred two patient cycles received treatment with CC and hMG and 118 patient cycles received treatment with LH-RH analog and hMG. Fifteen percent of cycles were canceled in the CC group and 8% in the analog group. Four percent of cycles in the CC group were canceled due to premature ovulation. The number of oocytes collected in the analog group was significantly higher than in the CC group (8.5 versus 5.5), as was the number of mature oocytes (3.5 versus 2.7). However, the percentage of mature oocytes was higher in the CC group (54.2% versus 42.3%). The number of embryos resulting from in vitro fertilization as well as the number of cleaving embryos were significantly higher in the analog group (5.2 versus 2.8 and 4.6 versus 2.3, respectively). The pregnancy rate in the analog group was significantly higher than in the CC group (30.6% versus 16.1%), as was the live birth rate (21% versus 8%). Early pregnancy loss was significantly higher in the CC group than in the analog group (35% versus 9%); and the serum level of LH on the day of human chorionic gonadotropin (hCG) administration was also significantly elevated in the CC group when compared with the analog group (8.1 versus 4.1).(ABSTRACT TRUNCATED AT 250 WORDS)     

Follitropin-alpha versus human menopausal gonadotropin in an in vitro fertilization program

OBJECTIVE: To compare the efficacy of recombinant FSH and urinary-derived hMG for ovarian stimulation during IVF. DESIGN: Retrospective analysis of data from IVF cycles conducted over 15 months. SETTING: University hospital IVF unit. PATIENT(S): Three hundred twenty-four women undergoing their first to sixth IVF cycle. INTERVENTION(S): After pituitary down-regulation, patients received recombinant FSH or hMG, according to personal choice. After hCG administration, patients underwent oocyte retrieval, oocyte fertilization, and embryo transfer. MAIN OUTCOME MEASURE(S): Implantation rate and clinical ongoing pregnancy rate per oocyte retrieval. RESULT(S): Patients who chose recombinant FSH were slightly younger than those who chose hMG (34.1 vs. 35.1 years, respectively). Although more embryos were transferred in the hMG group (3.6 vs. 3.2), the ongoing pregnancy and implantation rates were significantly higher in the recombinant FSH group (ongoing pregnancy rate, 50.0% vs. 36.2%). CONCLUSION(S): Recombinant FSH is more effective than hMG for ovarian stimulation in IVF cycles. This increased efficacy, which is achieved with fewer ampoules, is likely to offset the higher acquisition costs of recombinant FSH.     

Delaying human chorionic gonadotropin administration in human menopausal gonadotropin-induced cycles decreases successful in vitro fertilization of human oocytes

Correct timing of human chorionic gonadotropin (hCG) administration in induced cycles for in vitro fertilization is of crucial importance to oocyte maturation and normal luteal function. The purpose of this work was to compare the effect of hCG timing on follicular development, oocyte maturation, and fertilization in vitro, as well as on the pattern of luteal phase hormone secretion. Ovulation was induced in 32 normally cycling women by human menopausal gonadotropin (hMG)/hCG administration. In the first group (17 women) 10,000 IU hCG was administered 24 hours after the last injection of hMG and in the second group (15 women) 48 to 72 hours after the last hMG injection. Serum estradiol levels prior to oocyte aspiration were similar in both groups, as were the numbers of large follicles on the day of hCG administration (4.5 +/- 2.3 versus 4.1 +/- 1.9 follicles/woman, respectively). The distribution of oocyte-corona-cumulus complexes was similar in both groups and was comprised of 11% immature, 43% intermediate, and 45% mature complexes. The fertilization rate, however, was significantly (P less than 0.001) reduced in the group treated by delayed hCG injection (57% versus 84%), and the percentage of degenerated oocytes was increased (9% versus 1%). Luteal phase length as well as progesterone and estradiol levels were comparable in both groups. It is concluded that an interval longer than 24 hours between the last injection of hMG and the administration of an ovulatory dose of hCG does not affect follicular and luteal phase serum steroid patterns but may result in a decreased oocyte fertilization rate, possibly due to atretic changes in the follicles.     

The influence of oocyte maturity and embryo quality on pregnancy rate in a program for in vitro fertilization-embryo transfer

An important factor influencing the pregnancy rate after in vitro fertilization-embryo transfer (IVF-ET) appears to be the number of embryos transferred to the uterus. In this study, the influence of oocyte maturity and embryo quality on pregnancy rate was assessed in patients undergoing IVF-ET. Ovarian hyperstimulation was performed by human menopausal gonadotropin (hMG [n = 29]), clomiphene citrate (CC)/hMG (n = 81), and hMG/follicle-stimulating hormone (FSH [n = 13]) protocols. Oocyte maturity was graded on a scale from 1 to 5 based on the morphology of the ooplasm, cumulus mass, corona radiata, and membrana granulosa cells. Embryos were graded according to the symmetry of the blastomeres and the presence or absence of fragmentation. Mature preovulatory oocytes yielded the highest fertilization rates. No differences were found among the protocols in terms of fertilization rate, embryo quality, or pregnancy rate. When all protocols were combined, patients who conceived had a significantly higher number of embryos transferred than those who did not conceive (3.6 +/- 0.1 [mean = SEM] versus 2.7 +/- 0.1). When embryo quality was compared, there was no difference in the number of "B" embryos transferred between patients who conceived and those who did not (1.2 +/- 0.2 versus 1.2 +/- 0.1), but the patients who conceived had significantly more "A" embryos transferred (1.6 +/- 0.3 versus 0.8 +/- 0.1). These data suggest that the treatment protocol did not determine embryo quality. Furthermore, the increase in pregnancy rates seen with an increase in embryos transferred is the result of the transfer of more "A" embryos.     

The relationship between follicular fluid steroid concentration and successful fertilization of human oocytes in vitro

Follicular fluids (FF) and their matched oocytes were obtained from 64 follicles of 28 women who failed to conceive after in vitro fertilization ( IVF ) and 33 follicles of 8 women who successfully conceived after the procedure. Ovulation was induced with human menopausal gonadotropin, and follicular aspiration was performed 36 hours after human chorionic gonadotropin administration. The concentration of 17 beta-estradiol, progesterone, testosterone, dihydrotestosterone, and androsterone was correlated with the morphology of the oocyte-corona-cumulus complex ( OCCC ), oocyte fertilization, the rate of cleavage, and the incidence of pregnancy after embryo transfer. In both groups of women, FF progesterone was lowest in follicles containing immature OCCCs . However, follicles aspirated from women who conceived after IVF which contained intermediate and mature OCCCs had significantly higher FF estradiol levels than similar follicles from women who failed to conceive after the procedure. Fertilized oocytes and 4- to 6-cell stage embryos which were obtained from follicles of pregnant women contained significantly higher FF estradiol levels than fertilized oocytes and similar embryos from nonpregnant women. It appears that higher FF estradiol levels correlate well with successful fertilization and an enhanced cleavage rate of oocytes associated with pregnancy following IVF .     

Ovarian stimulation for in vitro fertilization and embryo transfer, human menopausal gonadotropin versus pure human follicle stimulating hormone: a randomized prospective study

A randomized, prospective study was conducted to compare ovarian stimulation with human menopausal gonadotropin (hMG) and human follicle-stimulating hormone (hFSH) in an in vitro fertilization and embryo transfer (IVF-ET) program. Minimal inclusion criteria included age less than or equal to 37, tubal infertility, regular menstrual cycles before IVF, and a normal semen analysis. Equivalent doses (225 IU/day) of either hMG (N = 20) or hFSH (N = 20) were administered, and the patients followed by serum estradiol (E2) levels and pelvic ultrasound. Parameters related to the ovarian response to therapy, the number and quality of ova recovered, and the cycle outcome were compared in the two groups using the Student's t-test and chi-square analysis. No difference was detected between the groups in peak E2 levels (828 +/- 78 versus 819 +/- 79 in the hMG and hFSH groups, respectively), day of human chorionic gonadotropin (hCG) administration (9.3 +/- 0.3 versus 9.7 +/- 1.01), occurrence of spontaneous luteinizing hormone (LH) surge (44% versus 27%, P greater than 0.05, chi square analysis), average number of ova recovered (5.0 +/- 0.7 versus 5.6 +/- 1), ova maturation (7.5% versus 12.7% rate of immature ova), rate of normal and abnormal fertilization (9.2% versus 8.1% polyspermic fertilization), cleavage stage at transfer (3.6 +/- 0.4 versus 3.4 +/- 0.7 cells per embryos), the number of embryos transferred (2.5 +/- 0.3 versus 2.6 +/- 0.3), or the occurrence of pregnancy (1 in the hMG group and 2 in the hFSH group).(ABSTRACT TRUNCATED AT 250 WORDS)     

Recombinant follicle-stimulating hormone versus human menopausal gonadotropin in the late follicular phase during ovarian hyperstimulation for in vitro fertilization

OBJECTIVE: To study the effect of exogenous LH in the late follicular phase on ongoing pregnancies and at the different stages of IVF-ET (stimulation, fertilization, and implantation) in patients with low endogenous LH. DESIGN: Retrospective cohort study with modeling of the different phases of IVF-ET. SETTING: IVF center of the teaching hospital in Bordeaux, France. PATIENT(S): Women undergoing IVF and ICSI treatment. INTERVENTION(S): One group received recombinant FSH alone (FSH group) and the other received recombinant FSH and hMG in the late follicular phase (i.e., when the largest follicle reached 14 mm) (FSH/hMG group). MAIN OUTCOME MEASURE(S): Ongoing pregnancy, number of oocytes, and number of embryos.RESULT(S): The FSH/hMG group had a higher probability of having at least one oocyte (odds ratio [OR] = 2.75 [1.11-6.80]), of having at least one embryo after oocyte retrieval (OR = 2.84 [1.33-6.07]), and of ongoing pregnancy after ET (OR = 2.04 [0.83-5.01]), and globally had a higher probability of ongoing pregnancy (OR = 2.83 [1.19-6.71]). CONCLUSION(S): In ovarian hyperstimulation for IVF-ET, LH supplementation in the late follicular phase of women with low endogenous LH is beneficial for ongoing pregnancy by increasing the rate of success of all stages of the treatment.     

The relative success of gonadotropin-releasing hormone analogue, clomiphene citrate, and gonadotropin in 1,099 cycles of in vitro fertilization.

OBJECTIVES: To evaluate the effectiveness of and analyze the factors influencing the outcome of three ovarian stimulation protocols used during in vitro fertilization (IVF) in a large population. DESIGN: Retrospective file review. SETTING: In vitro fertilization program in one center during the years 1985 to 1990. PATIENTS AND PROTOCOLS: Three hundred forty-one patients received clomiphene citrate (CC) and human menopausal gonadotropin (hMG), 365 received hMG alone, and 393 received gonadotropin-releasing hormone analogue (GnRH-a) for pituitary suppression followed by hMG stimulation. MAIN OUTCOME MEASURE: Rates of cancellation, total pregnancies, and ongoing pregnancies, with breakdown by age of patients. RESULTS: The cancellation rate because of early luteinization following GnRH-a/hMG was significantly reduced compared with the other two protocols: 3.6% versus 9.4% and 13.7% for CC/hMG and hMG, respectively. However, in women over 40 years of age, GnRH-a/hMG resulted in the highest rate of poor ovarian response. Significantly more oocytes were retrieved, fertilized, and cleaved after the use of GnRH-a/hMG compared with the other two protocols. Despite this, clinical pregnancy rate (PR) was the highest with CC/hMG compared with GnRH-a/hMG and hMG:31.4% versus 16.9% and 15.7%, respectively. Ongoing PRs were 20.5%, 9.7%, and 11.6%, respectively. CONCLUSIONS: Although the use of GnRH-a for pituitary suppression before ovarian stimulation for IVF reduced the cancellation rate and increased the number of retrieved oocytes, it was not found to result in higher PRs than those achieved by stimulation with CC/hMG. This suggests that treatment by GnRH-a/hMG should be reserved mainly for the prevention of early luteinization.     

Psychological side-effects of clomiphene citrate and human menopausal gonadotrophin

OBJECTIVE: This study evaluated the psychological side-effects of clomiphene citrate (CC) and hMG in women undergoing fertility treatment. METHOD: This study was a cross-sectional, self-report survey of 454 women at various stages of treatment for infertility. At the time of study, 139 women had not taken fertility drugs and 315 women had taken one or more cycles of CC or hMG. All subjects were asked to complete the State-Trait Anxiety Inventory (STAI). Women taking CC or hMG were also asked to complete a self-administered questionnaire on the side-effects of their medications. RESULT(S): In the CC group (n = 162) and hMG group (n = 153), 77.8% (126 of 162) and 94.8% (145 of 153) reported at least one side-effect, respectively. Irritability, mood swings, feeling down, and bloating had high frequencies in both CC and hMG groups, with a higher mean number of side effects reported in the hMG group (4.4 +/- 3.7 for the CC group and 6.8 +/- 3.7 for the hMG group, p < 0.001). There was no significant difference among the CC, hMG and no medication groups for mean state and trait anxiety scores. However, there were significant differences among the three side-effect groups (those who reported 1 to 4, 5 to 7, and more than 7 side-effects) for the mean scores of state (df = 2, F = 8.7, p < 0.001) and trait (df = 2, F = 11.9, p < 0.001) anxiety in women taking fertility drugs. CONCLUSION(S): Women taking CC or hMG reported high frequencies of psychological side-effects, and should be advised of these before treatment.     

Dose of human menopausal gonadotropin influences the outcome of an in vitro fertilization program

This study compares outcomes of in vitro fertilization (IVF) in two groups of 57 patients when either 2 (group 1) or 3 (group 2) ampules of human menopausal gonadotropin (hMG) were administered daily. Treatment began on day 3 of the cycle and was discontinued when at least 2 follicles attained diameters greater than or equal to 1.5 cm. Human chorionic gonadotropin (hCG) was given either 24 or 48 hours after the last dose of hMG. Although serum estradiol levels were lower in group 1, the average number of oocytes retrieved (3.2 versus 2.9), fertilized (1.9 versus 2.0), and cleaved (1.7 versus 1.8) per completed cycle did not differ between groups 1 and 2. Likewise, the number of oocytes that fertilized abnormally was similar in both groups (0.5 versus 0.3/cycle). However, the number of atretic oocytes (0.03 versus 0.5/cycle) and the percent of oocytes recovered from the cul-de-sac (0 versus 7.2%) were significantly (P less than 0.05) lower in group 1. In group 1, administration of hCG 48 hours after the last dose of hMG was associated with a higher number of cleaving embryos (2.1 versus 1.5/cycle) and a higher pregnancy rate (34.8 versus 14.7%; P less than 0.05) when compared with injection at 24 hours. In group 2, the interval between hMG and hCG did not influence these results. Together, the associations between fewer oocytes that were atretic or recovered from the cul-de-sac, and a trend toward a higher pregnancy rate, suggest that follicular recruitment with 2 ampules of hMG is more appropriate than 3 ampules in an IVF program.     

Ovarian stimulation with pure follicle-stimulating hormone/human menopausal gonadotropin and improved laparoscopic aspiration needles influence the success of an in vitro fertilization program

The effect of a combined pure follicle-stimulating hormone/human menopausal gonadotropin (pFSH/hMG) ovarian stimulation regimen and modified, sharpened laparoscopic follicular aspiration needles on the number of oocytes retrieved and the oocyte/follicle ratio in 43 consecutive cycles of in vitro fertilization (IVF) were retrospectively compared with 99 consecutive preceeding cycles stimulated with hMG alone and captured with aspiration needles that had never been sharpened. A modified laparoscopic follicular aspiration needle is described. Purified FSH/hMG ovarian stimulation significantly improved the mean serum estradiol levels, number of preovulatory follicles, and, therefore, the total number of oocytes recovered per cycle. The mean ratios of oocytes recovered per preovulatory follicle documented on ultrasound, and per aspirated follicle, increased significantly using sharpened needles. Both modifications improved the success rate of our IVF program.     

Immaturity and aneuploidy in human oocytes after different stimulation protocols

OBJECTIVE: To study immaturity and aneuploidy in human oocytes after two different stimulation protocols. DESIGN: Retrospective. SETTING: Outpatient IVF clinic/laboratory. PATIENTS: One hundred forty-three patients of whom 65 were stimulated with clomiphene citrate (CC)/human menopausal gonadotropin (hMG) and 78 were stimulated with gonadotropin-releasing hormone agonist (GnRH-a)/hMG. Only patients with at least one oocyte unfertilized were included in this study. RESULTS: Stimulation with GnRH-a/hMG, as compared with CC/hMG stimulation, resulted in larger numbers of oocytes (P less than 0.00001), a higher fertilization rate (P less than 0.02), and oocyte retrieval at a later average cycle day (P less than 0.000005). Cytogenetic findings of immaturity were observed in 33.9% of unfertilized oocytes after CC/hMG stimulation, compared with only 17.8% after GnRH-a/hMG stimulation (P less than 0.0005). Aneuploidy findings were the same for both groups. CONCLUSION: In GnRH-a/hMG stimulation, oocytes approach the normal day of ovulation more closely. This may allow for better oocyte maturation and higher fertilization and pregnancy rates.     

The appearance of one-pronuclear human oocytes is associated with a better ovulation-induction response and successful pregnancy outcome.

OBJECTIVE: To study the relationship between the presence of one-pronuclear oocytes in in vitro fertilization (IVF) patients and ovulation-induction response, oocyte and embryo development, and clinical outcome. DESIGN: Retrospective analysis of 535 consecutive IVF retrievals. Retrievals in which one or more oocytes exhibited one pronucleus were compared with retrievals in which no one-pronuclear oocytes (control) were observed. The following one-pronuclear versus control subgroups were also examined: leuprolide acetate/human menopausal gonadotropin (LA/hMG) ovulation inductions, high estradiol (E2) response cases, and retrievals in which a large number of oocytes (greater than or equal to 15) were recovered. SETTING: Brigham and Women's Hospital, a tertiary care, university-affiliated hospital. PATIENTS: Three hundred forty-six IVF patients were treated between January 1989 and May 1991. MAIN OUTCOME MEASURES: Parameters examined included E2 concentration and number of follicles with maximum diameter greater than or equal to 12 mm on day of human chorionic gonadotropin administration; number of total and mature oocytes retrieved; total fertilization rates; number of embryos; and percent per retrieval of embryo transfers (ETs), clinical pregnancies, and ongoing-livebirths. RESULTS: The one-pronuclear patients had higher E2 levels and larger number of follicles, yielded significantly more total and mature oocytes, had a higher overall fertilization rate, produced more embryos, and had higher ET, clinical pregnancy and ongoing-livebirth rates per retrieval than did the control patients. Analysis of the subgroup populations revealed no significant differences in the majority of the main outcome measures studied; however, the one-pronuclear patients yielded significantly more total and mature oocytes per retrieval. CONCLUSIONS: Although there was an increase in the clinical and ongoing-livebirth pregnancy rates (PRs) in one-pronuclear patients, this was probably associated with an improved ovulation-induction response in the one-pronuclear patients. They achieved significantly higher E2 levels, recruited a larger number of follicles, and yielded more oocytes and embryos per retrieval than the control patients. When only the LA/hMG, E2 greater than or equal to 1,500 pg/mL, or the greater than or equal to 15 oocytes/case retrievals were analyzed, the PRs were no longer different; however, the one-pronuclear patients still yielded significantly more total and mature oocytes per retrieval than the controls. Therefore, the appearance of one-pronuclear oocytes is probably associated with the maturation stage of the oocytes obtained and is indicative of an ovulation induction in which a large number of preovulatory, metaphase II oocytes have been recruited.     

Metformin treatment of patients with polycystic ovary syndrome undergoing in vitro fertilization improves outcomes and is associated with modulation of the insulin-like growth factors

OBJECTIVE: To determine if metformin therapy improves in vitro fertilization (IVF) outcomes in patients with clomiphene-resistant polycystic ovarian syndrome (PCOS). DESIGN: Retrospective data analysis of selective groups of patients. SETTING: A private IVF unit. PATIENT(S): Forty-six women with clomiphene citrate-resistant PCOS underwent 60 cycles of IVF embryo transfer with intracytoplasmic sperm injection. INTERVENTION(S): In half of the cycles, patients received metformin (1000 to 1500 mg) daily, starting the cycle prior to gonadotropin treatment. MAIN OUTCOME MEASURE(S): Total number of follicles; serum estradiol (E2) on the day of hCG administration and the cycle's E2 maximum; total number of oocytes, mature oocytes, embryos, fertilization, and pregnancy rates; and follicular fluid levels of insulin-like growth factors (IGF-I, IGF-II) and IGF-binding proteins (IGFBP-1, IGFBP-3). RESULT(S): In patients treated with metformin, the total number of follicles on the day of hCG treatment was decreased (23 +/- 1.2 vs. 33 +/- 2.6) with no change in follicles > or = 14 mm in diameter (21 +/- 1.2 vs. 25 +/- 1.7). Metformin treatment did not affect the mean number of oocytes retrieved (22 +/- 1.9 vs. 20.3 +/- 1.5). However, the mean number of mature oocytes (18.4 +/- 1.5 vs. 13 +/- 1.5) and embryos cleaved (12.5 +/- 1.5 vs. 5.9 +/- 0.9) were increased after metformin treatment. Fertilization rates (64% vs. 43%) and clinical pregnancy rates (70% vs.30%) were also increased. Metformin led to modulation of preovulatory of follicular fluid IGF levels with increases of IGF-I (140 +/- 8 vs. 109 +/- 7ng/mL) and decreased of IGFBP-1 (133 +/- 8 vs.153 +/- 9ng/mL). CONCLUSION(S): Metformin use appears to improve IVF outcomes in patients with clomiphene citrate-resistant PCOS.     

The day of initiation of human menopausal gonadotropin stimulation affects follicular growth in in vitro fertilization cycles

The attainment of synchronous follicular development in human menopausal gonadotropin/human chorionic gonadotropin-stimulated cycles for in vitro fertilization (IVF) continues to be a perplexing problem. Two regimens of follicle stimulation for IVF cycles were, therefore, compared. Twenty-nine patients commenced human menopausal gonadotropin (hMG) therapy on day I of the menstrual cycle (Group I), while 30 women received hMG from the third day of the cycle (Group II). The hMG therapy was tailored to the individual patients's response, based on ultrasonographic measurements of follicular size and serum estradiol (E₂) levels. Both groups of patients received a mean of 19.6±1.4 ampules of hMG over a mean of 6.1±0.2 days. The pattern of serum E₂ and progesterone levels in the periovulatory and luteal phase was not affected by the day of initiation of hMG therapy, although Group I patients demonstrated lower (P<0.05) E₂ levels on the 2 days prior to human chorionic gonadotropin (hCG) administration. In terms of follicle growth, Group II follicles consistently demonstrated a significantly (P<0.01,x ² test) larger proportion of medium- and large-sized follicles compared to Group I follicles on almost all of the days when ultrasonographic measurements were taken. In addition. Group II follicles demonstrated an earlier shift (day—1) to the larger follicles than Group I follicles (day 0). Significantly (P<0.001) more oocytes were recovered per uspirated follicle in Group II patients, but the fertilization rate per oocyte was greater (P<0.003) for Group I oocytes. Nevertheless, pregnancy rates did not differ between the two groups. It is suggested that a difference between the two groups of patients in the quantity or quality of gonadotropin receptor sites in the early part of the follicular phase may account for both the diminished E₂ production in the follicular phase and the persistent depressed follicular growth in Group I patients.