Ovarian hyperstimulation and oophorectomy following accidental daily clomiphene citrate use over three consecutive months.

We describe the longest-known continuous use of clomiphene citrate ever reported in a human. As a result of a pharmacy error, a woman took 50 mg/day clomiphene citrate for three months. The prolonged use of this medication resulted in ovarian hyperstimulation and unilateral oophorectomy for torsion.

Shared oocyte donation: society's benefits.

OBJECTIVE: To assess the efficacy of oocyte donation when a cohort of oocytes is shared between two phenotypically matched recipients. DESIGN: A retrospective analysis of a program using shared anonymous oocyte donation. SETTING: Academic infertility center. PATIENT(S): Recipient women with partial or complete ovarian failure; oocyte donors who have been properly screened. INTERVENTION(S): Each oocyte donor was phenotypically matched with two potential recipients. The cohort of donated oocytes were divided between these two recipients if eight or more mature oocytes were obtained at retrieval. Recipients underwent hormone replacement therapy consisting of down-regulation with a GnRH agonist, transdermal estradiol, and intramuscular progesterone in a dose determined by a previous preparatory cycle. MAIN OUTCOME MEASURE(S): Pregnancy and delivery rates for all transfers originating from a cohort of oocytes obtained by retrieval of a single donor; pregnancy and delivery rates per recipient; rate of conversion of a shared donation cycle to a single recipient. RESULT(S): A total of 249 donor cycles permitted 241 retrievals. Each recipient received 8.3 +/- 3.5 oocytes per donation. There were 424 fresh ETs and 48 frozen ETs performed. For fresh ETs, clinical pregnancy and ongoing or delivery rates per recipient were 56.8% and 49.7%, respectively. For frozen ETs, these rates were 50% and 39.5%. Implantation rates were 31.8% and 26.1% for fresh and frozen ET, respectively. When analyzed per donor retrieval, clinical pregnancy and ongoing or delivery rates were 109.5% and 95.4%. These high pregnancy rates per donor reflect the numerous fresh and frozen ETs that can result from one donor's retrieval. Conversion of a donation cycle from two recipients to one recipient occurred for 26 of 241 cycles (10.8%). CONCLUSION(S): Shared anonymous oocyte donation provides a very high pregnancy rate per donor retrieval that is not achievable with unshared donation. In addition, there is a diminished risk exposure of donors per total completed recipient transfers. We support shared oocyte donation as the most efficient use of the precious resource of human oocytes.

Human zona pellucida micromanipulation and monozygotic twinning frequency after IVF.

To assess the association of zona pellucida micromanipulation and subsequent development of monozygotic twins, cases of assisted embryo hatching (AH) and intracytoplasmic sperm injection (ICSI) were identified and related to treatment type, implantation and zygosity data. Embryology records from all patients undergoing in-vitro fertilization (IVF) at this centre from January 1995 to March 1998 were reviewed. In this study, 3546 transfer cycles were completed, with clinical pregnancy established in 1911 (54% per transfer) patients undergoing a single IVF cycle. These pregnancies occurred in 1674 (88%) IVF cycles, 120 (6%) donor oocyte cycles (DER), and 117 (6%) frozen embryo transfer (FET) cycles. During the study period, 23 cases of monozygotic (MZ) twins were identified, representing an overall frequency of 1.2%. Chorionicity was determined by transvaginal ultrasound at 7 weeks when the number of embryos transferred was less than the number of fetal heart-beats, or when >1 fetal heartbeat per gestational sac was seen. Zygosity was confirmed by placental evaluation at delivery, and corroborated the antenatal diagnosis in all cases. Among IVF study patients the frequency of MZ twinning was not statistically different between zona manipulated and zona intact subgroups. While this investigation is the largest to date describing the relationship between MZ twins and zona procedures, studies with even greater statistical power are needed to clarify it more precisely, particularly in DER and FET settings. A greater overall frequency of MZ twinning for IVF patients may be a function of the higher number of embryos transferred in IVF, rather than discrete zona manipulations.

A prospective, randomized comparison of ovulation induction using highly purified follicle-stimulating hormone alone and with recombinant human luteinizing hormone in in-vitro fertilization.

The commercial availability of highly purified, s.c. administered urinary follicle stimulating hormone (FSH) preparations for ovarian stimulation marked the beginning of a new era in the treatment of infertility. As these new formulations contain essentially no luteinizing hormone (LH), supplemental LH may be needed for optimal folliculogenesis. It was the aim of this pilot study to compare fertilization rates, embryo morphology, implantation rates and pregnancy outcomes prospectively in two age-matched patient groups: women who received highly purified FSH (FSH-HP) (n = 17), and women who received FSH-HP plus recombinant human LH (rhLH, n = 14) throughout ovarian stimulation. All patients received mid-luteal pituitary down-regulation with s.c. gonadotrophin-releasing hormone agonist (GnRHa) (leuprolide). Mean implantation rates were 26.9 and 11.9% in the FSH-HP only and FSH-HP + rhLH groups respectively. The mean clinical pregnancy/initiated cycle rate was 64.7 and 35.7% for the FSH-HP only and FSH-HP + rhLH patients respectively. FSH-HP patients and FSH-HP + rhLH patients achieved clinical pregnancy/transfer rates of 68.8 and 45.5% respectively. One patient in the FSH-HP + rhLH group had a spontaneous abortion; no pregnancy losses occurred in the FSH-HP only group. There were more cancellations for poor ovarian response among FSH-HP + rhLH patients (n = 3) than among FSH-HP patients (n = 1). The trend toward better pregnancy outcomes among patients who received FSH-HP without supplemental rhLH did not reach statistical significance. It is postulated that appropriate endogenous LH concentrations exist despite luteal GnRHa pituitary suppression, thereby obviating the need for supplemental LH administration.

Sperm integrity is critical for normal mitotic division and early embryonic development.

The human zygote relies on the paternal gamete to provide the centrosome component essential for the first mitotic division. It is not known whether normal centrosome function requires an intact spermatozoon, or whether donation of an isolated paternal centrosome component can result in normal zygotes and embryos. To explore this possibility, mature human oocytes were microinjected with either intact or dissected spermatozoa. Fertilization and cleavage rates were documented; nuclear and cytoskeletal changes were observed with fluorescent immunocytochemistry; and chromosomal normality was assessed with fluorescent in-situ hybridization. A pilot study was performed to identify cytoskeletal features suggestive of centrosome function. Unfertilized oocytes and tripronucleate (3PN) zygotes from in-vitro fertilization or intracytoplasmic sperm injection were assessed to confirm the sequence of the landmarks of human fertilization. Oocytes injected with mechanically-dissected spermatozoa appear to be capable of normal pronuclear formation and embryonic cleavage, but do not undergo normal mitotic division. Although decondensed, apposed nuclei are noted in combination with diffuse cytoskeleton assembly, no spindle was detected in any zygote resulting from the injection of a dissected spermatozoon. Analysis of selected embryos resulting from dissected sperm injection revealed chromosomal mosaicism in the majority of specimens. The lack of a bipolar spindle, in combination with chromosomal mosaicism, suggests abnormalities of the mitotic apparatus when sperm integrity is impaired following dissection.

The role of structural integrity of the fertilising spermatozoon in early human embryogenesis.

While the fertilising spermatozoon supplies the active centre directing the human zygote's first mitotic division, the relative contributions of the sperm head and tail (as well as the importance of the sperm's general structural integrity) to subsequent developmental processes remain incompletely studied. The sperm nucleus contains paternal chromatin necessary for restoration of a diploid genome, but the functional role of the sperm tail (either attached or dissected) in early human embryonic growth is not known. In this investigation using oocytes donated by in vitro fertilisation patients, human oocytes were injected with isolated sperm heads (n = 73), isolated sperm flagella (n = 11) or both (dissected sperm heads + free sperm tails, n = 26). The formation of bipronucleate zygotes was recorded for each method. Among oocytes surviving injection with isolated sperm heads, 44 of 66 (67%) formed two pronuclei. Of oocytes receiving only sperm tails, 2 of 11 (18%) displayed two pronuclei, but a single polar body was evident in both cases. When dissected spermatozoa parts (head + tail) were jointly injected, 12 of 26 (46%) developed two pronuclei. From embryos resulting from each of these three fertilisation regimes, blastomere biopsies were obtained and subjected to multiprobe fluorescent in situ hybridisation (FISH) analysis to detect mosaicism or aneuploidy arising from these experimental treatments. Only embryos with growth sufficient to permit sampling of at least two blastomeres were evaluated, and FISH analysis was successful in 25 of 29 (86%) embryos tested. Of 12 embryos derived from injection of an isolated sperm head, only one was normal diploid; the remaining 11 were mosaic. Both embryos resulting from injection of an unattached sperm tail were mosaic. Of 11 embryos generated from oocyte injection with sperm head + tail segments, 10 (91%) were mosaic and only one was normal diploid. Results from this study show that injection of isolated sperm segments can permit oocyte activation and bipronuclear formation. However, a high rate of mosaicism in human embryos originating from disrupted sperm or sperm components suggests that more than a 'sum of parts' is needed for later development. The structural integrity of the intact fertilising spermatozoon appears to contribute to normal human early embryogenesis.

Oocyte donation: insights into implantation.

OBJECTIVE: To ascertain whether obstetric, gynecologic, or congenital variables affect implantation efficiency or eventual delivery in donor oocyte recipients. DESIGN: Clinical study. SETTING: Academic tertiary care infertility clinic. PATIENT(S): A total of 370 recipients. INTERVENTION(S): Fresh ET following oocyte donation in a hormone replacement cycle. MAIN OUTCOME MEASURE(S): Regression analyses were performed to detect any statistically significant difference in the pregnancy rate (PR), delivery rate, miscarriage rate, or implantation rate associated with different obstetric, gynecologic, and congenital independent variables while accounting for the age of the recipient in each analysis. RESULT(S): For all recipients, a clinical PR per transfer of 58.9% was achieved, with an implantation rate of 30%. A significant decline in the implantation rate was noted in relation to increasing age of the recipient. A history of tubal disease was associated with a significantly lower implantation rate and a significantly lower ongoing and delivered PR. Asherman's syndrome, despite surgical correction, appeared to negatively affect the ongoing and delivered PR. CONCLUSION(S): With the exceptions of recipient age and a history of tubal disease, all other uterine factors studied did not appear to influence the implantation potential of an embryo resulting from oocyte donation. A history of tubal disease had a distinctly negative effect on implantation efficiency and delivery potential for a given recipient. This finding highlights the need to identify the mechanisms underlying the negative effect of tubal disease so that donor oocyte recipients and all other patients with this cause of infertility can benefit from directed therapy.

Implications of complete fertilization failure after intracytoplasmic sperm injection for subsequent fertilization and reproductive outcome.

With the introduction of intracytoplasmic sperm injection (ICSI), couples with severe male factor infertility have achieved fertilization and clinical pregnancy rates comparable to other in-vitro fertilization (IVF) patients. However, failure of fertilization still occurs in some patients despite the utilization of microsurgical sperm injection techniques. How such fertilization failure after ICSI might impact later ICSI treatment(s) is unknown. In this investigation, couples with complete fertilization failure after ICSI treated from August 1993 to August 1996 were identified (index cycle, n = 21). Additionally, fertilization data from any previous or subsequent infertility treatments were evaluated. Seven patients (33%) had at least one IVF treatment before the index cycle, although no deliveries occurred. Of patients with complete fertilization failure in the index cycle, 48% (n = 10) underwent at least one subsequent ICSI cycle which proceeded to oocyte retrieval. The remainder (n = 11) elected to discontinue treatment. Although six subsequent cycles were cancelled due to poor follicular response (< or = 2 mature oocytes), all patients electing to continue treatment eventually achieved a subsequent embryo transfer. The clinical pregnancy rate per transfer was 45.4% for this group; the delivery and ongoing pregnancy rate per transfer was 36.3%. Review of semen parameters, superovulation characteristics or other clinical parameters during the three study cycles (pre-index, index, and post-index) was not prognostic of fertilization success or reproductive outcomes in later treatments. Fertilization failure with ICSI therefore could not be predicted by prior cycle performance, although total immotility of spermatozoa at time of oocyte retrieval, total teratozoospermia, and low oocyte yield were common characteristics of couples experiencing complete fertilization failure with ICSI. These findings suggest that fertilization failure in one ICSI cycle does not preclude successful fertilization and delivery in a later ICSI treatment.

Oocyte donation: does a previous attempt affect a subsequent attempt?

OBJECTIVE: To analyze the effect of a previous donor oocyte cycle on the outcome of subsequent attempts. DESIGN: Retrospective study. SETTING: Oocyte donation program at The New York Hospital/Cornell Medical Center. PATIENT(S): Two hundred sixty-seven patients undergoing 354 fresh cycles of oocyte donation. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Clinical outcomes were divided into groups based on the attempt number of each cycle for each patient. Results were calculated for each recipient cycle. RESULT(S): A clinical pregnancy rate of 56.2% and ongoing pregnancy/delivery rate per retrieval of 50.3% were noted. No statistically significant differences in clinical outcomes were found between the first, second, and third attempts. A significant increase was noted in the ongoing pregnancy/delivery rate per recipient cycle for the second attempt in those patients who had a delivery after the first attempt compared with those who did not. CONCLUSION(S): We demonstrated an overall clinical pregnancy rate of 56.2% and an ongoing pregnancy/delivery rate of 50.3% per retrieval. Outcome for the second attempt was associated with success or failure during an initial attempt at oocyte donation.

Withholding gonadotropin administration is an effective alternative for the prevention of ovarian hyperstimulation syndrome.

OBJECTIVE: To evaluate the outcomes of IVF and the incidence of ovarian hyperstimulation syndrome (OHSS) after discontinuing gonadotropin therapy in patients at risk of developing OHSS by delaying hCG administration until a drop in serum E2 levels was observed. DESIGN: Retrospective study. SETTING: IVF program at a university center. INTERVENTIONS: Gonadotropin administration was withheld in 22 patients (group 1) when their serum E2 level was > or = 3,000 pg/mL (conversion factor to SI unit, 3.671). Patients continued GnRH analogue injections daily, and hCG was administered when serum E2 levels dropped to < or = 3,000 pg/mL. Outcomes were compared with 26 patients (group 2) in whom embryo transfer was canceled and all embryos cryopreserved for transfer during a subsequent unstimulated cycle. MAIN OUTCOME MEASURES: Outcomes of IVF and incidence of OHSS were compared in both groups of patients. In group 1, follicular and hormonal parameters before and after the coasting interval were compared in pregnant versus nonpregnant patients. In addition, serum hormonal profiles were evaluated daily during the coasting period to determine the effects of gonadotropin withdrawal. RESULTS: Although the mean number of oocytes retrieved was significantly higher in group 2, fertilization rates, miscarriage rates, delivery rates/stimulation cycle, and the incidence of OHSS did not differ significantly between the two groups. CONCLUSION: Withholding gonadotropin administration is an effective alternative to prevent the development of severe OHSS in a high-risk population. Although the risk of cancellation cannot be completely eliminated, this strategy can provide a high pregnancy rate without the need to repeat multiple frozen-thawed cycles.

Delay of gonadotropin stimulation in patients receiving gonadotropin-releasing hormone agonist (GnRH-a) therapy permits increased clinic efficiency and may enhance in vitro fertilization (IVF) pregnancy rates.

OBJECTIVE: To promote an even temporal distribution of patients starting IVF cycles at our center, patients undergoing GnRH agonist (GnRH-a) suppression frequently delay the start of gonadotropin stimulation. Our objective was to analyze the effect that the delay of initiation of gonadotropin stimulation has on outcome parameters in this population. DESIGN: Retrospective analysis. SETTING: A tertiary referral reproductive medicine unit. PATIENT(S): Patients undergoing IVF cycles on long GnRH-a protocols. INTERVENTION(S): Patients were treated with either a "standard-dose" or "low-dose" leuprolide acetate protocol initiated in the mid-luteal phase. MAIN OUTCOME MEASURE(S): Delay time, clinical pregnancy rate, ongoing pregnancy rate, cancellation rate. RESULT(S): Analysis of the overall group revealed associations between stimulation delay and decreases in stimulation duration and the number of gonadotropin ampules administered. Weighted linear regression analyzes revealed statistically positive relationships between delay time and both clinical pregnancy rates and ongoing pregnancy rates, despite a positive relationship between delay time and cancellation rates. Analysis of the standard-dose and low-dose subgroups revealed that the enhancement of pregnancy rates was attributable primarily to patients in the standard-dose protocol. CONCLUSION(S): Delay of gonadotropin stimulation while patients are receiving GnRH-a therapy allows for increased clinic efficiency. There appears to be an enhancement of clinical and ongoing pregnancy rates for the standard-dose leuprolide acetate protocol that is associated with stimulation delay.

Vulvar and vaginal melanoma. A clinicopathologic study.

Melanoma of the vulva is uncommon, and melanoma of the vagina is rare. The overall prognosis is poor and worse than for cutaneous melanomas. This appears to relate to diagnosis of genital lesions at an advanced stage. In a 28-year, retrospective analysis at Columbia Presbyterian Medical Center, there were 10 cases of primary melanoma of the lower genital tract. Seven cases of vulvar melanoma and three cases of vaginal melanoma were reviewed. All cases were in elderly women, and all were diagnosed at an advanced stage. The outcome in general was poor, regardless of therapy. This condition must be recognized earlier to afford an optimal patient outcome. Elderly women must undergo regular gynecologic care, and suspicious pigmented lesions must be biopsied.

In utero detection of ventriculomegaly during the second and third trimesters by transvaginal sonography.

The purpose of this study was two-fold. The first was to extend the previously developed and published nomograms of the fetal lateral ventricles from 18 weeks back to 14 weeks of gestation using transvaginal sonography, and, second, to test the performance of the nomograms by plotting the measurements of 36 fetuses whose transabdominal and/or qualitative transvaginal scans were suspicious for ventriculomegaly. In all the cases in which postnatal confirmation of the diagnosis was possible, prenatal ultrasound correctly identified the lesion. Although a total of nine nomograms was created, the clinically meaningful measurements were: the height of the occipital horn on the parasagittal plane, and the two ratios derived from the measurements performed on the parasagittal plane. In conclusion, the transvaginally generated nomograms were useful for the correct identification of fetuses with ventriculomegaly.

Nomograms of the fetal lateral ventricles using transvaginal sonography.

Nomograms of the fetal lateral ventricles were obtained by the transvaginal approach. Three hundred low-risk women with no sonographically apparent fetal anomalies were scanned prospectively in a cross-sectional study. Three measurements in the parasagittal plane, three in the midline coronal plane, and two in the posterior coronal plane were used to generate seven nomograms. Two additional nomograms reflecting two calculated ratios also were created. A mean regression line and the 5th and 95th confidence intervals were determined. We concluded that transvaginal sonography of the fetal brain generates images of both hemispheres of good enough resolution to allow several precise and reproducible measurements.

Prevalence of use of cocaine and other substances in an obstetric population.

Increasing use of cocaine among pregnant women has been reported. This study was conducted to determine the prevalence of positive urine toxicologic screens for cocaine and other substances of patients admitted to the Sloane Hospital for Women. Urine samples were obtained from 509 women admitted to the delivery suite. The overall prevalence of cocaine was 10% (n = 51). Cocaine use was 10 times more prevalent in the clinic population (14%) than in the private population, (1.4%). In addition, women whose urine samples were positive for cocaine were more likely to have no prenatal care, previous induced abortions, to be human immunodeficiency virus-positive, and admitted previous use of cigarettes, alcohol, cocaine, and other drugs. Amphetamines were detected in 13% (n = 65) of patients. However, the screens did not distinguish between metabolites of amphetamines and other drugs such as cold medications. The medical history alone predicted only 37% (n = 19) of the cocaine-positive screens and none of the amphetamine-positive screens.

Idiotypic control of the immune response.

Anti-idiotypic antibodies are antibodies against the antigenic determinants (idiotypes) of an antibody's antigen-binding region. Anti-idiotypes can bind near (Ab2 gamma) or away (Ab2 alpha) from the antigen-combining site or can carry the internal image of the antigen (Ab2 beta). Idiotypes and anti-idiotypes have been described in T- and B-cell systems. They have been used in basic research to purify and characterize receptors and ligands against receptors, to treat tumors, to make vaccines and to diagnose and suppress the immune response. In experimental myasthenia gravis anti-idiotypes protect animals against the disease, block idiotype binding and share idiotypic specificities.

Treatment of experimental myasthenia with autologous idiotypes linked to muramyl dipeptide.

In order to develop a new treatment of experimental autoimmune myasthenia gravis (EAMG), rabbits were injected with purified acetylcholine receptor (AChR) from Torpedo californica. Polyclonal affinity-purified anti-AChR antibodies (idiotypes, Ids) were coupled covalently to muramyl dipeptide and injected back into the same (i.e. autologous) rabbits from which the Ids were obtained. Treated animals developed anti-Ids that bound to the F(ab')2 fragments of the Ids as demonstrated by ELISA and that also blocked binding of Ids to AChR in a radioimmunoassay. Treated animals showed a protective effect compared to control animals when challenged with a second injection of AChR. Anti-AChR titres in surviving animals achieved a steady-state equilibrium. No apparent toxicity from the treatment was noted.