Susan A.J. Daniel

Future in vitro fertilization pregnancy potential of women with variably elevated day 3 follicle-stimulating hormone levels

OBJECTIVE To determine the IVF-ET pregnancy potential of women with variably elevated day 3 FSH. DESIGN Cohort evaluation of 1,868 consecutive IVF-ET cycles January 1991 to December 1994. SETTING University hospital infertility unit. PATIENTS Four cohorts of couples were defined based on day 3 FSH determinations with an arbitrary threshold of 20 mIU/mL, only > or = 20 mIU/mL, always < 20 mIU/mL, current < 20 mIU/mL but one previous > or = 20 mIU/mL, and current < 20 mIU/mL but two or more previous > or = 20 mIU/mL (conversion factor to SI unit, 1.00). INTERVENTION In vitro fertilization-embryo transfer. MAIN OUTCOME MEASURE Fetal heart activity on luteal day 40 transvaginal ultrasound. RESULTS No pregnancies occurred in 53 cycles with day 3 FSH only > or = 20 mIU/mL. In 1,750 women whose day 3 FSH levels were always < 20 mIU/mL, the pregnancy rate (PR) per cycle was 16.5%. In 54 cycles in which day 3 FSH was > or = 20 one time only, but < 20 mIU/mL during the treatment cycle, the PR was 5.6%. In 11 cycles where two or more previous FSH determinations were > or = 20 mIU/mL but with a current day 3 FSH < 20 mIU/mL, no pregnancies occurred. CONCLUSION Our data leads us to the conclusion that day 3 FSH determination precede every IVF cycle and that cycles with FSH > or = 20 mIU/mL be canceled. It also suggests that women with two previous elevations of day 3 FSH be discouraged from future IVF cycles. The 5.6% pregnancy per cycle with one previously elevated FSH warrants extreme pessimism in discussion of further cycles.

Randomized, prospective comparison of luteal leuprolide acetate and gonadotropins versus clomiphene citrate and gonadotropins in 408 first cycles of in vitro fertilization

OBJECTIVE To compare luteal phase leuprolide acetate (LA) initiated pituitary down regulation followed by human menopausal gonadotropins (hMG) versus clomiphene citrate (CC) and hMG for follicular recruitment and oocyte maturation before in vitro fertilization (IVF). DESIGN Randomized, prospective comparison in first cycles of IVF. SETTING University Hospital, a tertiary referral center offering assisted reproductive technologies. PARTICIPANTS Participants were couples undergoing their first ever cycle of IVF and consenting to participation in the trial. RESULTS Luteal phase initiated LA/hMG was associated with a lower probability of cycle cancellation, improved folliculogenesis, and a higher probability of embryo transfer (ET) compared with CC/hMG alone. Implantation rates were not different. CONCLUSION A higher rate of ET with LA/hMG suggests that gonadotropin-releasing hormone agonist for the induction of folliculogenesis before IVF may be appropriate.

Transferring more embryos increases risk of heterotopic pregnancy

OBJECTIVES To analyze symptoms and signs that may distinguish heterotopic pregnancy from solely ectopic pregnancy (EP) after IVF. To determine if the number of embryos transferred is a risk factor for heterotopic compared with solely EP. DESIGN Retrospective cohort of 587 IVF pregnancies, 328 with distorted tubal anatomy. SETTING University Hospital, London, a referral center for Ontario provincial government-supported assisted reproductive technologies. PARTICIPANTS Couples undergoing IVF. INTERVENTION None. MAIN OUTCOME MEASURES Heterotopic pregnancy, solely EP, intrauterine pregnancy, and distorted pelvic anatomy. RESULTS Of 587 pregnancies, 7 were heterotopic pregnancies and 24 were solely EP, all in the subset of 328 women with distorted tubal anatomy. Symptoms, signs and time of diagnosis were not different between heterotopic and solely ectopic gestations. Compared with solely EP, heterotopic pregnancies were associated with transfer of more embryos. With four or more embryos transferred, the odds ratio for development of heterotopic versus solely ectopic gestation was 10.0. CONCLUSION Heterotopic pregnancy occurred in 2% of gestations after IVF, all in women with distorted tubal anatomy. Transfer of four or more embryos was a risk factor for heterotopic pregnancy.

In vitro fertilization: diurnal and seasonal variation in luteinizing hormone surge onset and pregnancy rates *

The authors studied 740 consecutive in vitro fertilization (IVF) cycles over a 3-year period to compare the results of cycles in which an endogenous luteinizing hormone (LH) surge occurred with cycles in which human chorionic gonadotropin (hCG) was administered for induction of follicular maturation. Clomiphene citrate (100 to 150 mg daily on cycle days 5 to 9) and human menopausal gonadotropin (hMG; 75 to 150 IU daily from cycle day 6) were used for stimulation. Embryo transfer (ET) occurred in 164 (81.2%) of the LH surge cycles and 452 (84%; P = not significant [NS] of the hCG cycles. The first urinary rise in LH was detected in the 6 or 9 A.M. collections in 78 (47.3%) of the LH surge cycles, a greater number (P less than 0.01) than expected if LH surge onset was random. A total of 107 pregnancies was achieved, for an overall pregnancy rate of 17.4% per ET. The pregnancy rate in the hCG-stimulated cycles was 13.9% per ET (63/452) and, in spontaneous LH surge cycles, was 28.8% (44/166; P less than 0.001). The spontaneous abortion rate was 9.1% in LH surge cycles, compared with 25.4% in hCG-triggered cycles (P less than 0.001). The result was a 2.4 times increase in live births for LH surge cycles compared with cycles in which hCG was administered. In this program, occurrence of an LH surge is a favorable event, associated with higher pregnancy and live birth rates than hCG-stimulated cycles, and usually occurring in the early morning, allowing oocyte retrieval during normal working hours.

Confounding variables affecting in vitro fertilization success : a decade of experience

PurposeTo evaluate etiology of infertility, female age, ovarian response and stimulation protocol in affecting in vitro fertilization (IVF) success.MethodsRetrospective analysis was used. Computer records of all 5209 cycles initiated in 2391 couples from February 1, 1984 to December 31, 1993 were analyzed.ResultsThere were 644 intrauterine, 24 solely ectopic and 7 heterotopic pregnancies. Pregnancy rates increased with number of embryos transferred with a significant increase still found between transfer of three or four embryos. Multiple gestations also increased in association with an increasing number of embryos transferred. Pregnancy rates per cycle did not decline with repeated cycles. Reduced pregnancy rates were associated with a primary diagnosis of male infertility. Covariates associated with a better pregnancy rate were younger age of the female partner or higher peak preovulatory serum estradiol. Routine administration of GnRH-agonist was associated with a reduced cycle cancellation rate, an increase in oocytes retrieved and an improved pregnancy rate.ConclusionsCouples with male infertility and increased female age should be counselled regarding the reduced prognosis for success.

Epidermal growth factor (EGF) receptor localization in cultured human granulosa lutein cells and the stimulation of progesterone production by EGF and transforming growth factor-α (TGF-α)

PurposeThe purpose of this study was to investigate the expression of EGF receptor (EGF-R) in human granulosa cells undergoing luteinization and progesterone production by these cells in response to EGF and TGF-α alone or in combination with luteinizing hormone (LH). Granulosa cells were obtained from IVF patients following oocyte retrieval 34 to 36 hr post-hCG injection. EGF receptor was localized in cells by means of immunoperoxidase staining using a polyclonal primary antibody directed against the human EGF-R. To assess progesterone production, cells were seeded overnight, washed, and cultured with the growth factors ± LH. Medium and treatments were changed every 24 hr for 3 days.ResultsSpecific EGF-R staining was observed in the cultured cells compared to those incubated with antibody that was preabsorbed with a 10-fold excess of EGF. Basal progesterone accumulation per 24-hr period was stimulated dose dependently on each day of culture, by both EGF (up to 3.5-fold at 5 or 50 ng/ml) and TGF-α (up to 4-fold at 50 ng/ml). The addition of LH alone also stimulated progesterone accumulation daily, and this effect was further enhanced dose dependently by cotreatment with EGF or TGF-α. Furthermore, tyrphostin, an EGFR-specific tyrosine kinase inhibitor, inhibited both basal and growth factor-stimulated progesterone production.ConclusionThese data suggest an EGF receptormediated physiological role for EGF and TGF-α in human luteal function involving an autocrine and/or a paracrine stimulation of progesterone production.

Randomized trial of partial zona dissection for male infertility

OBJECTIVES To compare IVF rates using partial zona dissection versus zona intact insemination in couples with male infertility. To analyze pregnancy rates relative to sperm characteristics, fertilization rates, and treatment. DESIGN Randomized prospective comparison of fertilization in sibling oocytes. Transfer of the three best quality embryos from one or both treatments. SETTING Department of Gynaecology and Reproductive Medicine, University Hospital, London, Ontario, Canada. PARTICIPANTS Thirty-two couples undergoing IVF with a principal diagnosis of male infertility. INTERVENTION Treatment with partial zona dissection. MAIN OUTCOME MEASURES Fertilization and pregnancy. RESULTS Fertilization rates were 26% and 9% after partial zona dissection and IVF, respectively. Polyspermy was < 1% in each treatment. There were five singleton pregnancies in 29 completed cycles, three in cycles with fertilization only by partial zona dissection and two in cycles with both partial zona dissection and IVF fertilization. There were no pregnancies after fertilization by IVF only. Stepwise logistic regression analysis indicated that pregnancy was related to partial zona dissection, initial sperm concentration, and total acrosin activity. CONCLUSION Partial zona dissection was associated with minimal polyspermic fertilization and higher normal fertilization rates than sibling oocytes treated by modified IVF. Pregnancy occurred only after transfer of embryos from partial zona dissection or combined partial zona dissection and IVF.

Intra-Ovarian Actions of Steroids in Regulation of Follicular Steroid Biosynthesis

The follicle is the principal functional unit of the mammalian ovary, the primary function of which is the production and release of a mature oocyte at the culmination of each ovarian cycle. A secondary role of the follicle is the biosynthesis and secretion of a group of steroid hormones which serve many important functions in regulation of peripheral (i. e extra-ovarian) cells and tissues.

Conversion of Cycles Involving Ovarian Hyperstimlation With Intrauterine Insemination to in Vitro Fertilization

Conversion to in-vitro fertilization (IVF) and embryo transfer as an alternative to cancellation was offered in 27 consecutive cycles of controlled ovarian hyperstimulation and intra-uterine insemination (IUI) cycles with excessive follicular development in patients with idiopathic infertility. IVF and embryo transfer was performed in 25 cycles, resulting in 13 pregnancies (52%), with 22% of couples having at least two embryos cryopreserved. The pregnancies have resulted in one singleton and two twin births, one spontaneous abortion, and nine ongoing pregnancies (including one triplet gestation). Four patients developed severe ovarian hyperstimulation syndrome (OHSS) after IVF and embryo transfer, including two cases requiring paracentesis. Three of four OHSS patients were pregnant, resulting in live births of healthy twins, one spontaneous abortion and one ongoing singleton gestation. In two cycles a spontaneous luteinizing hormone (LH) surge occurred, preventing oocyte retrieval. For these two women, drainage of all follicles except the five most likely to fertilize (18-22 mm diameter) was performed, followed by IUI, with no pregnancies or OHSS observed. Conversion of patients from IUI cycles to IVF/embryo transfer cycles avoids cancellation of the very cycles with the best chance of achieving pregnancy. OHSS remains a problem, necessitating extensive pre-IVF counselling and post-transfer vigilance.

Total acrosin activity correlates with fertility potential after fertilization in vitro**Presented in part at the 16th Annual Meeting of the American Society of Andrology, Montreal, Quebec, Canada, April 27 to 30, 1991 and at the 47th Annual Meeting of The American Fertility Society, Orlando, Florida, October 19 to 24, 1991.

OBJECTIVE To evaluate the possible relationship between total acrosin activity in spermatozoa and fertility potential after fertilization in vitro. DESIGN Total acrosin activity of spermatozoa was measured in 101 in vitro fertilization (IVF) cases by an observer unaware of fertilization and cleavage results. SETTING University Hospital is a tertiary referral center offering a government supported In Vitro Fertilization Programme. PARTICIPANTS Participants were couples undergoing IVF. INTERVENTIONS A miniature assay measured total acrosin activity in the semen sample used for IVF. OUTCOME MEASURES The proportion of mature oocytes fertilized, the proportion of mature oocytes transferred, and fertilization of at least one mature oocyte were considered outcomes with fertility potential. RESULTS Total acrosin activity correlated with both the proportion of mature oocytes fertilized and the proportion of mature oocytes that were transferred as cleaving embryos. Total acrosin activity was higher in cycles when one or more mature oocyte fertilized compared with cycles with failed fertilization of all mature oocytes. CONCLUSIONS The likelihood ratio for subnormal results indicates that measurement of total acrosin activity is a fair test of the fertilizing capacity of sperm.