Shlomo Mashiach

Human menopausal gonadotropins for anovulation and sterility: Results of 7 years of treatment

Abstract Induction of ovulation with sequential application of human gonadotropins—follicle stimulating hormone (FSH) and luteinizing hormone (LH)—is today an established procedure. FSH, formerly obtained from animal sources and now extracted from urine of postmenopausal women (Pergonal), is available commercially and easy to administer. During the last 7 years, 110 patients suffering from various types of anovulation have been treated with 202 courses of Pergonal combined with human chorionic gonadotropins (HCG). The dosage of Pergonal was adjusted to the individual reaction of the patient, as evaluated by urinary estrogen excretion, the cervical mucus arborization test, and vaginal cytology. This treatment resulted in 61 pregnancies. There have been 34 deliveries, 11 patients are still pregnant, and there have been 16 abortions. Adverse reaction resulting from ovarian hyperstimulation were encountered. There is no relationship between the dosage of Pergonal administered and the severity or number of reactions. The combined administration of Pergonal with HCG can be regarded as a significant step forward in the treatment of anovulation.

Randomized management of the second nonvertex twin: Vaginal delivery or cesarean section

Sixty twin deliveries after the thirty-fifth gestational week with vertex-breech and vertex-transverse presentations were managed according to a randomization protocol. Thirty-three parturient women (21 vertex-breech and 12 vertex-transverse presentations) were allocated for vaginal delivery and 27 for cesarean section (18 vertex-breech and nine vertex-transverse). Six pairs of twins in the vaginal delivery group were delivered in a different mode than requested by the protocol (two women underwent cesarean section; in four cases the second twin spontaneously changed to vertex presentation). There were no significant differences between 1- and 5-minute Apgar scores and incidence of neonatal morbidity between the second-born twins in both study groups. Firstborn twins had higher 1-minute Apgar scores than the second-born infants irrespective of route of delivery (p less than 0.05). No case of birth trauma or neonatal death was recorded. Maternal febrile morbidity was significantly higher in the cesarean section group than in the vaginal delivery group (40.7% versus 11.1%, p less than 0.05). These results suggest that in twins with vertex-breech or vertex-transverse presentations after the thirty-fifth week of gestational age the neonatal outcome of the second twin was not significantly influenced by the route of delivery.

Cumulative conception rates following gonadotropin therapy

During the years 1963 to 1978, 515 patients were treated with HMG. They were divided into two groups depending upon the absence (Group I) or presence (Group II) of distinct endogenous estrogen activity. Group II patients were referred after failure of clomiphene therapy. None of the patients had mechanical or male infertility factors. The cumulative pregnancy rate (life table method) in Group I patients after six cycles of treatment was 91.2%. In 77 patients from Group I, further treatment was given for a second pregnancy after the first gonadotropin conception. In this group, the cumulative conception rate was 93.6% after eight cycles of treatment. In Group II the cumulative conception rate was 50% after 12 cycles of treatment. In both groups, the results were better in patients who were less than 35 years of age than those who were 35 or more when treated.

Immunoreactive circulating endothelin-1 in normal andhypertensive pregnancies

Summary OBJECTIVE : The purpose of this study was to measure the circulatory levels of endothelin-1 inthe serum of pregnant women with hypertension. STUDY DESIGN : Endothelin-1 levels were measured by means of radioimmunoassay in the serum of 26 pregnant women with hypertension (14 with pregnancy-induced preeclamptic toxemia, 12 with chronic hypertension) and in the serum of 17 control pregnant women and 18 control nonpregnant women. The mean levels in the different groups were subject to statistical analysis with the analysis of variance RESULTS : The mean level among the women with preeclampsia (29.9 ± 13.2 fmol/ml) was significantlyhigher than those of the chronically hypertensive women (16.1 ± 7.3 fmol/ml, p = 0.002) and of the control pregnant women (19.7 ± 9.2 fmol/ml, p = 0.011). The mean level of the control nonpregnant women (26.9 ± 9.3) was significantly higher than that of the control pregnant women ( p = 0.029). Among the patients with preeclampsia there was no correlation between endothelin-1 levels and the mean arterial blood pressure. Six to 10 weeks after delivery the mean levels of 15 studied patients (7 with preeclampsia, 8 with chronic hypertension) were similar to the levels of the nonpregnant control women CONCLUSION : We conclude that increased endothelin-1 production may play a role in the pathogenesisof preeclampsia

Intravenous immunoglobulin in the prevention of recurrent miscarriage

adrenal insufficiency in a study of 71 fetuses of asthmatic mothers receiving predntsolone. The adrenocortical reserve of six newborns whose mothers had received steroids long term was assessed and the response to exogenous ACTH found to be normal (Arad & Landau 1984). Chan and Wilson draw attention to a recognised complication of prolonged or high dose steroid therapy. We accept that avascular necrosis in their patient is likely to have been related directly to the use of steroids to treat her hyperemesis. However, the dose of steroids used was extremely high; 24 mg dexamethasone is equivalent to 640 mg hydrocortisone. Their patient therefore received a dosage of glucocorticoid equivalent to 160-640 mg hydrocortisone (40-160 mg prednisolone) for a total of six to seven weeks. In our experience lower initial doses (200-300 mg hydrocortisone, 50-75 mg prednisolone) have been sufficient. After control of symptoms is achieved, patients can usually be weaned to a dose of 30-40 mg prednisolone per day within a few days, and thereafter to 20 mg per day within four weeks of starting treatment. In addition, avascular necrosis may rarely occur as a complication of pregnancy itself (Kay et al. 1972; Zolla-Pazna et a/ . 1980). It is important, and part of our practice, to discuss the possible risks of steroid therapy with the pregnant woman as Oladipo suggests. Since our original case report was accepted for publication, we have treated (or recommended the treatment of via telephone consultation) an additional six women with severe hyperemesis gravidarum with corticosteroid therapy. All 10 patients in this series had complete remission of their symptoms within 48 hours of starting treatment. We accept that parenteral steroid therapy may be required as Wong and Daniel suggest, and six out of ten women in our series required intravenous steroids. However, we fail to see the advantage of dexamethasone over hydrocortisone, and there are theoretical disadvantages since relatively more dexamethasone reaches the fetus. These pilot data support a beneficial role for corticosteroids in the treatment of severe hyperemesis gravidarum, but a definitive, randomised, double-blind, placebo-controlled trial is now in progress. Since the natural history of hyperemesis gravidarum is of gradual improvement with increasing gestation, the design of this multicentre study incorporates strict inclusion criteria. An intravenous arm to the study will ensure that steroids receive a fair trial.

Chromosome analysis of multipronuclear human oocytes fertilized in vitro

In an in vitro fertilization and embryo transfer program composed mainly of patients with tubal infertility, the incidence of fertilized oocytes with multiple pronuclei was 4.3%. An attempt was made to fix such oocytes with supernumerary pronuclei in order to assess the chromosome constitution of the gametes. Nine multipronuclear oocytes containing a total of 29 pronuclei were successfully fixed before the first cleavage division, and another oocyte containing 3 pronuclei was fixed before the second cleavage division. On analysis, chromosome counts could be obtained for 28 of the 29 total pronuclei, and 24 gave informative results. Nineteen pronuclei had a normal haploid chromosome count, 2 pronuclei contained one extra chromosome, and 3 pronuclei had one chromosome missing. The presence of a Y chromosome in six pronuclei identified their paternal origin; two of the six sperm pronuclei had a 22,Y,-E chromosome constitution. Only three pronuclei could be conclusively ascertained to be maternal in origin, yet two of these were aneuploid; one pronucleus had a 24,X,+D karyotype and the second had only 22 chromosomes. Multipronuclear oocytes present ideal material for analyzing the chromosome constitution of those human gametes which can undergo fertilization in vitro.

Abortion rate in pregnancies following ovulation induced by human menopausal gonadotropin/human chorionic gonadotropin*

Despite the high incidence of fetal loss following gonadotropin therapy, the etiologic factors that contribute to this loss remain unknown. In 203 women who conceived following gonadotropin therapy, the abortion rate was 28.5%. However, in 84 women who conceived a second time, also with gonadotropin treatment, the abortion rate was 11.9%. Second- and third-degree hyperstimulation of the ovary are accompanied by a 50% abortion rate, and the occurrence of abortion is more frequent in the first pregnancy. The contribution of multiple pregnancy, maternal age, and number of gonadotropin treatment cycles are also evaluated and discussed.

Zygote intrafallopian transfer may improve pregnancy rate in patients with repeated failure of implantation

OBJECTIVEnTo evaluate the efficacy of zygote intrafallopian transfer (ZIFT) on implantation rates and pregnancy rates (PRs) in patients with repeated failure of implantation in IVF-ET cycles.nnnDESIGNnA case-control study.nnnPATIENT(S)nCriteria for patient selection included male factor or unexplained infertility, normal uterine cavity, and at least three failures of implantation in IVF-ET cycles in which at least three embryos were placed per transfer. Data on 70 patients who underwent 92 ZIFT cycles are presented. A control group consisted of patients with the same selection criteria who underwent an additional standard IVF-ET cycle during the same time period.nnnINTERVENTION(S)nOvulation induction consisted of down-regulation with GnRH analogue followed by ovarian stimulation with FSH and hMG. Intracytoplasmic sperm injection was performed on the oocytes of all patients with male factor infertility. Zygotes were transferred by laparoscopy into the fallopian tube 24-26 hours after oocyte retrieval.nnnMAIN OUTCOME MEASURE(S)nImplantation rates and PRs in the ZIFT and control groups were compared.nnnRESULT(S)nThe PRs and implantation rates were significantly higher in the ZIFT group than in the control group: 34.2% (24/70) and 8.7% (29/333) versus 17.1% (12/70) and 4.4% (13/289), respectively (P = 0.002 and P = 0.04). The cumulative conception rate for two ZIFT cycles was 59.3%.nnnCONCLUSION(S)nZygote intrafallopian transfer should be considered a beneficial mode of treatment for patients with repeated failure of implantation in IVF and transcervical ET. More prospective randomized studies are needed to support this observation.

The relative success of gonadotropin-releasing hormone analogue, clomiphene citrate, and gonadotropin in 1,099 cycles of in vitro fertilization

Objectives To evaluate the effectiveness of and analyze the factors influencing the outcome of three ovarian stimulation protocols used during in vitro fertilization (IVF) in a large population. Design Retrospective file review. Setting In vitro fertilization program in one center during the years 1985 to 1990. Patients and Protocols Three hundred forty-one patients received clomiphene citrate (CC) and human menopausal gonadotropin (hMG), 365 received hMG alone, and 393 received gonadotropin-releasing hormone analogue (GnRH-a) for pituitary suppression followed by hMG stimulation. Main Outcome Measure Rates of cancellation, total pregnancies, and ongoing pregnancies, with breakdown by age of patients. Results The cancellation rate because of early luteinization following GnRH-a/hMG was significantly reduced compared with the other two protocols: 3.6% versus 9.4% and 13.7% for CC/hMG and hMG, respectively. However, in women over 40years of age, GnRH-a/hMG resulted in the highest rate of poor ovarian response. Significantly more oocytes were retrieved, fertilized, and cleaved after the use of GnRH-a/hMG compared with the other two protocols. Despite this, clinical pregnancy rate (PR) was the highest with CC/hMG compared with GnRH-a/hMG and hMG: 31.4% versus 16.9% and 15.7%, respectively. Ongoing PRs were 20.5%, 9.7%, and 11.6%, respectively. Conclusions Although the use of GnRH-a for pituitary suppression before ovarian stimulation for IVF reduced the cancellation rate and increased the number of retrieved oocytes, it was not found to result in higher PRs than those achieved by stimulation with CC/hMG. This suggests that treatment by GnRH-a/hMG should be reserved mainly for the prevention of early luteinization.

Cytokine levels in follicular fluid of polycystic ovaries in patients treated with dexamethasone

Objective To assess the levels of cytokines in the follicular fluid of stimulated ovaries. Design The study included two groups of four patients with polycystic ovarian disease. These were diagnosed by clinical and ultrasonic features and characteristic hormonal profiles, treated with gonadotropin-releasing hormone-analogue and human menopausal gonadotropin. One group received dexamethasone (DEX). Main Outcome Dexamethasone is capable of directly affecting granulosa and immune cells. It was also expected to affect cytokine production of granulosa and immune cells of the ovary. Results This study demonstrates that FF from patients treated with DEX has reduced tumor necrosis factor (TNF) activity and elevated colony-stimulating factor levels. Regardless of the treatment with DEX, the follicles with high levels of TNF contained minimal concentrations of estradiol. Interleukin-6 did not differ between the FF samples. Conclusions These results suggest a role for cytokines in the process of folliculogenesis and ovarian maturation. Modification of cytokines by DEX might explain the beneficial effect of fertility.