Joseph M. Brandes

Induction of preovulatory luteinizing hormone surge and prevention of ovarian hyperstimulation syndrome by gonadotropin-releasing hormone agonist *

OBJECTIVE To use gonadotropin-releasing hormone agonist (GnRH-a) instead of human chorionic gonadotropin (hCG) to induce oocyte maturation for in vitro fertilization (IVF). DESIGN Pituitary and ovarian responses to GnRH-a and the outcome of IVF were studied prospectively. Data from patients injected with hCG were analyzed retrospectively. SETTING Program of IVF at the Rambam (Governmental) Hospital, Haifa, Israel. PATIENTS AND INTERVENTIONS One or two doses of buserelin acetate 250 to 500 micrograms were administered to six patients with moderate response (Estradiol [E2], 1,494 +/- 422 [+/- SD] pg/mL) and 8 patients with exaggerated response (E2, 7,673 +/- 3,028 pg/mL) to gonadotropin stimulation. Progesterone (P) and E2 were administered for luteal support. MAIN OUTCOME MEASURES Gonadotropin-releasing hormone agonist effectively triggered luteinizing hormone (LH)/follicle-stimulating hormone (FSH) surge. Mature oocytes were recovered in all patients. Luteal E2 and P were lower than in patients injected with hCG. No signs of ovarian hyperstimulation syndrome were observed. RESULTS Serum LH and FSH rose over 4 and 12 hours, respectively, and were significantly (P less than 0.05) elevated for 24 hours. Of all mature oocytes, 67% fertilized and 82% cleaved. Four pregnancies were obtained. CONCLUSIONS A bolus of GnRH-a is able to trigger an adequate midcycle LH/FSH surge, resulting in oocyte maturation and pregnancy. Our preliminary results also suggest that it allows a more accurate control of ovarian steroid levels during the luteal phase and may prevent the clinical manifestation of ovarian hyperstimulation syndrome.

Changes in uterine blood flow during human pregnancy.

A transvaginal duplex Doppler ultrasonography system was used to measure blood flow characteristics in the ascending uterine artery before and during pregnancy. The system uses a 5 MHz Doppler transducer coupled to a 6.5 MHz imaging probe. There was a steady increase in volume flow rate in the left ascending uterine artery from a mean of 94.5 ml/min before pregnancy to a mean of 342 ml/min in late gestation (reflecting a 3.5-fold increase). With the assumption of equal flow on both uterine arteries, the fraction of the cardiac output that is distributed to these vessels was calculated to be 3.5% in early pregnancy and to reach 12% near term. The mean diameter of this vessel in the nonpregnant state was 1.6 mm, increasing to 3.7 mm toward term. The resistance to flow, expressed as the peak systolic to end-diastolic flow velocity ratio, declined from a mean of 5.3 in the nonpregnant state to a mean of 2.3 near term. These changes reflect the perpetual growth and development of the uteroplacental circulation, which provides the metabolic demands of the growing fetus throughout gestation.

Premature ovarian failure—the prognostic application of autoimmunity on conception after ovulation induction

OBJECTIVE To assess whether the presence of autoimmune activity in patients with premature ovarian failure (POF) can predict the response to ovulation induction and conception. DESIGN Assessment of autoimmune activity in patients with POF, correlating the response to ovulation induction with this autoreactivity. SETTING Tertiary care academic center. PATIENTS Forty women with POF, 15 of them treated by ovulation induction because of infertility. INTERVENTIONS All patients were tested for the presence of autoimmune activity, antibodies against various tissues, and 15 of them were treated with combinations of hMG/hCG, glucocorticosteroids as immunosuppressant, and some of them also with a long-acting GnRH agonist. Those patients not interested in infertility were put on hormone replacement therapy (HRT). MAIN OUTCOME MEASURES Serum E2 and P were measured during ovulation induction as well as follicular diameter monitoring by transvaginal sonography. Achievement of gestations and their outcome were monitored in the group in which ovulation induction was accomplished. RESULTS Antibodies against thyroglobulin, nuclear antigens, heart, tissue gluten, or increased levels of immunoglobulin (Ig)M, or decreased levels of complement C3 and C4 were significantly different in the patients with POF than in the control population. Autoreactivity of at least one class of the tested antibodies was found in 31 of 40 patients (77%). In 15 patients with autoimmune activity who have undergone ovulation induction using hMG/hCG, 14 pregnancies were achieved in 8 patients. Two of the pregnancies were spontaneous, and 12 were generated by hMG/hCG and fluocortolone, with or without pretreatment with GnRH-a. Twelve healthy babies were generated by 10 gestations, 3 ended in spontaneous abortions (23%), and 1 is ongoing. All the nonspontaneous pregnancies were achieved in the first three cycles of ovulation induction. CONCLUSIONS Patients with POF and autoimmune activity, suggesting an autoimmune etiology to the ovarian failure, may respond to ovulation induction and have a conception rate of approximately 40% in three cycles. Those who do not conceive in three treatment cycles have a very low probability to conceive; therefore, further attempts of ovulation induction should be discouraged. However, some patients may spontaneously conceive in association with HRT.

Gonadotropin- and estrogen-induced increase of peripheral-type benzodiazepine binding sites in the hypophyseal-genital axis of rats

Peripheral-type benzodiazepine binding sites (PBS) were demonstrated in the cell membranes of various organs (ovary, uterus, oviduct, pituitary and kidney) of mature and immature female rats by using the PBS-specific ligand [3H]PK 11195. The equilibrium dissociation constants of [3H]PK 11195 for PBS in mature rats ranged from 3 to 4 nM. The specific binding of [3H]PK 11195 (2 nM) in the hypophyseal-genital axis of immature (19-27 days old) female rats was found to be significantly increased in the ovary and uterus, concurrently with the increase in age. Administration of pregnant mare serum gonadotropin or diethylstilbestrol to immature rats increased the density of PBS in the ovary and uterus 2- to 3-fold but no change was found in the kidney. The affinity of [3H]PK 11195 to these tissues did not change following hormonal treatment. These results suggest that gonadotropin and estrogen are involved in the induction of PBS in the organs of the hypophyseal-genital axis in female rats.

Uterine artery flow velocity waveforms and color flow imaging in women with perimenopausal and postmenopausal bleeding. Correlation to endometrial histopathology.

We performed Doppler studies of the uterine artery in 85 women with postmenopausal and perimenopausal bleeding. Sixty‐six women had non‐malignant changes and 19 women had malignant changes on histologic examination of the endometrium. Uterine fibroids were detected in 30 women. When malignant changes were detected in the endometrium, uterine artery resistance index was always below 0.83. The mean uterine artery resistance index was significantly lower in the group of women with pathologic changes of the endometrium (RI = 0.77±0.03) compared to the group with non pathologic changes (RI=0.85±0.08 p<0.01), excluding the women with uterine fibroids. The lowest mean resistance index in the uterine artery was observed in the group of women with uterine fibroids (RI = 0.60 ± 0.09 p< 0.001). In five of six patients with endometrial carcinoma blood vessels were detected around the myometrium by using color flow imaging. Their RI was always less than 0.5. In five patients, blood vessels were detected in uterine fibroids but their RI was always more than 0.5. All six women with endometrial carcinoma but only seven of 13 women with endometrial hyperplasia, had endometrial thickness greater than 5 mm. Doppler velocimetry of the uterine artery carries a high sensitivity (100%) in detecting pathological changes of the endometrium in patients presenting with postmenopausal or perimenopausal bleeding. The presence of high resistance in this vessel, may allow a more conservative approach in this group of patients.

Spontaneous fetal reduction in multiple gestations assessed by transvaginal ultrasound

Objective To assess the occurrence of disappearance of one or more of the fetuses in pregnancies which start as multiple gestation.

Transfer and accumulation of cadmium, and the level of metallothionein in perfused human placentae

The purpose of the present study was to investigate the effect of perfusion with a medium containing 12 or 24 μg Cadmium (as CdCl2) per ml on this metals accumulation, transfer rate and metallothionein (MT) level. The experiments were performed with an isolated lobule of a dually-perfused human term placenta. Placental cell integrity and viability were characterised by their morphology and metabolic function, manifested in the tissues electron microscopic structure and glucose and oxygen (O2) consumption, respectively. Perfusion with 24 μg Cd/ml medium for 5 h resulted in significant elevation in MT. The transfer rate of Cd to the fetal side of the placenta was very slow, and not until 40 min after the addition of Cd into the maternal side was a significant increase in the metals level observed in the fetal perfusate. Thereafter, the level of the metal increased gradually and reached a steady state about 1 h later, at a level which was less than 1/20th of its concentration in the maternal perfusate. There was a 60-fold increase in Cd level in the cytosolic fraction obtained from the Cd-treated samples. At 12 μg Cd/ml no significant changes were noted in morphology, metabolic function and MT content. None of the Cd levels caused a signicant change in O2 and glucose consumption, in spite of the fact that with the higher Cd dose the microstructure of the tissue showed some pathological changes. The observed elevation in MT may provide the fetus some protection against the harmful effects of the metal.

Treatment of Ovarian Hyperstimulation Syndrome: the Physiologic Basis for a Modified Approach

A case of severe ovarian hyperstimulation syndrome (OHSS) secondary to human menopausal gonadotropin-human chorionic gonadotropin therapy is presented. Draining 4000 ml of exudate by abdominal paracentesis under real-time B-scan imaging induced a marked improvement in the patients condition. Fluids from the third space were rapidly excreted, renal function improved, and the patients weight decreased substantially. The underlying physiologic factors responsible for these changes are discussed. Other modes of treatment, including salt and water restriction and the use of volume expanders and diuretics, had no significant effect on the course of the syndrome. Paracentesis has a definite therapeutic value and is recommended in cases of OHSS with tense ascites.

Meconium during delivery: A sign of compensated fetal distress

Abstract The fetal scalp pH was examined in 80 parturients in whom meconium appeared during the first stage of labor. These were matched with 80 control parturients in whom the amniotic fluid was clear. No significant differences were found between the two groups in fetal outcome, Apgar score, or number of interventions during delivery. The meconium group was subdivided into two groups: (1) thin and watery and (2) thick and solid. No differences were found between the two subdivisions in fetal scalp pH, fetal outcome, Apgar score, or the number of interventions during delivery. Our data support the assumption that the passage of meconium during delivery could be a state of compensatory fetal distress.

Hemorrhagic ovarian cyst detection by transvaginal sonography: The great imitator

The sonograms of 102 hemorrhagic ovarian cysts (HOC) were reviewed to ascertain the full spectrum of sonographic findings as visualized by transvaginal sonography (TVS). The diagnoses, in 11 cases, were proven by surgery and the rest have undergone conservative follow-up until resolution (clinically and sonographically). The accurate diagnosis of HOCs by transabdominal sonography is quite difficult. The appearance of these cysts as visualized by TVS is described. We advise TVS as a better means for identification of HOCs, thus decreasing the rate of diagnostic invasive procedures.