Effects of a copper-medicated intrauterine device on ovarian artery, uterine artery, and intrauterine blood flow.

AIM: To determine the effect of a copper-medicated intrauterine device (IUD) on ovarian, uterine, arcuate, radial and subendometrial Doppler-derived indices of blood flow. METHOD: 23 regularly menstruating patients requested insertion of an IUD. All patients had a copper T (Nova T) IUD inserted between days 8 and 11 of the menstrual cycle. Ovarian, uterine, arcuate, radial and subendometrial artery pulsatility indices (PIs) were assessed by transvaginal color Doppler prior to insertion between days 8 and 11 of the menstrual cycle, and after 2 months in the same period of the cycle. Ovarian, uterine, arcuate, radial and subendometrial artery PIs were considered prior to and following IUD insertion. RESULTS: No differences were recorded in any of the blood vessels sampled between pre- and post-insertion PIs. CONCLUSION: No significant change in ovarian or in uterine system vascular impedance is associated with the presence of a copper-medicated IUD.

Successful polar body-based preimplantation genetic diagnosis for achondroplasia.

Achondroplasia, the most common form of dwarfism, is a candidate for preimplantation genetic diagnosis (PGD) because a single mutation accounts for almost all cases. Multiplex fluorescent assay including the common G380R mutation in the FGFR3 gene and eight close polymorphic markers was developed. First and second polar bodies (PB) were used for PGD analysis. An affected woman was treated with routine long-protocol ovarian stimulation and puncture. In the first PGD cycle, out of four fertilized oocytes, PB analysis revealed two mutant oocytes, one with total amplification failure of the maternal allele and one with inconclusive results. In the second PGD cycle, 14 oocytes were retrieved following a higher FSH dose and by performing oocyte retrieval and by placing the patient in the anti-Trendelenburg position using abdominal pressure to allow all follicles to be drained. Following PB analysis, two embryos containing the wild-type FGFR3 allele were transferred. This led to an uncomplicated pregnancy and delivery by Caesarean section at week 38 of a healthy boy, carrying the FGFR3 wild-type maternal allele. In conclusion, oocyte retrieval, while difficult in patients with achondroplasia, can be successfully performed. PB analysis is a reliable and sensitive method for PGD for maternal achondroplasia.

Investigation and treatment of repeated implantation failure following IVF-ET.

Pregnancy rate following one cycle of IVF and ET can be as high as 60%. But even in the very successful units, some couples fail repeatedly. The causes for repeated implantation failure (RIF) may be because of reduced endometrial receptivity, embryonic defects or multifactorial causes. Various uterine pathologies, such as thin endometrium, altered expression of adhesive molecules and immunological factors, may decrease endometrial receptivity, whereas genetic abnormalities of the male or female, sperm defects, embryonic aneuploidy or zona hardening are among the embryonic reasons for failure of implantation. Endometriosis and hydrosalpinges may adversely influence both. In this mini review, we discuss the suggested methods for evaluation and treatment of RIF: repeated hysteroscopy, myomectomy, endometrial stimulation, immunotherapy, preimplantation genetic screening (PGS), assisted hatching, zygote intra-Fallopian transfer (ZIFT), co-culture, blastocyst transfer, cytoplasmic transfer, tailoring stimulation protocols and salpingectomy for hydrosalpinges.

Serum inhibin B levels measured early during FSH administration for IVF may be of value in predicting the number of oocytes to be retrieved in normal and low responders.

BACKGROUND: In a previous study we have found that in normal ovulatory women, serum inhibin B levels on days 4-6 of FSH administration correlated with the number of oocytes retrieved. In the current study we examined the significance of earlier inhibin B measurements in predicting the oocyte number, in both normal and low responders. METHODS: Study A consisted of 19 patients undergoing their first IVF cycle (n = 10) or had a normal response ( vertical line 6 oocytes retrieved, n = 9), while study B consisted of 15 patients with a previous low ovarian response (16. Study B: oocyte number correlated significantly with inhibin B and inhibin A on all days of FSH treatment, even on day 2 (r = 0.90, P < 0.001 and r = 0.65, P < 0.05 for inhibin B and A respectively). No significant correlation was found with E(2) levels. In both studies, all patients with inhibin B >100 pg/ml on treatment day 2 had >6 oocytes. CONCLUSIONS: Our data suggest that serum inhibin B measured early during FSH stimulation may indicate whether sufficient oocytes will be retrieved, in both normal and low responders. Serum inhibin B measured during early FSH treatment may be of predictive value in monitoring ovarian stimulation treatment for IVF.

The questionable use of albumin for the prevention of ovarian hyperstimulation syndrome in an IVF programme: a randomized placebo-controlled trial.

BACKGROUND: The role of intravenous (IV) albumin administration in the prevention of ovarian hyperstimulation syndrome (OHSS) and in the improvement of IVF conception outcomes was evaluated in a prospective, randomized, placebo-controlled double blind study. METHODS: Ninety-eight women were enrolled in the study and were consecutively assigned to either a treatment group or a control group. Eleven patients were lost to follow-up after assignment. Of the remaining 87 women, 46 received albumin on the day of oocyte retrieval, and 41 received 0.9% sodium chloride solution as a placebo control. Outcome measures included OHSS incidence rates and pregnancy rates in the two trial groups. RESULTS: Four of the 46 patients in the study group developed severe OHSS and six developed moderate OHSS. In the control group, one of the 41 developed severe OHSS and five developed moderate OHSS. The difference in OHSS incidence rates between the two groups was not statistically significant [relative risk (RR) = 1.49, 95% CI = 0.59-3.73]. Fourteen patients (30%) in the intervention group conceived, compared with 16 patients (39%) in the control group. The difference in conception rates between the two groups was not statistically significant (RR = 0.78, 95% CI = 0.44-1.39). CONCLUSIONS: Albumin appears to have no positive effect on OHSS or conception rates, while its use carries the risk of undesirable side effects, including exacerbation of ascites in OHSS, nausea, vomiting, febrile reaction, allergic reaction, anaphylactic shock and risk of virus and prion transmission. We suggest that this form of treatment should not be included in the prevention of OHSS.

Familial Mediterranean fever and menstruation.

OBJECTIVE: To study the prevalence, the nature and the genotype correlation of menstruation associated familial Mediterranean fever attacks. METHODS: One hundred and forty-one female patients with familial Mediterranean fever were studied. A questionnaire regarding the presence and nature of menstruation associated with familial Mediterranean fever was designed and filled in by the authors during the patients' visits to the familial Mediterranean fever clinic. The patients who had a positive history for this manifestation were analysed for their familial Mediterranean fever mutations. RESULTS: Ten out of 141 familial Mediterranean fever female patients (7%) had menstruation-associated familial Mediterranean fever attacks. These patients varied in their disease age of onset and disease duration. Increase of colchicine dose, daily or during the perimenstrual period or oral contraceptives were beneficial in preventing these familial Mediterranean fever attacks. No correlation was found with specific mutations causing familial Mediterranean fever. CONCLUSIONS: Menstruation-associated familial Mediterranean fever attacks are relatively uncommon. They are not related to the age of the women, the chronicity of their disease or to the mutations they bear. Various therapeutic approaches have to be tried in order to abolish these attacks. A decrease in oestrogen level during menstruation may have a role in this unique manifestation of familial Mediterranean fever.

Correction of hyperandrogenemia by laparoscopic ovarian cautery in women with polycystic ovarian syndrome is not accompanied by improved insulin sensitivity or lipid-lipoprotein levels.

Polycystic ovarian syndrome (PCOS) is a common disorder associated with hyperandrogenemia and infertility. Abdominal obesity, insulin resistance, and dyslipoproteinemias are other common metabolic disorders typically found in women with PCOS. The cause-effect relationship between hyperandrogenemia and insulin resistance-dyslipoproteinemia remains unclear. In this study, we have investigated the changes in androgenemia, insulin sensitivity, and plasma lipid-lipoprotein levels after laparoscopic ovarian cautery (LOC) for ovulation induction in eight infertile women with clomiphene citrate-resistant PCOS. After LOC, significant decreases in androstenedione (43%), testosterone (48%), and free testosterone (48%) concentrations were observed (P < 0.05). Glucose utilization during an euglycemic-hyperinsulinemic clamp did not change after LOC. In addition, no significant changes after the surgical procedure were observed for cholesterol, triglycerides, and apolipoprotein concentrations measured in total plasma and in different lipoprotein fractions. In conclusion, within the short duration of observation of this study, our findings demonstrate that insulin resistance and lipoprotein abnormalities associated with PCOS are not secondary to hyperandrogenemia. The clinician, therefore, must be cognizant of the persistence of these metabolic risk factors for cardiovascular disease once successful ovulation and fertility is restored, and institute appropriate monitoring, counseling, and medical intervention as required.

Ultrasonographic endometrial changes after intrauterine insemination: a comparison of two catheters.

OBJECTIVE: To determine and compare the transvaginal ultrasonographic (US) endometrial changes immediately after IUI using the Edwards Wallace (H.G. Wallace, Limited, Colchester, Essex, UK) and Tom-Cat (Sherwood Medical, St. Louis, MO) catheters. DESIGN: Prospective study. SETTING: IVF unit. PATIENT(S) AND INTERVENTION(S): Eighty-two infertile patients underwent 112 cycles of ovulation induction with IUI. Either the Edwards Wallace catheter (group 1, n = 32) or the Tom-Cat catheter (group 2, n = 80) was used for sperm insemination. The presence of an endometrial three-layer pattern before IUI was a prerequisite for inclusion in the study. After each IUI, the endometrium was reassessed by transvaginal US. MAIN OUTCOME MEASURE(S): Ultrasonographic endometrial changes, clinical pregnancy rates (PRs), complications, and patients' complaints were compared between the two groups. RESULT(S): Total destruction of the endometrial three-layer pattern was observed in 12.5% of the cycles in group 1, compared with 50% of the cycles in group 2. Clinical pregnancies occurred in 14 (12.5%) of the 112 IUI cycles. A higher PR was achieved when the endometrial three-layer pattern was preserved after IUI. The patients in group 2 had more complaints of bleeding and pain during the procedure. CONCLUSION(S): Ultrasonographic changes after IUI suggest that the Edwards Wallace catheter is significantly less traumatic to the endometrium than the Tom-Cat catheter. Although both catheters yielded the same overall PR, there was a trend indicating that sparing the endometrial three-layer pattern from damage increases the chance of conception.

An IVF fallacy: multiple pregnancy risk is lower for older women.

INTRODUCTION: Multiple pregnancy is one of the most important and preventable complications of in vitro fertilization (IVF) and embryo transfer. The general clinical practice in many IVF clinics is to transfer four or five embryos to older women if available, since pregnancy rates are lower in women older than 35 years of age. However, it is not clear whether the risk for multiple pregnancy is also lower. OBJECTIVE: Our objective was to investigate whether transferring a higher number of embryos actually improves pregnancy outcome in older women, without increasing the risk for multiple pregnancy and to investigate other factors that may affect the occurrence of multiple pregnancy. SETTING: The setting was university-based IVF program at The Toronto Hospital. DESIGN: The design was a retrospective case series. PATIENTS AND METHODS: The outcome of 1116 IVF cycles between January 1992 and December 1993 was investigated according to different age groups. MAIN OUTCOME MEASURE: The main outcome measure was multiple pregnancies. RESULTS: Seventy multiple pregnancies resulted from a total of 242 pregnancies. Overall pregnancy and multiple pregnancy rates were inversely correlated with age. However, when the data were adjusted for the number of embryos transferred, this trend disappeared. The result of multiple regression analysis showed that the multiple pregnancy rate was higher without improving the pregnancy rate when the number of embryos transferred exceeded three, regardless of the age of the patients, especially when more embryos were available than the number of transferred ones. CONCLUSIONS: The number of embryos transferred should be limited to a maximum of three regardless of the age of patients, to reduce the high frequency of multiple gestations in an IVF program.

In vitro fertilization programmed for weekday-only oocyte harvest: analysis of outcome based on actual retrieval day.

OBJECTIVE: Our aim was to assess the effect of the day of ovum retrieval on outcome in an IVF program scheduled for weekday-only ovum retrievals. DESIGN: This was a retrospective study of patients who underwent transvaginal ultrasound-guided ovum retrieval (TVUS-OR) in an IVF program from August 10, 1992, to April 30, 1993. SETTING: A university-based tertiary referral hospital center was the setting. PARTICIPANTS AND METHODS: All patients (n = 501) who underwent TVUS-OR were divided into three groups: (1) patients who underwent TVUS-OR on Monday; (2) patients who underwent retrieval on Tuesday, Wednesday, or Thursday; and (3) patients who underwent retrieval on Friday. All patients were induced by the same controlled ovarian hyperstimulation protocol, which consisted of a GnRH analogue "flare-up" followed by parenteral menotropins, after a scheduled oral contraceptive-induced menses. Patients and cycle characteristics in the three groups were compared and clinical outcome was evaluated. RESULTS: The similarity of patients and cycle characteristics confirmed the uniformity of the three groups. No difference was found in any of the clinical outcomes. However, in the first half of the program, we revealed a trend in which patients at high risk for ovarian hyperstimulation syndrome, requiring freezing all embryos and not allowing transfer during the treatment cycle, occurred more commonly in women whose retrieval occurred on Monday. This trend disappeared in the second half of the analysis. CONCLUSIONS: In an in vitro fertilization program in which ovum retrievals occurred only on weekdays, no significant difference in outcome was found in patients undergoing ovum retrieval on Monday or Friday versus midweek. In addition to significant savings by eliminating weekend retrievals, IVF outcome is not compromised.

Transfer of embryos from yeast-colonized dishes.

OBJECTIVE: To report yeast colonization in IVF dishes, where ET was carried out, and the IVF outcome was not compromised. DESIGN: Retrospective study of patients who underwent IVF cycle during the last 4 years. SETTING: In vitro fertilization program at the Shaare-Zedek hospital in Jerusalem. PATIENTS: Five couples who underwent standard IVF cycles and whose dishes were colonized with yeast. After thorough discussion ET was carried out. RESULTS: Although colonized with yeast, the quality of the embryos was not compromised. One to three of these embryos were transferred. All five women conceived. CONCLUSIONS: In vitro fertilization outcome is not necessarily compromised by yeast colonization. Nevertheless, the possible teratogenic effect of yeast on embryos has not been investigated and research is required to address this concern.

Ovarian response to recombinant human follicle-stimulating hormone in luteinizing hormone-depleted women: examination of the two cell, two gonadotropin theory.

OBJECTIVE: To evaluate the relative contribution of FSH to ovarian estrogen production. DESIGN: Nonrandomized, prospective study. SETTING: University of Toronto teaching hospital reproductive biology unit. PATIENTS: Five women who had been treated with depot GnRH agonist with hormonal add-back for 4 to 48 months and who were confirmed to be gonadotropin depleted by both bioassay and RIA. INTERVENTIONS: Subjects received 75 IU SC recombinant human FSH daily for 7 days followed by 150 IU daily for 7 days and 225 IU daily for the third week. MAIN OUTCOME MEASURE: Serum steroid determination and vaginal sonography for follicle size and endometrial thickness were performed serially and follicular fluid hormone levels were measured in two subjects. RESULTS: Bioactive LH and FSH activity were less than the detection limit of the assay (0.1 mIU/mL; conversion factor to SI units, 1.00 for LH and FSH) before recombinant FSH treatment in all five women. In all subjects, at least one preovulatory follicle developed by the end of two to three weeks. Endometrial thickness increased to between 7 and 9 mm in four women. Mean serum E2 in the five subjects increased from 17 pg/mL (range: 5 to 33 pg/mL; conversion factor to SI unit, 3.671) at baseline to 230 pg/mL (range: 37 to 489 pg/mL) at the end of the study. Follicular fluid E2 concentrations ranged from 44,296 to 69,367 pg/mL in the four follicles aspirated. CONCLUSION: Our results indicate that LH is not necessary for ovarian E2 production. We speculate that the granulosa cells, in the absence of detectable LH bioactivity, can use circulating adrenal androgens or constitutive or FSH-stimulated thecal androgens, to produce intrafollicular E2.

Coculture with ovarian cancer cell enhances human blastocyst formation in vitro.

OBJECTIVE: To examine the effect of human embryo coculture with an ovarian cancer cell line. DESIGN: Prospective, randomized in vitro study. SETTING: University of Toronto IVF clinic at The Toronto Hospital. PATIENTS: Couples undergoing IVF who chose not to cryopreserve their spare embryos and were willing to donate spare embryos for research. INTERVENTION: Spare embryos were cultured randomly either under regular conditions with Ham's F-10 medium supplemented with 10% heat inactivated human serum (n = 189) or were cocultured in the same medium, with human ovarian epithelial cancer cells (n = 173). MAIN OUTCOME MEASURE: Blastocyst formation. RESULTS: Coculture with the cancer cell line improved the preimplantation embryo development to the blastocyst stage. There was a significant increase in the number of cavitating morulae (68%) and the proportion of embryos reaching the fully expanded blastocyst stage (39%) compared with those in standard culture medium (34% and 23%, respectively). CONCLUSION: Coculture of early cleavage stage human embryos with epithelial cancer cells markedly improves in vitro human blastocyst formation compared with standard culture conditions.

Recombinant human leukemia inhibitory factor does not enhance in vitro human blastocyst formation.

OBJECTIVE: To assess the effect of human recombinant leukemia inhibitory factor in different doses on human blastocyst formation. SETTING: A university-based tertiary referral center (The Toronto Hospital). INTERVENTIONS: Nontransferable human embryos (n = 473) at the two- to six-cell stage were obtained from patients undergoing IVF and were split randomly into five groups. Embryos in group A (n = 164) were cultured as the control group in Ham's F-10 (GIBCO-BRL, Grand Island, NY) + 10% human sera. Embryos in groups B, C, D, and E (n = 54, 78, 87, and 80, respectively) were cultured in the same medium supplemented with human recombinant leukemia inhibitory factor in four different concentrations (5, 7.5, 10, and 20 ng/mL, respectively). Morphological assessment of embryo development was recorded daily. MAIN OUTCOME MEASURE: Human blastocyst formation. RESULTS: No significant difference was detected in the rate of blastocyst formation of embryos in the study groups when compared with embryos in group A. CONCLUSIONS: This study shows that 5 to 20 ng/mL of recombinant leukemia inhibitory factor in standard medium does not enhance in vitro human blastocyst formation. It is possible that recombinant leukemia inhibitory factor may play a role at later stages of human embryogenesis and during implantation.

Recurrent maternal virilization during pregnancy associated with polycystic ovarian syndrome: a case report and review of the literature.

Maternal virilization in pregnancy is associated, in most benign cases, with luteoma of pregnancy and hyperreactio luteinalis. Only a few reports relate this phenomenon to hyperthecosis or polycystic ovarian syndrome (PCOS). A case of recurrent maternal virilization during two consecutive pregnancies in a patient with PCOS is presented. In both pregnancies, the deepening of her voice, facial hirsutism and scalp hair loss began at the end of the first trimester and regressed 3-4 months post-partum. The patient underwent ovarian venous catheterization, and androgen secretion from both ovaries was found to be markedly high but similar, therefore ruling out an ovarian androgen-secreting tumour. Reviewing the English literature of similar cases, we found reports of only seven cases of maternal virilization during pregnancy associated with PCOS. Here, we present a case of recurrent maternal virilization in pregnancy associated with PCOS.

In vitro fertilization outcome in the presence of severe male factor infertility.

OBJECTIVE: To assess the outcome of standard IVF treatment (nonmicromanipulated) with respect to total motile sperm number recovered by swim-up, particularly for couples with severe male factor infertility defined as total motile sperm number < 0.5 x 10(6). DESIGN: Retrospective study of patients who underwent successful oocyte retrieval in an IVF program from August 10, 1992 to December 31, 1993. SETTING: A university-based tertiary referral center (The Toronto Hospital). PATIENTS: All cycles (n = 672) were divided into four groups according to total motile sperm number recovered using standard swim-up: group 1, total motile sperm number < or = 0.50 x 10(6); group 2, total motile sperm number between 0.51 and 1.00 x 10(6); group 3, total motile sperm number between 1.01 and 1.50 x 10(6); and group 4, total motile sperm number > or = 1.51 x 10(6). All patients received the same controlled ovarian hyperstimulation protocol, which consisted of a GnRH analog flare-up followed by parenteral menotropins. Clinical and cycle characteristics in the four groups were analyzed and outcome was evaluated. RESULTS: There was no significant difference in clinical and cycle characteristics between the groups. The uniformity of the groups justified analysis of their outcome. A fertilization rate of 21.5% was achieved in couples with severe male factor (group 1). Fertilization rate and number of embryos transferred increased directly with the total motile sperm number. There was no significant difference in implantation rate per embryo between the groups. CONCLUSIONS: The results in couples with severe male factor infertility compare favorably with monospermic fertilization rates reported in the literature using partial zona dissection and subzonal insertion but is lower than with intracytoplasmic sperm injection. Therefore, we believe that couples with severe male factor infertility should be considered for standard IVF, as long as adequate total motile sperm can be recovered (100 x 10(3) per dish). If intracytoplasmic sperm injection is available, it should be offered to these couples.

Systemic lupus erythematosus induced by ovulation induction treatment.

Infertile women are treated with various regimens for ovulation induction. The ultimate end-result of these treatments is a significant rise in levels of serum gonadotropins and estradiol--the most potent natural estrogen. Estrogens may affect diverse biologic functions, including immune and inflammatory reactions. A role for estrogens in the development or exacerbation of systemic lupus erythematosus (SLE) has been suggested by many studies. In this report, we present 3 cases of otherwise healthy women who received ovulation induction agents and subsequently developed full-blown SLE. The possible association between this treatment and SLE is discussed.

Cytokine-mediated regulation of rat ovarian function: interleukin-1 inhibits plasminogen activator activity through the induction of plasminogen activator inhibitor-1 (PAI-1).

Intraovarian IL-1 has recently been implicated as a mediator in the ovulatory process. Since PA activation is an established component of the ovulatory cascade, consideration was given in this report to the possibility that IL-1 may modulate ovarian PA economy. Whole ovarian dispersates from immature rats (25-27-days-old) were cultured under serum-free conditions for 48 h in the absence or presence of IL-1beta. Cellular PA activity was measured by plasminogen-dependent cleavage of 14C-labeled globin. Cells grown in the absence of IL-1 exhibited appreciable PA activity, as assessed by the cleavage of 0.074 +/- 0.026 mg [14C]-globin/5 x 10(5) cells (mean +/- SD). Exposure to IL-1 (10 ng/ml) led to a 30% reduction in cell-associated PA activity (p < 0.001). The IL-1-mediated inhibition occurred concurrently with a 10-fold increase in the ability of the corresponding conditioned media to inhibit exogenous urokinase activity. At similar cell densities of 5 x 10(5) cells/well, isolated cultures of theca and granulosa cells exhibited comparable PA activity in the absence of IL-1. However, only theca cells responded to IL-1 with inhibition of plasminogen activation and enhancement of urokinase inhibitory activity. Granulosa cells in turn failed to respond to IL-1. Both the inhibition of PA activity and the increase in urokinase inhibitory activity proved cell-density- and IL-1 dose-dependent. The IL-1-induced inhibition of urokinase was abolished by the administration of a polyclonal anti-rat PAI-1 IgG. Both effects of IL-1 were counteracted in a dose-dependent fashion by the soluble IL-1 receptor (which specifically complexes with IL-1), and by a highly-specific IL-1 receptor antagonist suggesting that the IL-1 effects are receptor-mediated. The present observations indicate that ovarian PA activity is subject to inhibition by IL-1 probably by way of PAI-1 of theca-interstitial origin. Inasmuch as IL-1 may be involved in initiating and maintaining the preovulatory cascade, the periovulatory activation of plasminogen must be accomplished by agents other than IL-1.