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Background: Recently detorsion has replaced salpingo-oophorectomy as treatment for the twisted ischaemic adnexa. This paper asssess whether the ovary resumes normal function after preservation by detorsion., Methods: The results of detorsion performed between January 1988 and December 2001 were retrospectively analysed. Post-operative complications and subsequent ovarian function were assessed including: ultrasound monitoring of follicular development, adnexal appearance during subsequent surgery, and the outcome of IVF., Results: A total of 102 detorsions were performed; 67 by laparoscopy, 35 by laparotomy. No patient developed thromboembolism. Post-operative fever occurred in 15% of patients after laparoscopy and 29% after laparotomy (P < 0.01). Patients were hospitalized for a mean (+/- SD) of 2.1 +/- 1.2 and 7.4 +/- 1.5 days after laparoscopy and laparotomy respectively (P < 0.001). Ultrasound showed normal follicular development in 93 and 91% of patients after detorsion by laparoscopy and laparotomy respectively. At subsequent surgery, the adnexa appeared normal in nine out of nine patients after laparoscopy and in four out of five patients after laparotomy. Four patients of the laparoscopy group and two patients of the laparotomy group underwent subsequent IVF. In all six patients oocytes retrieved from the previously ischaemic ovary were fertilized., Conclusions: Detorsion with adnexal sparing is the treatment of choice for twisted ischaemic adnexa, and preferably performed by laparoscopy.

Background: We aimed to evaluate the effect of the levonorgestrel-releasing intrauterine system (LNG-IUS) on the uterine vasculature and the endometrium., Methods: The study was a prospective controlled study evaluating the local effects of LNG-IUS compared with the copper intrauterine device (IUD). Forty-seven women carrying LNG-IUS (group A) were compared with 35 women carrying copper IUD in a control group (group B). Clinical measures of menstrual bleeding, endometrial thickness and Doppler flow of the cervical branch of the uterine artery and spiral artery were evaluated and compared between the two groups., Results: Doppler flow in the cervical branch of the uterine artery did not reveal any changes between the groups (resistance index = 0.6 +/- 0.01 in both groups). Endometrial width was significantly thinner in group A (4.1 +/- 0.2 mm) compared with group B (7.3 +/- 0.2 mm) (P < 0.0001). Subendometrial flow in the spiral artery was significantly reduced in 35 women of group A (75%) and in none of group B (P < 0.0001)., Conclusions: The present study offers an explanation for the oligomenorrhoea in LNG-IUS users, i.e. a local progestational effect on the endometrium with no change in the blood flow in the uterine artery. This should be presented to the women in the pre-contraceptive counselling in order to lessen the discontinuation rate.

Background: We evaluated interactions between perinatal outcome after oocyte donation and various maternal factors., Methods: The study included 134 parturients after oocyte donation. Data were collected from medical files and personal interviews. Stepwise logistic regression analyses were used to evaluate associations between perinatal outcomes and selected maternal variables., Results: Fifty percent of the women were >43 years old, 30.6% were >45 years and 67.9% were nulliparous. The rates of pregnancy induced hypertension (PIH), gestational diabetes and first and second trimester vaginal bleeding (STB) were 27.6, 23.9, 43.3 and 6% respectively, while 72% had Caesarean deliveries. The rates of preterm (PD), low birth weight (LBW), small for gestational age (SGA) deliveries and major malformations were respectively 14.9, 14.9, 7.6 and 2.2%. Using a logistic regression, PD was significantly associated with PIH, STB and maternal smoking. LBW deliveries were significantly associated with PIH, STB, nulliparity and maternal smoking. SGA babies were significantly associated with PIH. These perinatal outcomes were not associated with advanced maternal age or ovarian failure., Conclusions: There is a high risk of obstetric complications in singleton oocyte donation pregnancies, but the perinatal outcomes are favourable. Patients should be counselled about these risks and monitored for these complications during pregnancy.

Background: Our objective was to evaluate the use of cervical suture in cervical pregnancy., Methods and Results: All cases of cervical pregnancy diagnosed and treated in the gynaecological department at the Sheba Medical Center between 1994-2000 were included in the study. Eight such cases were diagnosed. The first four cases were treated medically. The last four cases (the study group) of cervical pregnancy, including one case of heterotopic pregnancy, were treated successfully with placement of Shirodkar cerclage., Conclusion: Cervical cerclage may be considered as the treatment of choice in cases of cervical pregnancies. It may be the only therapy in cases of heterotopic pregnancies (intrauterine and cervical pregnancy).

Background: The aim of this study was to investigate a possible role for interleukin-6 (IL-6) and tumour necrosis factor (TNF-alpha) as pre-operative markers for the diagnosis of ovarian torsion., Methods: Twenty consecutive patients admitted to the gynaecological emergency room with suspected clinical diagnosis of ovarian torsion were prospectively assigned to the study. Blood samples were drawn pre-operatively and examined for serum concentrations of IL-6 and TNF-alpha. Surgeons were blinded to laboratory results prior to laparoscopy., Results: The pre-operative diagnosis of ovarian torsion was confirmed during an urgent diagnostic laparoscopy in 8 (40%) patients. The surgical diagnosis among the remaining 12 patients was a large ovarian cyst not in torsion. In six out of eight (75.0%) patients with ovarian torsion serum IL-6 concentrations were elevated. None of the 12 patients without torsion had elevated serum IL-6 concentrations. This difference was statistically significant (P < 0.001). There was no significant difference in the proportion of women with elevated serum TNF-alpha concentrations, two of eight (25.0%) patients with torsion and four of 12 (33.3%) control cases., Conclusions: Elevated serum IL-6 concentrations, but not serum TNF-alpha concentrations, were significantly associated with the occurrence of ovarian torsion. In patients with vague clinical signs of ovarian torsion, serum IL-6 might help to distinguish which patients should undergo diagnostic laparoscopy.

The aim of this prospective randomized study was to compare the effects of two gonadotrophin-releasing hormone (GnRH) agonists, buserelin and triptorelin, on human ovarian follicular steroidogenesis, oocyte fertilization and IVF treatment outcome. Ovulatory, healthy women undergoing IVF were treated either with human menopausal gonadotrophin (HMG) alone or with HMG and one of the two GnRH agonists. Serum and follicular fluid hormonal concentrations and cultures of luteinizing granulosa cells obtained during follicular aspiration were analysed. GnRH agonist treatment significantly affected steroidogenesis both in serum and follicular fluid. In follicular fluid, progesterone and oestradiol concentrations were significantly elevated while testosterone concentrations were significantly lower in the triptorelin group. The ratios of testosterone/progesterone, oestradiol/progesterone but not oestradiol/testosterone concentrations were significantly affected by GnRH agonist administration. Similarly, the steroidogenic activity of luteinizing granulosa cells in vitro was significantly decreased in women treated with GnRH agonists. Women treated with GnRH agonists had significantly more fertilized oocytes and cleaving embryos. The results indicate a marked effect of GnRH agonists on the pattern of ovarian follicular steroidogenesis that cannot be explained solely by changes in gonadotrophin concentrations.

Follicular fluid (FF) induces sperm chemotaxis in human spermatozoa. Progesterone also causes sperm accumulation. However, sperm accumulation can be caused by chemotaxis, chemokinesis, and trapping of various kinds. It has been suggested that progesterone also induces chemotaxis in human spermatozoa. In view of the physiological significance of sperm chemotaxis in human fertilization and its potential clinical implications, it is important to determine unequivocally whether chemotaxis is induced by progesterone and, if so, whether progesterone in FF is the chemoattractant. To resolve these questions we looked for characteristic changes in the direction of sperm swimming toward pure progesterone as well as toward FF before and after progesterone removal. Progesterone caused sperm accumulation and hyperactivation-like motility, but it caused very few changes in the direction of sperm swimming that are characteristic of chemotaxis. Removal of progesterone (and other steroids) from FF by charcoal treatment abolished the sperm hyperactivation-like motility but not sperm chemotaxis. These results suggest that while progesterone might be a weak chemoattractant, it is not the major chemoattractant in FF. Progesterone probably causes human sperm accumulation mainly by inducing hyperactivation-like motility and, as a consequence, sperm trapping.

A retrospective analysis in 50 couples of 53 cycles of intracytoplasmic sperm injection (ICSI) with immotile spermatozoa from testicular-retrieved spermatozoa was performed to evaluate whether total immotile spermatozoa achieved after testicular sperm extraction could fertilize ova and result in pregnancies. We assessed the efficacy of ICSI with totally immotile testicular spermatozoa extracted from the testes of azoospermic patients with severe spermatogenic failure (group 1) and compared these results with those from spermatozoa which were recovered after several hours of incubation and were motile (group 2) at the time of injection. In 19 cycles, only totally immotile spermatozoa were injected at the time of ICSI. For the remaining 34 cycles, at least one motile spermatozoon was found for injection. The oocyte fertilization rates were 51% for group 1 and 62% for group 2 (P < 0.02). Eighteen of 19 cycles in group 1 (90%) and all 34 (100%) cycles in group 2 had embryos for replacement. The mean number of embryos per cycle was 5.2 +/- 0.8 and 7.5 +/- 0.9 in groups 1 and 2 respectively; this and the embryo quality (cumulative embryo scoring = 40 +/- 8 for group 1 and 50 +/- 7 for group 2), and clinical pregnancy rates (15.8% per oocyte retrieval in group 1 and 23.5% in group 2) were not significantly different between groups. Fertilization, cleavage and pregnancy can be achieved with intracytoplasmic testicular sperm injection from patients with immotile spermatozoa, at levels comparable with those of ICSI using motile spermatozoa.

In-utero assessment of the internal female genitalia is important for determination of fetal gender in fetuses with suspected genital tract anomalies. We therefore measured fetal uterine transverse width and circumference from 19 weeks of gestation until term, using transvaginal and transabdominal high-resolution ultrasound techniques in order to establish nomograms. A prospective, cross-sectional study on 180 normal singleton pregnancies was performed. Data were obtained for 140 normal fetuses. The mean +/- SD uterine width and circumference were 12.9 +/- 4.1 mm (95% confidence interval 12.1-13.7), and 40.2 +/- 12.5 mm (95% confidence interval 37.9-42.5) respectively. Uterine size as a function of gestational age was expressed by the regression equations: uterine width (mm) = 12.9 + 0.7 x gestational age (weeks), and uterine circumference (mm) = 40.2 + 2.1 x gestational age. The correlation coefficients, r = 0.885 and r = 0.888, for uterine width and circumference, by gestational age respectively, were highly statistically significant (P < 0.001). A nomogram of uterine width and circumference per gestational week, and the 95% prediction limits were defined. The present data offer baseline measurements of the fetal uterus that may allow intrauterine assessment of the female genital tract and associated fetal gender.

Due to a paucity of donated eggs, we have excluded, until recently, couples with severe male factor infertility from our egg donation programme, except for those who accepted insemination with donor spermatozoa. The purpose of this study was to assess the feasibility of a shared in-vitro fertilization (IVF)-embryo transfer treatment whenever the recipients have severe oligoasthenoteratozoospermia (OTA) and need intracytoplasmic sperm injection (ICSI) for egg fertilization. The results from 163 consecutive couples with ovarian failure who underwent 273 cycles of IVF with donated eggs and augmented with ICSI were analysed. The rate of diploid fertilization was 54.7%; in 92.3% of the cycles, at least one embryo was available for transfer. Forty-seven clinical pregnancies were achieved, representing 18.6% conceptions per transfer. The highest pregnancy rate was achieved in menopausal patients aged 40-45 years (26.2% per cycle) and the lowest in patients >45 years old (10.8% per cycle, P = 0.03). Overall, 28.8% of the couples achieved a clinical pregnancy. A total of 196 treatment cycles resulted in 46 clinical pregnancies (23.5%) among the donors. No statistical differences were found in pregnancy rate achieved by the donors when compared with the recipients. We conclude that ICSI with egg donation is a reliable treatment in patients with ovarian failure and severe OTA.

Among 2,496 infertile Israeli women treated between 1964 and 1974, 143 cancer cases were observed as compared with 116.1 expected (standardized incidence ratio (SIR) = 1.2, 95% confidence interval (CI) 1.0-1.5) through 1991. Site-specific analysis revealed 12 ovarian cancers versus 7.2 expected (SIR = 1.6, 95% CI 0.8-2.9), 21 endometrial cancers versus 4.3 expected (SIR = 4.85, 95% CI 3.0-7.4), and 59 breast cancers versus 46.6 expected (SIR = 1.3, 95% CI 0.96-1.6). Sensitivity analysis revealed that confounding was unlikely to explain the raised risk of endometrial cancer, but nulliparity might explain the increased risk of ovarian cancer. The excess of endometrial cancer was prominent among patients with normal estrogen production but progesterone deficiency (SIR = 9.4, 95% CI 5.0-16.0). The risk for ovarian cancer was similar among the total groups of treated and untreated patients (SIR = 1.7 vs. 1.6). The standardized incidence ratio for endometrial cancer was higher among the treated group than the untreated group, although not significantly. Treatment with ovulation-inducing drugs does not appear to increase the risk for ovarian cancer, but its role cannot be completely excluded.

Rather than investigate whether paternal leukocyte immunization improves the live birth rate in women with three or more abortions, we analysed the results of patients expected to have a poor outcome in a subsequent pregnancy if untreated, i.e. women with five or more abortions and no anti-paternal complement-dependent antibody (APCA) at initial testing. The analysis included the results of patients treated by us over the last 8 years and the results of randomized and non-randomized trials reported by the Recurrent Miscarriage Immunotherapy Trialists Group. Patients with a previous live birth were classified into two groups: secondary aborters if there was an initial live birth followed by miscarriages, or tertiary aborters if there were miscarriages followed by a live birth and at least three subsequent miscarriages. The results were evaluated separately for primary, secondary and tertiary aborters who demonstrated APCA activity as a result of immunization. The 107 primary aborters had double the live birth rate if immunized, with an overall benefit of 31%. The 45 tertiary aborters had an almost 3-fold increase in the live birth rate, with an absolute benefit of 50%. The number of patients needed to treat to achieve one extra live birth was three to four primary aborters or two tertiary aborters. Immunization had little beneficial effect in secondary aborters but was effective in preventing abortion in primary or tertiary aborters with five or more abortions.

The study was conducted to examine the efficacy of the zona drilling technique for promotion of successful implantation and pregnancy by assisting embryo hatching in women of advanced age undergoing treatment by in-vitro fertilization. A total of 839 embryos from 211 patients aged >38 years underwent assisted hatching during 312 cycles of therapy. The outcome of this micromanipulation procedure was compared to 540 non-hatched pre-embryos transferred to 174 patients during 274 cycles of therapy. Assisted hatching was performed on four- to eight-cell stage embryos using the zona drilling technique. In the assisted hatching group, 839 micromanipulated embryos were replaced (two to four embryos per patient) compared to 540 embryos transferred in the control group. Despite the fact that the pregnancy rate was not statistically different between the groups (8.9% in the assisted hatching group versus 5.1% in the controls) a trend towards an increase was noted in the assisted hatching group. The implantation rate was 3.75 and 3.55% per patient respectively, and there was no significant difference in abortion rate between the groups. The delivery rate was 3.8 and 3.4% per cycle respectively. The results of this study demonstrated that assisted hatching by zona drilling in a selected group of patients aged >38 years does not increase the take-home baby rate after in-vitro fertilization treatment.

In all, 58 couples suffering from infertility because of congenital bilateral absence of the vas deferens underwent a total of 67 combined microsurgical epididymal aspiration or testicular sperm extraction (TESE) and in-vitro fertilization (IVF) treatments. The oocytes recovered were inseminated by either the microdroplet IVF technique (N = 20), subzonal insemination (SUZI; n = 10) or intracytoplasmic sperm injection (ICSI; n = 37). Of the ICSI cycles, 12 were performed using spermatozoa obtained by TESE. Fertilization rates for epididymal spermatozoa were significantly higher for SUZI (17.9%, 17/95) and ICSI (34.4%), 137/398) than for microdroplet IVF (5.2%, 18/343) cycles. The proportion of cycles in which fertilization was achieved was higher in the SUZI (80%) and ICSI (95%) cycles than in the IVF cycles (45%). Delivery or an ongoing pregnancy was achieved in one (5%) IVF cycle, two (20%) SUZI cycles and seven (18.95) ICSI cycles. SUZI or ICSI using epididymal or testicular spermatozoa significantly improved the oocyte fertility rate. The ICSI procedure was especially advantageous in patients for whom spermatozoa were obtained from a testicular biopsy.

Ovarian hyperstimulation syndrome in a spontaneous singleton pregnancy is exceedingly rare. We report a case of ovarian hyperstimulation presenting as bilateral ovarian masses in association with spontaneous pregnancy, occurring in a woman with disturbed liver function. A possible mechanism is discussed.

During the years 1984-1992, 951 couples completed 2252 in-vitro fertilization (IVF) treatment cycles at the In-Vitro Fertilization Unit of The Chaim Sheba Medical Centre. This study was conducted to evaluate the success of IVF using the cumulative pregnancy rate (CPR), with special emphasis on the optimal number of treatment cycles, the age of the patients and female infertility factors. It was found that the CPR showed a constant rise during the six initial IVF treatments (56% CPR), and plateaued in the subsequent three cycles (63% CPR). Various female infertility factors did not influence this rate. Women > or = 40 years of age have a significantly lower CPR. Thus, it was concluded that the CPR in IVF declined after the sixth initial treatment cycle, and in women > or = 40 years of age. The infertility factor did not significantly influence CPR.

The objective of this study was to assess the temporal relationships of serum oestradiol and luteinizing hormone (LH) with regard to the feedback mechanism leading to the LH surge. Daily measurements of oestradiol, LH and follicle stimulating hormone were made in 65 women with ovarian failure undergoing an evaluation of endometrial response to oral cycle stimulation. Patients received incremental oral oestradiol valerate for varying durations at the in-vitro fertilization unit of the Sheba Medical Center, Tel Hashomer, Israel. The treatment protocol involved the administration of daily oestradiol valerate, starting with 1 mg/day, followed by a daily increment of 1 mg for a total of 4, 6 and 8 days. After the last day, a daily maintenance dose of 2 mg was continued. Serum oestradiol concentrations correlated with the dose of oral oestradiol valerate. Peak oestradiol concentrations (mean +/- SEM) were 572 +/- 60, 721 +/- 42 and 797 +/- 53 pg/ml for 4, 6 and 8 days of oestradiol valerate administration respectively. Serum LH, after an initial suppression, peaked 2 days after maximal oestradiol valerate dose and 1 day after peak serum oestradiol. The magnitude of the LH peak was proportional to the duration of incremental oestradiol valerate treatment. In conclusion, the LH surge is temporally related to the cessation of serum oestradiol increase. Consequently, the occurrence of this surge can be explained by a simple negative feedback inhibition of pituitary LH release rather than by a dual negative/positive mechanism.

The reproductive outcome of women with repeated abortions or infertility was assessed following treatment by operative hysteroscopy for an intrauterine septum or adhesions. A prospective follow-up study (mean +/- SD, 21.1 +/- 10.3 months) of 47 patients with an intrauterine septum (36 suffering from infertility and 11 from recurrent abortions) and 36 patients with intrauterine adhesions (24 complaining of infertility and 12 of recurrent abortions) was performed. The pregnancy rate in infertile women following hysteroscopic resection of an intrauterine septum or adhesions was 53 and 48% respectively. The pregnancy wastage in women with recurrent abortions who underwent hysteroscopic resection of an intrauterine septum or adhesions decreased postoperatively from 87.5 to 44.4% and from 86.5 to 42.8% respectively. Our results suggest that hysteroscopic resection of an intrauterine septum or adhesions may benefit patients suffering from infertility or recurrent pregnancy wastage.

A prospective study was carried out on 153 couples with recurrent abortions who desired pregnancy. The object was to determine the incidence of raised luteinizing hormone (LH) levels; to compare the outcome of further pregnancies in habitually aborting women with and without raised circulating LH concentrations; and to assess whether the efficacy of paternal leukocyte immunization is affected in the presence of raised LH concentrations. Of the 153 women with recurrent abortions (> 3) included in this study, 56 (36.6%) had follicular phase serum LH concentrations > 10 mIU/ml. Of the 103 pregnancies that were followed prospectively, 65 (63.1%) resulted in a birth of a live infant. There was no significant relationship between the pregnancy outcome and LH concentrations. Women who underwent immunization with paternal leukocytes had significantly more live births (75.8%) than those who were not immunized (43.6%). However, the live birth rate was lower after paternal leukocyte immunization in the presence of raised LH concentrations or a raised LH/follicle stimulating hormone (FSH) ratio.

The objective of the study was to assess the effect of growth hormone (GH) supplementation to a combined gonadotrophin-releasing hormone agonist/human menopausal gonadotrophin (GnRHa/HMG) treatment protocol on ovarian response in 'poor responders' undergoing in-vitro fertilization (IVF). GH or a placebo were administered in a prospective randomized double-blind manner. A total of 14 poor-responder patients (oestradiol < 500 pg/ml, less than three oocytes retrieved in two previous IVF cycles) were randomly allocated to a combined treatment of either GnRHa/HMG/GH (18 IU on alternate days, total dose 72 IU) or GnRHa/HMG placebo. No difference was found between the study and control groups in the number of HMG ampoules used, the number of follicles (> 14 mm) and serum oestradiol concentrations on the day of administration of human chorionic gonadotrophin (HCG), the number of oocytes retrieved and fertilized, and the number of embryos transferred. The GH group (n = 7) did not show a better ovulatory response in the study cycles; mean +/- SD serum oestradiol on day of HCG 411 +/- 124 versus 493 +/- 291 pg/ml, aspirated oocytes 2.2 +/- 1.5 versus 1.9 +/- 2.0. Interestingly, when the above results for the placebo group were compared with their previous cycles (serum oestradiol 403 +/- 231 pg/ml; 0.4 +/- 0.5 aspirated oocytes), a non-specific effect was found. Follicular recruitment, oestradiol secretion by mature follicles and the number of oocytes retrieved in poor responders were not improved by GH supplementation.

This study was undertaken to report the results of microsurgical lysis of peri-adnexal adhesions and identify the patients who should be offered surgery and those who should be treated by in-vitro fertilization (IVF). In all, 19 women had filmy adhesions and 32 had dense adhesions; 68.4% of women with filmy adhesions conceived compared with 34.4% of women with dense adhesions (P = 0.02). In patients with filmy adhesions, the cumulative pregnancy rate 2 years after operation (47%) is similar to that reported after five cycles of IVF (52%), leading us to conclude that such patients should be offered surgery first. Dense adhesions are best treated by IVF. Lysis of filmy adhesions produces a similar intra-uterine pregnancy rate whether performed by laparotomy (57.9%) or laparoscopy (56.6%). As operative laparoscopy offers the greatest patient comfort, it is the treatment of choice in these patients.

We present a rare case in which therapy of primary ovarian pregnancy, using laparoscopic laser surgery (videolaseroscopy), was successfully performed without the need of laparotomy. Because operative laparoscopy has the benefits of reduced morbidity, reduced hospitalization and rapid recovery, and because it has the advantage of reducing postoperative adhesions as compared to laparotomy, it is the preferable technique for treatment of ovarian gestation after a laparoscopic diagnosis, especially for a woman who desires to preserve her fertility potential.

Recent studies have indicated that human spermatozoa respond to follicular fluid by attraction to chemotactic factor(s) in the fluid, accompanied by enhancement of motility and ultimately hyperactivation. In this study, we quantified the sperm response. We exposed spermatozoa to a gradient of a chemotactically active fraction of follicular fluid (denoted as "the attractant") and separated the spermatozoa that accumulated in the attractant and those that did not. We thus obtained two subpopulations: one enriched with chemotactically responsive spermatozoa, and one deficient in such spermatozoa. The fraction of the responsive spermatozoa out of the total sperm population was 2-12% at any measured time point. With time, the responsive spermatozoa lost their ability to be attracted, while such activity was gradually acquired by the subpopulation originally deficient in responsive spermatozoa. These results indicate that the identity of responsive spermatozoa is continuously changing. If the in vitro results are representative of the physiological conditions in vivo, they imply that the role of sperm chemotaxis combined with enhanced motility may be to select capacitated spermatozoa and bring them to the egg. Such a mechanism may, over an extended period of time, increase the prospect that an egg will meet capacitated spermatozoa as soon as it ovulates.

Human spermatozoa accumulate in vitro in diluted follicular fluids obtained from follicles from which the eggs have been fertilized. Using capillary assays under a variety of experimental conditions (ascending or descending gradients of follicular fluid, or no gradient at all) and microscopic assays in which individual spermatozoa could be followed, we found that the sperm accumulation in follicular fluid was the result of both sperm chemotaxis and chemokinesis and eventually hyperactivation-like motility. We determined the optimal conditions for sperm accumulation, which involved sperm preincubation (possibly to induce sperm capacitation) and proper dilution of follicular fluid. In all the assays, the net accumulation was low, probably reflecting the chemotactic responsiveness of only a small fraction of the sperm population at any given time. We partially fractionated follicular fluid in a Centricon microconcentrator (Amicon, Danvers, MA) and by acetone precipitation, and found that at least one of the chemotactic factors is a small (< 10-kDa) molecule that is probably nonhydrophobic. This is the first time that sperm chemotaxis and chemokinesis in response to a follicular factor(s) in mammals has been established and has been distinguished from other processes that might cause sperm accumulation. The physiological significance of these findings is discussed.

Between January 1984 and August 1991, 511 cases of extrauterine pregnancies were diagnosed by laparoscopy in our department. In 374 cases salpingectomy was performed: 184 by explorative laparotomy, and 190 by operative laparoscopy. Patients were scheduled for salpingectomy if one or more of the following criteria were fulfilled: (i) a ruptured tube which was surgically unsuitable for conservation; (ii) no interest in future fertility; (iii) tubes with ectopic gestation previously operated on; (iv) a previous tubal pregnancy on the same side, which was treated expectantly. Salpingectomy was performed via operative laparoscopy with bipolar diathermy forceps and laparoscopic scissors. Pregnancy rates, i.e. intra-uterine and repeat extra-uterine, were evaluated. The reproductive performance following salpingectomy did not differ significantly, whether by laparotomy or laparoscopy: the intra-uterine pregnancy rate was 78 and 64%, respectively and the repeat ectopic pregnancy rate was 12 and 6%, respectively. Salpingectomy via laparoscopy can be performed safely with a low incidence of complications, with subsequent reproductive performance comparable to laparotomy.

Reports of successful treatment of ectopic pregnancies by administration of methotrexate have recently attracted a great deal of attention. This review summarizes the results of therapy with methotrexate in tubal pregnancy. Different technical approaches and pharmacological doses have been reported. These methods, however, present various problems, including the occurrence of toxicity, long therapeutic periods and treatment failure. With proper selection of patients, a success rate of approximately 90% has been achieved. Preliminary assessment of subsequent fertility provides promising results. However, the majority of the reports do not include controls.

Our objective was to describe the characteristics of pregnancies, deliveries and children at birth following in-vitro fertilization (IVF) and related technologies in Israel, from 1982 to 1989. A national survey with collaboration from all IVF units in the public hospitals was designed and data were collected on individual patients. Comparison of results was made with data from a national delivery census and from other national IVF registries. During the period covering this survey, 1149 deliveries resulted in 1475 newborns; 98% of deliveries occurred following conventional IVF and embryo transfer (IVF-ET), 2% after in-vivo fertilization and gamete intra-Fallopian transfer. Following IVF-ET, 23% of the pregnant women were hospitalized due to a complication of pregnancy and 47.3% of the deliveries were by Caesarean section (41% if multiple births are omitted). The male to female birth ratio was 1.07:1.0; 23.6% of the deliveries were multiple births, 28.6% of deliveries were pre-term and the median length of gestation decreased with multiple births. At delivery, 23.8% of newborns weighed less than 2500 g. The incidence of low birthweight newborns was significantly higher in multiple births. The ratio of perinatal mortality (22.8/1000), double the incidence found in a national census (13/1000), increased dramatically with multiple births (12.7, 24.5 and 75.8/1000 for singleton, twins and triplets respectively). The incidence of a major congenital malformation was 2.2%, no higher than in the general population. A survey of published national IVF registries from Australia and New Zealand, Great Britain, USA and France showed much similarity in all aspects of pregnancy outcome following IVF and related technologies.(ABSTRACT TRUNCATED AT 250 WORDS)

Local regulation of insulin-like growth factor binding protein-1 (IGFBP-1) production in the human ovarian follicle was investigated using cultured human granulosa-luteal cells. Both insulin-like growth factor-I (IGF-I) and follicle-stimulating hormone (FSH) exerted a dual effect on granulosa cells: while estradiol (E2) production was increased by both stimulants, the addition of either of the two hormones led to a reduction in IGFBP-1 secretion by more than 50%. Inhibition of IGFBP-1 production in response to IGF-I was dose-dependent,with the highest effect observed at 5 nM IGF-I. A significant correlation was found between the increase in E2 and inhibition of IGFBP-1 secretion in response to IGF-I. These observations may suggest a novel mechanism, at the follicular level, by which FSH and IGF-I amplify the IGF-I effect in the ovarian follicular cells.

Insulin-like growth factor-I (IGF-I) stimulates growth and differentiation in follicular granulosa cells (GC). To examine whether this effect is prerequisite to human folliculogenesis, a patient with Laron-type dwarfism (IGF-I deficiency secondary to GH receptor abnormality) was examined while undergoing in vitro fertilization treatment. Despite low levels of IGF-I in serum and follicular fluid (less than 3 and less than 2 nmol/L) and very high levels of IGF-I-binding protein, the patient developed normal ovarian follicles. After the administration of GnRH analog (GnRHa) and human menopausal gonadotropin in a dose similar to that used in normovulatory women, estradiol (E2) levels reached above 5000 pmol/L on the day of hCG administration, and mature fertilizable oocytes were retrieved during ovum pickup. The patient's GC E2 production, tested in a primary culture, did not respond to IGF-I after 4 days of incubation, while control cultures showed a significant increase. Only after a priming period of 7 days did IGF-I have a significant effect on E2 production, as observed in the patient's GC culture. This delayed response suggests that the patient's GC were not exposed in vivo to IGF-I. Our data support the view that IGF-I is not required for normal follicular development, but is, rather, a nonessential modulator of FSH action.

A patient who suffered from polycystic ovarian disease and anovulation, was treated with pure follicle stimulating hormone for induction of ovulation. The treatment was stopped and human chorionic gonadotrophin was not administered because of high serum oestradiol levels and multiple follicular development. Ovulation occurred 11 days after pure follicle stimulating hormone was discontinued, the patient developed third-degree ovarian hyperstimulation syndrome and conceived with a quintuplet pregnancy.

Ovarian hyperstimulation syndrome is a common and serious complication of human menopausal gonadotrophin/human chorionic gonadotrophin treatment. We evaluated the changes in the pituitary and ovarian hormone profiles and ultrasonographic follicular regression in 12 patients in whom human menopausal gonadotrophin was discontinued due to 'imminent' ovarian hyperstimulation. Following discontinuation, three distinct periods were observed: (i) days 1-2, the levels of oestradiol, testosterone and prolactin, and the total number of follicles continued to rise; (ii) days 3-6, the levels of oestradiol, testosterone and prolactin declined sharply and the total number of follicles was reduced significantly, while the large and medium sized follicles continued to increase. Levels of follicle-stimulating hormone and luteinizing hormone gradually declined to reach their lowest levels by days 5-6 and then increased. (iii) Thereafter the number of follicles and steroid output declined to early follicular phase levels. We conclude that discontinuation of human menopausal gonadotrophin and withholding human chorionic gonadotrophin in cycles with laboratory signs of 'imminent' ovarian hyperstimulation syndrome, allows regression of the ovarian ultrasonographic finding and prevents the development of clinical symptoms. However, if rescue of the cycle is attempted, human chorionic gonadotrophin should be given during the first 4 days after discontinuation of stimulation.

It has recently been claimed that growth hormone (GH) and insulin-like growth factors have a role in follicular development; different mechanisms of action have been proposed. Of late, many investigators have been led by these findings to use GH and growth hormone-releasing hormone (GHRH) for induction of ovulation, in combination with human menopausal gonadotrophins. It is, however, still doubtful whether or not growth hormones and/or insulin-like growth factors are mandatory for follicular development and fertility. In this study we describe two women with Laron-type dwarfism who lacked insulin-like growth factors and who had spontaneous pregnancies. We also discuss different natural defects in the production and metabolism of growth hormone and insulin-like growth factors in humans, and the fertility performance of the affected females. It is our assumption that GH and systemic insulin-like growth factors may modulate follicular development, but that they are not necessarily mandatory for ovarian follicular development.

This study investigated the influence of cigarette smoking on the outcome of in-vitro fertilization-embryo transfer. Forty-one women under the age of 37 years, suffering from mechanical infertility, were suppressed with gonadotrophin releasing analogue from day 21 of the cycle. Twenty women were smokers and 21 women were non-smokers. Gonadotrophin releasing analogue was injected daily before ovarian stimulation with gonadotrophin was begun. The follicular phase was longer and the number of human menopausal gonadotrophin ampoules required to reach adequate stimulation were higher in smokers. The peak serum oestradiol level was not significantly different in smokers compared to non-smokers. However, follicular fluid levels of oestradiol were significantly lower in smokers than in non-smokers (657 +/- 367 versus 1077 +/- 786 ng/ml) respectively. Furthermore, the fertilization rate was also lower in smokers than in non-smokers (40.9 versus 61.7%) respectively. Four pregnancies were achieved in the non-smokers group, while only one ectopic pregnancy was diagnosed in the smokers group. These findings suggest that cigarette smoking has a detrimental effect on the outcome of in-vitro fertilization and embryo transfer.

Steroid synthesis in luteal/granulosa cells harvested after follicular aspiration in a patient with 17 alpha-hydroxylase deficiency was investigated. Follicular stimulation with purified FSH after the suppression of ACTH and gonadotropin secretion by corticoid analogs and superactive GnRH agonist permitted ovum pick-up and the study of steroid synthesis in the obtained granulosa cells. Progesterone synthesis was elevated while 17 alpha-hydroxy progesterone, testosterone, androstenedione, and estrogen production was minimal. Aromatase activity was retained in these cells, as demonstrated by the 100-fold increase in estrogen levels after the addition of androgens. Progesterone levels in follicular fluids were in the normal range, while estrogen, 17 alpha-hydroxy progesterone, and androgen levels were minimal. These results provide in vitro evidence of 17 alpha-hydroxylase deficiency in the granulosa cells of this patient.

Sixteen patients with polycystic ovarian syndrome (PCO) were treated by in-vitro fertilization (26 treatment cycles). The results were compared with 37 normo-ovulatory women with tubal disease (37 treatment cycles). The oestradiol and progesterone levels were higher during the follicular phase in the PCO patients, but were statistically significantly higher only on the day after human chorionic gonadotrophin administration. Although more oocytes were recovered per cycle from the PCO group (19.3 +/- 6.1) than from the control group (5.4 +/- 2.9) with P less than 0.004, the mean numbers of embryos per cycle were similar in both groups (3.7 +/- 2.4 versus 3.6 +/- 2.2, respectively). The pregnancy rate was also comparable in both groups (30.7 versus 29.7%, respectively). The fact that more oocytes are recovered from PCO patients, balances their lower fertilization and cleavage rates. We conclude, therefore, that IVF treatment may be a viable solution for PCO patients resistant to an in-vivo protocol treatment regimes.

The effect of bovine corneal extracellular matrix (ECM) on gonadotropin-primed rat granulosa cells in vitro was studied by examining the following parameters: 1) rate of cell attachment to culture dishes; 2) modulation of cell morphology; 3) specific binding of [125I]human(h)CG to LH/hCG receptors; 4) cAMP response to hCG stimulation; and 5) basal and hCG stimulated progesterone production. Attachment of cells to culture dishes occurred significantly earlier on ECM, as compared with uncoated dishes (6 h vs. 24 h). Cells grown on ECM were epitheloid and organized in multilayer aggregates, closely resembling their organization in the intact wall of the ovarian follicle. In contrast, cultures on uncoated dishes grew as a monolayer of markedly flattened cells. A 2-fold increase in number of LH/hCG receptors occurred on ECM within 48 h, probably due to de novo synthesis. Scatchard analysis revealed no change in hormone affinity to the receptor during the culture period [association constant (Ka) = 2.5 X 10(10)M-1 for hCG]. Cells grown on ECM had a parallel increase in cAMP responsiveness to hCG stimulation. Cells grown in serum-free medium on ECM-coated dishes preserved only 50% of LH/hCG receptors and cAMP responsiveness after 48 h. Cells cultured on ECM showed a marked elevation in progesterone production even in the absence of gonadotropin stimulation, whereas cells grown on uncoated dishes almost completely lost their ability to produce progesterone both in the presence and absence of hCG. These results indicate that ECM plays a substantial role in the maintenance and further propagation of granulosa cell differentiation in vitro.

Congenital adrenal hyperplasia due to 17 alpha-hydroxylase deficiency in genotypic females is characterized by primary amenorrhea and the absence of sexual maturation due to inadequate biosynthesis of ovarian androgens and estrogens. We induced ovarian follicular development in a woman with this syndrome. Ovum pick-up, in vitro fertilization, and primary embryonic development were achieved despite undetectable plasma estradiol and extremely low ovarian androgen concentrations and minute concentrations of these hormones in the ovarian follicular fluid.

Determination of fetal lung maturity by measurement of the fluorescence polarization (P) value of the amniotic fluid at room temperature has become the method of choice in an increasing number of perinatal units because of its simplicity and relatively high predictive value. Nevertheless, its power to discriminate between cases with and without hyaline membrane disease (HMD) needs improvement. To this end, we assessed the discriminative power of the P value at the physiological temperature of 37 degrees C (P37) as compared with the power at 25 degrees C (P25). The study group consisted of 288 consecutive cases at risk for preterm delivery. Samples from all 288 cases were measured at 25 degrees C and samples from 112 of these were measured concurrently at 37 degrees C as well. HMD occurred in 27 infants of the total group, nine of whom belonged to the subgroup tested at both temperatures. When sensitivity was fixed at 100% the specificity of P37 was 97% as compared to 79% for P25 (p less than 0.001). The percentage of cases with infants free of HMD who had borderline P values was also significantly smaller: 1% vs 21%, respectively (p less than 0.001). Although data on more HMD cases are needed to establish the precise threshold of lung maturity for P37, we conclude that P37 is a considerably better discriminator for fetal lung maturity determination than P25.

Daily plasma beta-HCG levels from days 11 to 18 after ovum retrieval (OR) were evaluated in a group of 73 women who became pregnant following in-vitro fertilization and embryo replacement (IVF-ER). The 47 patients who had a normal ongoing pregnancy could be distinguished from the 26 patients with a pathological pregnancy (pre-clinical abortion, clinical abortion and tubal pregnancy) by the mean daily beta-HCG levels, their mean daily increase and the intercept and slope of the beta-HCG regression analysis. The mean daily beta-HCG levels of the normal pregnancies were significantly higher than: (i) pre-clinical abortions on days 12-18 after OR; (ii) clinical abortions on days 12-16; and (iii) tubal pregnancies on days 12-17. Using quadratic discriminant analysis, normal and pathological pregnancies could also be distinguished by their absolute beta-HCG levels on day 13 after OR with 27.6 mIU/ml being the cut-off point. Our results indicate that the outcome of pregnancy following IVF-ER could be predicted with a high degree of probability by monitoring daily beta-HCG levels within the first 2 weeks following OR.

Pituitary reactivity to GnRH, characteristic of polycystic ovarian disease (PCOD), has been attributed both to a primary ovarian cause and to hypothalamic-pituitary dysfunction. If the heightened pituitary reactivity characteristic of PCOD patients is secondary to chronic anovulation, ovulatory cycles should produce changes in the LH to FSH ratio and reduce the augmented response to GnRH. In a randomized cross-over study of 10 women with PCOD, GnRH (100 micrograms) was injected iv on the fifth day of 2 consecutive cycles, 1 of them following anovulation and progesterone withdrawal bleeding and the other following an induced ovulatory cycle. Mean basal plasma 17 beta-estradiol, progesterone, and FSH levels were similar after ovulatory and anovulatory cycles. However, mean basal serum testosterone (P less than 0.05) and LH (P less than 0.01) levels were significantly lower, as were LH levels 30, 60, and 90 min (P less than 0.01) and FSH levels 60 and 90 min (P less than 0.05) after GnRH injection, after an ovulatory cycle than after an anovulatory cycle. The pituitary response to GnRH in those PCOD patients, therefore, was more normal after an ovulatory cycle than after an anovulatory cycle. We conclude that the heightened pituitary reactivity characteristic of PCOD patients is associated with chronic anovulation.

The effects of L-T4 and betamethasone treatment of newborn mice on the development of the cholinergic muscarinic receptor in certain brain regions was studied using the potent labeled muscarinic antagonist [3H]4-N-methyl-piperidyl benzilate. Treatment with both L-T4 and betamethasone caused an accelerated accumulation of muscarinic receptors in the cortex 16 days post partum, with a subsequent reduction in level at 30 days. In the cerebellum and caudate putamen, only betamethasone caused a similar early accumulation of muscarinic receptors, while the later effect, namely a reduction in the level at 30 days, was seen with both hormones in these two regions as well as in the hippocampus. The results can explain some behavioral effects observed in other studies after treatment with these hormones.