Search

Background: Treatment of poor-responder patients to controlled ovarian stimulation for assisted reproduction, who have normal basal FSH concentrations, is one of the most difficult challenges in reproductive medicine. This study investigated the usefulness of testosterone pretreatment in such patients., Methods: Prospective, therapeutic, self-controlled clinical trial including 25 consecutive infertile patients who had a background of the first and second IVF treatment cycle cancellations due to poor follicular response, in spite of vigorous gonadotrophin ovarian stimulation and having normal basal FSH levels. In the third IVF attempt, all patients received transdermal testosterone treatment (20 microg/kg per day) during the 5 days preceding gonadotrophin treatment., Results: Twenty patients (80%) showed an increase of over fivefold in the number of recruited follicles, produced 5.8+/-0.4 (mean+/-SEM) oocytes, received two or three embryos and achieved a clinical pregnancy rate of 30% per oocyte retrieval. There were 20% cancelled cycles., Conclusion: Pretreatment with transdermal testosterone may be a useful approach for women known to be low responders on the basis of a poor response to controlled ovarian stimulation but having normal basal FSH concentrations.

Background: Anti-Müllerian hormone (AMH) has been recently proposed as a marker for ovarian ageing and poor ovarian response to controlled ovarian hyperstimulation in assisted reproduction cycles. The present study was undertaken to investigate the usefulness of baseline cycle day 3 AMH levels and AMH serum concentrations obtained on the fifth day of gonadotropin therapy in predicting ovarian response and pregnancy in women undergoing ovarian stimulation with FSH under pituitary desensitization for assisted reproduction., Methods: A total of 80 women undergoing their first cycle of IVF/intracytoplasmic sperm injection (ICSI) treatment were studied. Twenty consecutive cycles which were cancelled because of a poor follicular response were initially selected. As a control group, 60 women were randomly selected from our assisted reproduction programme matching by race, age, body mass index, basal FSH and indication for IVF/ICSI to those in the cancelled group. For each cancelled patient, three IVF/ICSI women who met the matching criteria were included., Results: Basal and day 5 AMH serum concentrations were significantly lower in the cancelled than in the control group. Receiver-operating characteristic (ROC) analysis showed that the capacity of day 5 AMH in predicting the likelihood of cancellation in an assisted reproduction treatment programme was significantly higher than that for basal AMH measurement. However, the predictive capacity of day 5 AMH was not better than that provided by day 5 estradiol. In addition, neither basal nor day 5 AMH or estradiol measurements were useful in the prediction of pregnancy after assisted reproductive treatment., Conclusions: AMH concentrations obtained early in the follicular phase during ovarian stimulation under pituitary suppression for assisted reproduction are better predictors of ovarian response than basal AMH measurements. However, AMH is not useful in the prediction of pregnancy. Definite clinical applicability of AMH determination as a marker of IVF outcome remains to be established.

Background: There is scanty information analysing the predictive value of a poor response, in terms of cancellation of the IVF cycle because of poor follicular development, as a predictor of ovarian response in a subsequent treatment cycle. This study, where logistic regression analysis was used, was undertaken to investigate the relative power of the woman's age, basal FSH, and previous cycle cancellation both as single and combined predictors of ovarian response in an IVF program where pituitary desensitization is routinely used., Methods: One hundred and twenty-nine consecutive patients having their first cycle of IVF/ICSI treatment cancelled because of poor follicular response and undergoing a second attempt within 6 months after the failed treatment cycle were initially selected (group 1). Group 2 comprised 129 patients undergoing the first cycle of IVF/ICSI treatment and who were randomly selected from our assisted reproductive treatment program matching by BMI and indication for IVF/ICSI to those in group 1., Results: Cancellation rate was significantly higher but ovarian response significantly lower in group 1 as compared with group 2. As indicated by the AUC(ROC) determined with ROC analysis, such a poor outcome in patients having a previous IVF/ICSI cycle cancelled due to poor response was observed whatever the level of basal FSH. In a logistic regression analysis and according to the odds ratio values, the predictive capacity of a previous poor response was 9 and 7.6 times higher than the predictive capacity of age and basal FSH, respectively. Any two or all three variables studied did not improve the predictive value of previous cycle cancellation alone., Conclusions: The history of an IVF/ICSI cancelled cycle due to poor follicular response in a standard stimulation protocol is a better predictor of cancellation in subsequent treatment cycles than age or FSH. The poor ovarian response associated with previous cycle cancellation occurs whatever the level of basal FSH.

Halving the standard daily dose of triptorelin at the start of ovarian stimulation in down-regulated women stimulated with recombinant FSH is enough for pituitary suppression and was associated with higher LH serum concentrations in the follicular phase. However, this did not translate into higher serum concentrations of androstenedione and E2 and had no significant effect on ovarian response and the outcome of IVF/intracytoplasmic sperm injection.

Problem: The majority of women with recurrent miscarriage have no discernible cause but it has been postulated that immunologic aberrations may be the cause in most of such cases. Also, it has been stressed that deliberate modification of the maternal host defense system can improve the chances of success. We tested the hypothesis that it is possible to potentiate maternal immune functions so as to improve reproductive performance by replacing several embryos into the uterus, thus favoring the recognition of fetal antigens., Method of Study: A total of 57 couples with three or more (mean 5.52; range 3-12) consecutive first-trimester spontaneous clinical abortions of unknown etiology were treated with in vitro fertilization (IVF) and embryo transfer for a total of 84 cycles. Patients underwent IVF after combined gonadotropin-releasing hormone agonist/gonadotropin treatment for ovarian stimulation, and up to four embryos were replaced into the uterus., Results: There were 32 pregnancies (three of them after frozen-thawed embryo transfers) and 26 (81%) of them were viable gestations. Overall, patients had a previous obstetric history of 315 pregnancy losses and 15 live-born babies. Thus, the probability of having a live baby before treatment was 4.54% (95% CI, 2.78-7.36) a figure significantly lower (P < 0.0001) than that observed under IVF treatment (81%; 95% CI, 64.53-91.01). None of selected variables potentially related with the outcome of pregnancy after IVF and embryo transfer in recurrent aborters (including pre-implantation genetic diagnosis) was found to be associated with miscarriage., Conclusions: This study shows that replacement of several embryos after IVF is a useful treatment in the prevention of unexplained recurrent spontaneous abortion thus providing further evidence for immunologically modifiable pregnancy loss.

At present, there is considerable debate about the utility of supplemental LH in assisted reproduction treatment. In order to explore this, the present authors used a depot gonadotrophin-releasing hormone agonist (GnRHa) protocol combined with recombinant human FSH (rhFSH) or human menopausal gonadotrophin (HMG) in patients undergoing intracytoplasmic sperm injection (ICSI). The response to either rhFSH (75 IU FSH/ampoule; group rhFSH, 25 patients) or HMG (75 IU FSH and 75 IU LH/ampoule; group HMG, 25 patients) was compared in normo-ovulatory women suppressed with a depot triptorelin injection and candidates for ICSI. A fixed regimen of 150 IU rhFSH or HMG was administered in the first 14 days of treatment. Treatment was monitored with transvaginal pelvic ultrasonographic scans and serum measurement of FSH, LH, oestradiol, androstenedione, testosterone, progesterone, inhibin A, inhibin B and human chorionic gonadotrophin (HCG) at 2-day intervals. Although oestradiol serum concentrations on the day of HCG injection were similar, both the duration of treatment and the per cycle gonadotrophin dose were lower in group HMG. In the initial 16 days of gonadotrophin treatment, the area under the curve (AUC) of LH, oestradiol, androstenedione and inhibin B were higher in group HMG; no differences were seen for the remaining hormones measured, including the inhibin B:inhibin A ratio. The dynamics of ovarian follicle development during gonadotrophin treatment were similar in both study groups, but there were more leading follicles (>17 mm in diameter) on the day of HCG injection in the rhFSH group. The number of oocytes, mature oocytes and good quality zygotes and embryos obtained were significantly increased in the rhFSH group. It is concluded that in IVF patients undergoing pituitary desensitization with a depot agonist preparation, supplemental LH may be required in terms of treatment duration and gonadotrophin consumption. However, both oocyte, embryo yield and quality were significantly higher with the use of rhFSH.

Objective: To characterize the chronology of hemodynamic changes in in vitro fertilization (IVF) cycles and its relationship with circulating ovarian steroids, cytokines, and their mediator nitric oxide., Design: Prospective, cross-sectional study., Setting: University teaching hospital., Patient(s): Eighty-eight IVF patients., Intervention(s): Ovarian stimulation with FSH under pituitary suppression., Main Outcome Measure(s): Circulating levels of estradiol, progesterone, nitrite/nitrate, interleukin-6, vascular endothelial growth factor, tumor necrosis factor alpha, aldosterone, norepinephrine, as well as measurements of plasma renin activity and mean arterial pressure., Result(s): The maximal stimulation of the renin-aldosterone and sympathetic nervous systems was seen 7 days after hCG administration, although values still remained elevated over normal control values on day of hCG + 11. Mean arterial pressure in IVF patients remained significantly reduced throughout the luteal phase. Changes in the stimulation of the renin-aldosterone system correlated temporally with progesterone but not estradiol levels. No significant changes were observed in circulating concentrations of cytokines investigated or nitric oxide., Conclusion(s): The circulatory changes and the homeostatic activation of the renin-aldosterone system and sympathetic nervous system that consistently develop in patients undergoing controlled ovarian hyperstimulation for IVF is a feature associated with the luteinization process. These hemodynamic changes occur in the absence of variations in the circulating levels of cytokines potentially involved in ovarian hyperstimulation syndrome.

Background: It has been recently suggested that gonadotrophin-releasing hormone agonist down-regulation in some normogonadotrophic women may result in profound suppression of LH concentrations, impairing adequate oestradiol synthesis and IVF and pregnancy outcome. The aims of this study, where receiver-operating characteristic (ROC) analysis was used, were: (i) to assess the usefulness of serum LH measurement on stimulation day 7 (S7) as a predictor of ovarian response, IVF outcome, implantation, and the outcome of pregnancy in patients treated with recombinant FSH under pituitary suppression; and (ii) to define the best threshold value, if any, to discriminate between women with 'low' or 'normal' LH concentrations., Methods: A total of 144 infertile women undergoing IVF/intracytoplasmic sperm injection (ICSI) treatment were included. Seventy-two consecutive patients having a positive pregnancy test (including 58 ongoing pregnancies and 14 early pregnancy losses) were initially selected. As a control non-pregnant group, the next non-conception IVF/ICSI cycle after each conceptual cycle in our assisted reproduction programme was used., Results: The median and range of LH values in non-conception cycles, conception cycles, ongoing pregnancies, and early pregnancy losses, clearly overlapped. ROC analysis showed that serum LH concentration on S7 was unable to discriminate between conception and non-conception cycles (AUC(ROC) = 0.52; 95% CI: 0.44 to 0.61) or ongoing pregnancy versus early pregnancy loss groups (AUC(ROC) = 0.59; 95% CI: 0.46 to 0.70). To assess further the potential impact of suppressed concentrations of circulating LH during ovarian stimulation on the outcome of IVF/ICSI treatment, the three threshold values of mid-follicular serum LH proposed in the literature (<1, < or =0.7, <0.5 IU/l) to discriminate between women with 'low' or 'normal' LH were applied to our study population. No significant differences were found with respect to ovarian response, IVF/ICSI outcome, implantation, and the outcome of pregnancy between 'low' and 'normal' S7 LH women as defined by those threshold values., Conclusions: Our results do not support the need for additional exogenous LH supplementation in down-regulated women receiving a recombinant FSH-only preparation.

Recent reports investigating the value of basal inhibin B determination as a predictor of ovarian reserve and assisted reproduction treatment have led to discordant results. This study was undertaken to further assess the relative power of day 3 inhibin B and follicle stimulating hormone (FSH) (defined before treatment) and the woman's age both as single and combined predictors of ovarian response and pregnancy in an in-vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) programme. A total of 120 women undergoing their first cycle of IVF or ICSI was included. Forty consecutive cycles cancelled because of poor follicular response were initially selected. As a control group, the nearest completed IVF/ICSI cycles before and after each cancelled cycle (i.e. the closest cycles in temporal relationship to the index cycle) were used. Mean age and basal FSH concentrations were significantly higher in the cancelled than in the control group (P: < 0.01 and P: < 0.001 respectively), whereas basal inhibin B was significantly higher in the latter (P: < 0.05). The association of basal FSH (with an accuracy or predictive value of ovarian response of 79%) with cancellation rate was significant, independent of, and stronger than the effects of age and inhibin B (P: < 0.05). Any two or all three of these variables studied did not improve the predictive value of FSH alone. Woman's age was the only variable independently associated with pregnancy rate. It is concluded that the stronger predictors of success in patients undergoing their first IVF/ICSI treatment cycle are age and basal FSH rather than inhibin B. Basal FSH concentration was a better predictor of cancellation rate than age, but age was a stronger predictor of pregnancy rate.

The present study investigates the usefulness of inhibin A, inhibin B and serum oestradiol concentrations obtained in the fifth day of gonadotrophin therapy in predicting ovarian response and assisted reproductive treatment outcome in women undergoing ovarian stimulation under pituitary desensitization. A total of 80 women undergoing their first cycle of in-vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) treatment were studied. Twenty consecutive cycles which were cancelled because of a poor follicular response were initially selected. As a control group, 60 women were randomly selected from our assisted reproductive treatment programme matching by race, age, body mass index, and indication for IVF/ICSI to those in the cancelled group. For each cancelled cycle, three IVF/ICSI women who met the matching criteria were included. Basal follicle stimulating hormone (FSH) concentrations were significantly higher in the cancelled than in the control group, whereas basal inhibin B was significantly higher in the latter. Basal oestradiol concentrations were similar in both groups of patients. On day 5 of gonadotrophin therapy serum concentrations of oestradiol, inhibin A and inhibin B were significantly lower in the cancelled group as compared with controls. Logistic regression analysis showed that the association for day 5 inhibin B (with a predictive value of ovarian response of 91.03%) with cancellation rate was significant, independent of, and stronger than, the effects of any other hormone variable investigated. In addition, day 5 inhibin B concentrations were correlated directly with parameters of ovarian response, ovum retrieval and oocyte and fertilization outcome. However, day 5 inhibin B was not a better predictor of pregnancy than the other hormone variables studied on this day. It is concluded that inhibin B concentrations obtained early in the follicular phase during ovarian stimulation under pituitary suppression for assisted reproductive treatment are highly predictive of ovarian response.

Background: Nitric oxide (NO) may play an important role in embryo implantation and early embryo development. This study investigated the potential role of circulating nitric oxide (NO) measurement to predict the outcome of implantation and pregnancy after IVF and ET., Methods: Two blood samples were collected from 237 IVF patients on days 13-14 and 20-21 after ET. Serum concentration of nitrite/nitrate (the two stable oxidation products of NO metabolism), estradiol (E2), progesterone and beta-hCG were measured on days 13-14 after ET and one week later., Results: No significant differences were found with respect to nitrite/nitrate serum concentrations in conception versus non-conception cycles, viable versus abnormal pregnancies, and viable pregnancy group versus non-conception cycles, respectively, despite that significant differences were observed regarding E2 and progesterone values. Nitrite/nitrate serum concentrations were similar for singleton and multiple pregnancies at both study points. In viable pregnancies, no significant change was observed for nitrite/nitrate serum concentration from days 13-14 to 20-21 after ET. No correlation was found between nitrite/nitrate serum concentration and E2 or progesterone serum levels., Conclusions: Circulating levels of nitrite/nitrate are similar in successful and unsuccessful implantation after IVF and are unrelated to the outcome of pregnancy. This precludes the use of serum NO measurement as a marker of implantation and successful pregnancy in IVF.

Marked granulosa cell proliferation along with important changes in the vascular bed of the ovary characterize IVF cycles associated with multiple follicular growth and maturation. The present report investigated follicular fluid (FF) and circulating concentrations of adrenomedullin, vascular endothelial growth factor (VEGF) and nitric oxide (NO) in 70 IVF patients (14 of whom became pregnant); these three vasoactive substances may be implicated in extensive ovarian tissue remodelling. Serum and FF concentrations of oestradiol and progesterone were also measured in the 70 IVF cycles studied. Follicular fluid concentrations of VEGF and adrenomedullin but not nitrite/nitrate (the two stable oxidation products of NO metabolism) were significantly higher (P < 0.0001) than the corresponding circulating concentrations. Follicular fluid concentrations of oestradiol and progesterone were not correlated with those of adrenomedullin, VEGF or nitrite/nitrate. No relationship existed between circulating concentrations of adrenomedullin, VEGF or nitrite/nitrate on the day of oocyte aspiration and parameters of ovarian response to gonadotrophin stimulation. In contrast, FF adrenomedullin concentration showed a direct relationship with day 3 FSH serum concentration (r = 0.53, P < 0.01) and the number of ampoules of gonadotrophin administered (r = 0.36, P < 0.005), but an inverse correlation with the total number of oocytes retrieved (r = -0.29, P < 0.01) and the number of mature oocytes (r = -0.25, P < 0. 05). A positive correlation was found for FF VEGF concentration and chronological age (r = 0.29, P < 0.05) and ampoules of gonadotrophins administered (r = 0.30, P < 0.05). There was no relationship between nitrite/nitrate FF concentrations and parameters of ovarian response. Neither serum concentrations nor FF concentrations of adrenomedullin, VEGF or nitrite/nitrate were correlated with IVF outcome. This study suggested for the first time that increased FF concentrations of adrenomedullin can be a marker of decreased ovarian response in IVF. Our results also provide further evidence favouring an association between FF VEGF and patient's age, while on the basis of our findings NO measurements are not a useful marker of ovarian response.

Purpose: Our purpose was to determine prospectively, using receiver-operating characteristic (ROC) analysis, whether the ovarian reserve test with hMG could improve the predictive value of a woman's age and basal levels of follicle stimulating hormone (FSH), E2, and inhibin or any combination of them regarding ovarian response and pregnancy rate in IVF treatment following pituitary desensitization., Methods: The hMG test was performed within 3 months of IVF treatment in 80 women undergoing the first cycle of IVF and consisted of 2 ampoules of hMG daily for 5 days starting on cycle days 2 to 3. Hormone and ultrasound evaluation was performed on cycle days 2 to 3 and 7 to 8., Results: The mean age and basal FSH levels were significantly higher in the canceled (n = 28) than in the control (n = 52) group, whereas the basal inhibin level was significantly higher in the latter. Regarding ovarian response, the combination FSH plus inhibin had the better diagnostic accuracy (predictive value of 70%) among basal variables. When post-hMG parameters (alone or in combination) were analyzed, E2 alone, with a 77% diagnostic accuracy, emerged as the best predictive variable of cancellation in IVF cycles. When ROC analysis was used, the area under the ROC curve for E2 post-hMG (diagnostic accuracy of 84.5%) was significantly higher than that for the estimates based on the combination of basal FSH and inhibin (diagnostic accuracy of 71.3%). However, woman's age was the only variable independently associated with pregnancy rate., Conclusions: The predictive power of the hMG test of ovarian reserve is better than that of age and basal hormone values (FSH and inhibin) and it is based mainly on the E2 response to hMG treatment. However, given that age is the only predictor of pregnancy and considering the cost and discomfort of the hMG test, the usefulness, if any, of the test in predicting IVF performance in the daily clinical setting remains to be established.

Background: Estradiol has marked systemic vasodilator effects which may be partially mediated by nitric oxide. Recently, a new vasodilator peptide, adrenomedullin, having potent vasodilatory action which is mediated at least in part by nitric oxide, has been isolated. This study investigated whether a relationship exists between circulating levels of estradiol, adrenomedullin, and nitrite/nitrate (the two stable oxidation products of NO metabolism) both in the spontaneous menstrual cycle and IVF cycles., Methods: Ten normal ovulatory infertile patients were included in this prospective longitudinal study. Circulating levels of estradiol, adrenomedullin, and nitrite/nitrate were investigated. Follicular fluid concentrations of adrenomedullin and nitrite/nitrate, as well as estradiol, were also determined in IVF cycles., Results: Serum nitrite/nitrate levels were significantly elevated in the late follicular phase compared to cycle day 3 of the spontaneous menstrual cycle thus paralleling plasma estradiol. However, no significant change in serum nitrite/nitrate concentration was found associated to multifollicular development and supraphysiological levels of estradiol in IVF cycles. Adrenomedullin plasma levels did not show significant variation either in menstrual or IVF cycles. No correlation was found between plasma estradiol levels and nitrite/nitrate serum concentrations or adrenomedullin plasma levels nor between circulating adrenomedullin and nitrite/nitrate both in menstrual and IVF cycles. Follicular fluid concentrations of estradiol and adrenomedullin but not nitrite/nitrate were significantly higher than those found in plasma or serum. Neither estradiol follicular fluid concentration correlated with those of adrenomedullin or nitrite/nitrate nor a relationship was observed between adrenomedullin and nitrite/nitrate., Conclusions: Circulating levels of nitrite/nitrate show a significant increase during the late follicular phase in the normal menstrual cycle which is unrelated to adrenomedullin. In addition, this does not necessarily indicate a cause and effect relationship between nitrite/nitrate and estradiol levels given that no increase in nitrite/nitrate was observed from a hypoestrogenic to a hyperestrogenic state during IVF cycles. Further studies are necessary to clarify this subject. Also, the biological and clinical significance of the presence of adrenomedullin in the human follicular fluid remains to be elucidated.

Objective: To investigate the effects of long-term down-regulation (4 months) used in combination with gonadotropin ovarian stimulation for IVF-ET., Design: Prospective randomized study., Setting: Assisted Reproduction Unit of the Hospital Clinic i Provincial in Barcelona, a tertiary care setting., Patient(s): Thirty pairs of IVF patients who were matched for age, indication for IVF, and number of attempts., Intervention(s): Women were randomized to receive a standard long protocol of SC leuprolide acetate (n = 30, group L) or a monthly injection of leuprolide acetate depot for 4 months (n = 30, group D) before gonadotropin stimulation., Main Outcome Measure(s): Ovarian response and IVF outcome., Result(s): Days of ovarian stimulation, follicular recruitment and growth during gonadotropin treatment, and the endometrial thickness on the day of hCG administration were similar for the 2 groups of IVF patients. However, the serum concentration of E2 was significantly higher in group L even though group D received a higher total dose of gonadotropins. The number of follicles punctured, the number of oocytes retrieved, the number of oocytes fertilized, the number of embryos suitable for replacement and cryopreservation, the number of patients with ET, and implantation and clinical pregnancy rates were similar for groups L and D. However, the percentage of metaphase II oocytes was significantly higher in group L than in group D., Conclusion(s): Long-term down-regulation does not improve pregnancy rates in a general IVF program.

Severe ovarian hyperstimulation syndrome (OHSS) is consistently associated with a circulatory dysfunction characterized by arterial hypotension, low peripheral vascular resistance, and increased activity of the renin-aldosterone system. To investigate whether circulatory dysfunction also occurs in asymptomatic patients undergoing controlled gonadotropin ovarian hyperstimulation under pituitary suppression for in vitro fertilization (IVF), 12 women without clinical manifestations of OHSS underwent sequential blood, urine, and hemodynamic measurements at five study points: the 7th day of the menstrual cycle preceding IVF (study point 1 or baseline), the day when pituitary suppression was shown (study point 2), the day of hCG ovulatory injection (study point 3), the day after hCG was injected (study point 4), and 7 days after hCG administration (study point 5). Mean arterial pressure, cardiac output, peripheral vascular resistance, plasma concentrations of estradiol (E2) and aldosterone, and plasma renin activity (PRA) were measured at each study point in all women. Serum levels of nitrite/nitrate, and plasma concentration of atrial natriuretic peptide, norepinephrine, adrenomedullin, and cyclic guanosine 3'5'-monophosphate were measured in samples obtained at study points 1 and 5. Multiple follicular development during ovarian stimulation associated with increased plasma E2 concentration (mean peak plasma E2 level, 2430 +/- 428 pg/mL, range 1630-3840 pg/mL) were observed in each woman. All patients developed a significant increase in cardiac output and decrease in arterial pressure and peripheral vascular resistance, and a marked elevation in PRA and aldosterone, all indicating the development of arteriolar vasodilation. Changes in circulatory measurements were temporarily related with the increase in E2 both being detected at study points 3-5. In contrast, there was a clear chronological dissociation between the increase in plasma E2 concentration and the stimulation of the renin-aldosterone system. PRA and aldosterone only reached abnormal levels at study point 5 in association with a significant increase in plasma norepinephrine concentration. Serum levels of nitrite/nitrate and plasma concentrations of atrial natriuretic peptide, adrenomedullin, and cyclic GMP were similar at study points 1 and 5. It is concluded that the circulatory dysfunction that characterizes severe OHSS is a universal event in patients undergoing controlled ovarian hyperstimulation for IVF. Although the increase in E2 levels during IVF cycles is associated with significant circulatory changes, the circulatory dysfunction that characterizes severe OHSS is clearly unrelated to the onset of hyperestrogenemia. Arteriolar vasodilation during IVF cycles was not associated with an increased activity of the vasodilator substances atrial natriuretic peptide, adrenomedullin, and nitric oxide.

Increased antiphospholipid antibody prevalence has been demonstrated by a number of recent studies in in-vitro fertilization (IVF) patients but the potential effects of antiphospholipid antibodies on the different components of the reproductive process and the consideration of whether to test IVF patients for antiphospholipid antibodies are controversial. The present study was undertaken to investigate the possible association between the presence of circulating antiphospholipid antibodies (namely the lupus anticoagulant and anticardiolipin antibodies), among a series of 21 consecutive IVF patients having a clinical spontaneous abortion after their first embryo transfer. As a control group (n=42), the nearest IVF cycle resulting in an ongoing pregnancy before and after each miscarried IVF cycle (i.e. the closest cycles in temporal relationship to the index cycle) was used. One patient (4.8%) in the study group and two women (4.8%) among controls were seropositive for antiphospholipid antibodies. These low and similar seropositivity rates found in the two groups studied lead us to conclude that antiphospholipid antibodies testing in IVF patients should be considered only in those women having repeated failures of implantation/clinical abortion after embryo transfer but not in an infertile general population reaching an IVF programme.

Objective: To present a case of IVF failure evaluated by fluorescence in situ hybridization (FISH)., Design: Case report., Setting: Research university laboratory and clinical IVF laboratory., Patient(s): An infertile couple with recurrent IVF failure., Intervention(s): Fluorescence in situ hybridization study of the complete cohort of "zygotes" obtained at the third IVF attempt., Main Outcome Measure(s): Fluorescence in situ hybridization studies of chromosomes X, Y, 13, 18, and 21., Result(s): All the recovered putative zygotes were abnormal for the expected ploidy, presumably as a result of abnormal oocytes., Conclusion(s): Fluorescence in situ hybridization techniques represent a promising approach to analyze zygotes that fail to divide normally in vitro and eggs that fail to become fertilized. In cases of recurrent IVF failure, the results of FISH could be used to counsel couples and thus to help them choose among methods other than IVF for assisted reproduction.

At present, it is well accepted that maternal recognition of paternally derived fetal antigens occurs during normal pregnancy and may be beneficial for implantation and maintenance of gestation. Thus, we have investigated the compatibility of human leukocyte antigens (HLA) in couples with successive failed in-vitro fertilization (IVF) cycles. Study group 1 included 50 couples with prior primary infertility who had not achieved a pregnancy after > or = 3 (range 3-7, mean 3.7) IVF cycles where at least two embryos (mean 3.3, range 2-4) were transferred in each attempt. An infertile control group (group 2) included 50 infertile couples undergoing IVF with the same indications as couples in group 1, who achieved a viable pregnancy with their first IVF attempt. The results were compared with those found in a population sample including 100 men and 100 women from the local population (group 3). We found a statistically significant (P < 0.05) excess of HLA sharing (> or = 2 antigens) between partners in group 1 as compared to groups 2. There was a trend toward increased HLA sharing in group 1 when groups 1 and 3 were compared. We conclude that some cases of implantation failure after IVF and embryo transfer might be caused by underlying close histocompatibility between partners.

Zygotes morphologically classified as tripronuclear (3PN) after intracytoplasmic sperm injection (ICSI), which are thought to be digynic in their origin, were studied by fluorescent in-situ hybridization (FISH). FISH results allowed us to assess the suspected ploidy after morphological evaluation of the zygote and to determine the origin of the third pronuclei. Our results show that, firstly, 36% of those zygotes classified as 3PN following their morphological evaluation were, in fact, diploid, and secondly, the main cause for triploidy after ICSI is the non-extrusion of the second polar body.

We report a case of pituitary-ovarian suppression obtained with sequential danazol/leuprolide acetate administration in a patient undergoing in vitro fertilization and unresponsive to leuprolide acetate alone and sequential oral contraceptive-leuprolide acetate therapy. Leuprolide acetate (1 mg daily subcutaneously) was administered after 5 weeks of danazol treatment (800 mg daily) while the latter was maintained for 1 additional week. Ovarian activity was assessed by transvaginal ultrasonography and serum estradiol determination. After 5 weeks of danazol therapy, ovarian arrest was obtained despite the fact that gonadotropin serum levels did not change relative to basal values. Leuprolide acetate injection for 14 days was associated with a decrease in serum concentrations of follicle-stimulating hormone and luteinizing hormone and a further decrease of the estradiol level. We conclude that sequential danazol/leuprolide acetate therapy is a useful alternative for obtaining ovarian arrest in patients unresponsive to leuprolide acetate alone.

The use of pure follicle stimulating hormone (pFSH) and highly purified FSH (FSH-HP) versus the combinations pFSH/human menopausal gonadotrophin (HMG) and FSH HP/HMG, respectively, was compared for stimulating follicular development after gonadotrophin-releasing hormone agonist (GnRHa) suppression in women undergoing in vitro fertilization (IVF)-embryo transfer. Two consecutive prospective, randomized studies were carried out at the Assisted Reproduction Unit of the Hospital Clínic i Provincial in Barcelona, a tertiary care setting. Two groups of 188 (study 1) and 252 (study 2) consecutive infertile patients respectively, scheduled for IVF-embryo transfer were included. Pretreatment with leuprolide acetate (long protocol) was followed by gonadotrophin treatment in all patients. In study 1, 92 patients received i.m. pFSH alone (group pFSH) and 96 were treated with the combination of i.m. pFSH and i.m. HMG (group HMG-1). In study 2, 123 patients received s.c. FSH-HP alone (group FSH-HP) and 129 patients were given the combination of s.c. FSH-HP and i.m. HMG (group HMG-2). Main outcome measures included follicular development, oocyte retrieval, fertilized oocytes, duration and dose of gonadotrophin therapy, and clinical pregnancy. There were no significant differences between pFSH and pFSH/HMG nor between FSH-HP and FSH-HP/HMG cycles with regard to the number of ampoules of medication used, day of human chorionic gonadotrophin (HCG) administration, mean peak serum oestradiol concentrations, number of follicles punctured, and number of oocytes aspirated, embryos transferred, or pregnancies. We conclude that urinary FSH (either purified of highly purified) alone is as effective as the conventional combination of urinary FSH/HMG for ovarian stimulation under pituitary suppression in IVF cycles. Therefore, they can be used interchangeably in IVF programmes.

Objective: Our purpose was to determine the relative power of basal inhibin and follicle-stimulating hormone (defined before treatment) and the woman's age both as single and combined predictors of ovarian response in an in vitro fertilization program where pituitary desensitization was routinely used., Study Design: The study was a retrospective analytic investigation of 120 women undergoing the first cycle of in vitro fertilization. Forty consecutive cycles canceled because of poor follicular response were initially selected. As a control group, the nearest completed in vitro fertilization cycles before and after each canceled cycle (i.e., the closest cycles in temporal relationship to the index cycle) were used., Results: The mean age and basal follicle-stimulating hormone level were significantly higher in the canceled than in the control group, whereas the basal inhibin level was significantly higher in the latter. Follicle-stimulating hormone and inhibin alone, with an accuracy (predictive value of ovarian response) of 70%, were better predictors of cancellation than age was. Any two or all three of these variables studied did not improve the predictive value of follicle-stimulating hormone or inhibin alone., Conclusion: Age is a poorer predictor than pretreatment basal follicle-stimulating hormone and inhibin levels for ovarian response in in vitro fertilization cycles stimulated with gonadotropin-releasing hormone agonist-gonadotropin treatment. Basal follicle-stimulating hormone and inhibin have similar predictive properties and could therefore be used interchangeably.

To determine the effectiveness of in-vitro fertilization (IVF) and embryo transfer for patients with unexplained habitual abortion, we carried out a prospective observational study using a historical comparison group. A total of 12 couples with three or more (mean 4. 91, range 3-10 miscarriages) first trimester spontaneous abortions of unknown aetiology were treated with IVF and embryo transfer (group 1). Patients underwent IVF after combined gonadotrophin-releasing hormone agonist/gonadotrophin treatment for ovarian stimulation, and three to four embryos were replaced into the uterus in all women. Eight of the 12 women (66.6%) in group 1 became pregnant (one patient after a frozen-thawed embryo transfer), and all of them had viable pregnancies. A patient with 10 previous abortions became pregnant and carried to term after IVF and embryo transfer, and subsequently miscarried two new spontaneous gestations. A historical comparison group (group 2) included the last eight women with unexplained recurrent abortion (mean 4, range 3-8 miscarriages) who underwent the same investigations for the condition and received identical early supportive care in their next spontaneous pregnancy as patients in group 1. Three of the eight pregnancies in group 2 ended in an abortion. Our results suggest that IVF and embryo transfer may be a new therapeutic approach for unexplained recurrent miscarriage.

Objective: To determine the effectiveness of immunotherapy with high-dose IV immunoglobulin preceding IVF-ET for patients with repeated failure of ET., Design: Prospective, observational., Setting: Assisted Reproduction Unit of the Hospital Clínic i Provincial in Barcelona, a tertiary care setting., Patients: Twelve consecutive tubal infertility patients experiencing repeated unexplained IVF-ET failure including at least three ETs replacing three to four fresh embryos each. Two women shared three or more human leukocyte antigens (HLA) with the husband., Intervention: During the subsequent new IVF-ET cycle, each patient received 400 mg/kg IV immunoglobulin daily for 5 days during ovarian stimulation, that is, 5 to 7 days before ET., Main Outcome Measures: Clinical pregnancies., Results: No implantation occurred. There were no side effects., Conclusions: High-dose IV immunoglobulin is not a useful tool for IVF-ET failure.

The luteal phase of in vitro fertilization-embryo transfer (IVF-ET) cycles has come under great scrutiny as the cause for the discrepancy between fertilization rates (> 70%) and pregnancy rates (around 20%) in most IVF programs is sought. The effects of the various stimulation protocols on the subsequent hormonal events of the luteal phase are both important and controversial but information regarding cycles where ovarian stimulation has been carried out with gonadotropins under pituitary suppression is scanty. The effect of high levels of estrogen in the late follicular phase and around the time of implantation is a matter of concern. As combined gonadotropin-releasing hormone analog (GnRH-a) gonadotropin treatment for superovulation is associated with supraphysiological ovarian steroid levels, both in the follicular and luteal phase of IVF cycles, we compared preovulatory (estradiol), midluteal (estradiol, progesterone and prolactin) and late luteal (estradiol and progesterone) hormone levels in on-going pregnancies, abortions and non-conception cycles in 222 patients accomplishing their first IVF-ET attempt who received such ovarian stimulation therapy. For both successful and unsuccessful implantation cycles, estradiol on the day of human chorionic gonadotropin (hCG) administration correlated positively with progesterone and estradiol levels and negatively with the progesterone/estradiol ratio in the midluteal phase. Mean peak follicular estradiol, midluteal estradiol and progesterone levels, mean mid- and late luteal progesterone/estradiol ratio, and mean midluteal prolactin concentration, were similar in the three groups studied. The mean late luteal estradiol and progesterone in the on-going pregnancy group were significantly higher than in non-conception cycles (p < 0.005 and p < 0.001, respectively) as a reflection of trophoblastic hCG production. Forty-eight patients (21.6%) had hyperprolactinemia.(ABSTRACT TRUNCATED AT 250 WORDS)

Malignant struma ovarii is a very rare tumour, with considerable controversy concerning the necessary histologic features for malignancy. Still more infrequent is the condition termed 'metastatic ovarian strumosis' or simply 'benign strumosis or strumatosis' and characterized by the presence of peritoneal implants of mature thyroid tissue occurring in struma ovarii. 'Strumosis' should not be confused with malignancy. Presented is a case of 'metastatic ovarian strumosis' in a 36-year-old woman with primary infertility who underwent three in-vitro fertilization (IVF) cycles with ovarian stimulation. She received hormonal treatment for 6 months after her last IVF because of 'persistent enlarged ovarian follicles' which were in fact 'thyroid follicles'.

Spontaneous pregnancies associated with inadvertent periconceptional administration of a gonadotrophin-releasing hormone agonist (GnRHa) occur in approximately 1% of in-vitro fertilization (IVF) cycles. The two main issues to be considered in these circumstances are the luteolytic effect of the agonist and embryotoxicity. In addition, some authors have suggested a higher incidence of ectopic implantations. In view of these concerns, we report on 15 patients who conceived during pituitary desensitization with a GnRHa in the luteal phase of the menstrual cycle, and review the literature on the subject. A detailed analysis of the data available so far, which include 59 pregnancies exposed to GnRHa, shows that: (i) there is no clinical evidence for impaired luteal function, and hormonal supplementation does not improve pregnancy outcome; (ii) with only two cases of reported minor malformations among 37 deliveries, both having a genetic component, there is no evidence of teratogenic effects; and (iii) ectopic implantations in these circumstances are related to tubal disease but not to the drug. Considering the long history of infertility in these patients who had previously been treated unsuccessfully by different therapeutic modalities, it is likely that the occurrence of those pregnancies is not merely coincidental and that GnRHa might have a positive role in fecundity. The improved fecundity may be explained by the mechanisms of luteinizing hormone action in the corpus luteum.

Major histocompatibility differences between mother and fetus may facilitate implantation and maintenance of pregnancy. Thus, we have investigated the compatibility of HLAs in couples with three successive failed IVF-ET cycles. The study couples (n = 15) shared a statistically greater number of HLAs than IVF couples achieving a viable pregnancy with their first IVF-ET attempt (n = 15) and a control group of 100 fertile couples. No difference between fertile and infertile control couples was observed regarding HLA sharing. Thus, we conclude that some cases of unsuccessful ETs after IVF might be caused by underlying close histocompatibility between partners.

Objective: To compare two gonadotropin-releasing hormone agonists (GnRH-a), buserelin acetate and leuprolide acetate [LA], used in combination with gonadotropins in ovarian stimulation for in vitro fertilization (IVF)., Design: Randomized prospective study., Setting: Assisted Reproduction Unit of the Hospital Clínic i Provincial in Barcelona., Patients: Thirty-five pairs of IVF patients who were matched on age, indication, and number of attempts. These women were randomized to receive either buserelin acetate plus gonadotropins (group B) or LA plus gonadotropins (group L)., Main Outcome Measures: Luteolysis, ovarian response, and IVF outcome., Results: The mean time for total ovarian arrest and the total dose of gonadotropins and estradiol levels on the day of human chorionic gonadotropin administration were similar in the two groups of patients. The number of follicles punctured, the number of oocytes retrieved, and the percentage of mature oocytes in group L were significantly higher. The number of embryos suitable for replacement and cryopreservation was higher in group L compared with group B approaching statistical significance., Conclusion: Our results warrant further studies to compare different GnRH-a as therapeutic tools in IVF.

So far, the few studies performed on endometrial steroid receptors in in vitro fertilization (IVF) cycles have been carried out by the dextran-coated charcoal (DCC) method. Despite widespread efforts to standardize the DCC assay method, assay results still vary and thus, data obtained in IVF cycles are controversial. In the present article, late luteal estradiol (E2) and progesterone (P) receptor (R) levels were measured by a new monoclonal enzyme immunoassay (EIA) method in endometrial samples obtained from 21 patients in an IVF program who received no embryo transfer (ET) after ovarian stimulation with follicle-stimulating hormone/human menopausal gonadotrophin/human chorionic gonadotrophin under pituitary suppression with buserelin. Plasma levels of E2, P and prolactin (PRL) were measured in three blood samples collected in the midluteal phase. Results were compared with those obtained in a control group of 21 spontaneous cycles. E2, P and PRL were significantly higher in stimulated than in spontaneous cycles. The level of E2R was decreased in endometrium in IVF stimulated cycles, but PR remained unchanged.

A hormonal and histological study of the luteal phase was performed in 21 stimulated in-vitro fertilization (IVF) patients not undergoing embryo transfer. Ovarian stimulation was carried out with gonadotrophins [follicle stimulating hormone (FSH) + human menopausal gonadotrophin (HMG)] under pituitary suppression with buserelin. Ovulation was induced with 5000 IU human chorionic gonadotrophin (HCG) and additional doses of 5000, 2500 and 2500 IU were given on the day of follicular aspiration, and 2 and 5 days later respectively, to support the luteal phase. Supraphysiological levels of oestradiol (E2) and progesterone in plasma were found in the midluteal phase of all women, while prolactin was in the normal range. An endometrial biopsy taken in the late luteal phase was normal in 90.5% (19/21) of patients, most of them (15/19, 79%) having E2 greater than 1500 pg/ml on the day of HCG. Conversely, both patients with defective endometrial biopsies had E2 levels less than 1500 pg/ml.

We report a case of a twin pregnancy at term obtained after five multiple embryo transfers in a patient who presented diethylstilbestrol (DES)-associated cervical and uterine structural abnormalities, a septate uterus and bilateral tuberculous salpingitis. The suitability of in-vitro fertilization/embryo transfer in DES-exposed women is discussed.

We report a case of severe ovarian hyperstimulation syndrome which developed in a patient after ovarian stimulation for in-vitro fertilization (IVF). This was complicated by prerenal oliguria due to indomethacin therapy and liver dysfunction. The pathogenetic mechanisms involved are discussed.

The results of in vitro fertilization (IVF) with the husband's semen were compared in 3 groups of fully investigated infertile couples. In those with tubal infertility (n = 43) 194 out of 273 (71.1%) oocytes were fertilized, at least 1 oocyte being fertilized in 42 of the 43 couples (97%). In couples with unexplained infertility and a 'good' postcoital test (PCT) (n = 9), 39 out of 64 (61.5%) oocytes were fertilized in 8 of the 9 (88%) couples. In couples with unexplained infertility and a 'poor positive' PCT despite normal semen analysis, 16 out of 44 (36.3%) oocytes were fertilized in 5 of the 6 (83%) couples. These results show a good correlation between in vivo sperm penetration of cervical mucus and human IVF in couples with unexplained infertility.