Does the intravenous infusion of ritodrine or magnesium sulfate alter the hemodynamic response to hemorrhage in gravid ewes?

The purpose of this study was to determine whether the intravenous infusion of ritodrine or magnesium sulfate alters the hemodynamic response to maternal hemorrhage in gravid ewes. Twenty-seven experiments were performed in 12 chronically instrumented animals at 0.8 of timed gestation. Each animal was subjected to hemorrhage (20 ml/kg over 60 minutes) during infusion of ritodrine (0.004 mg/kg/min), magnesium sulfate (4 gm/hour), or saline solution control. Infusion of magnesium sulfate increased the mean (+/- SEM) maternal serum magnesium concentration to 4.8 +/- 0.2 mg/dl before hemorrhage and 5.3 +/- 0.3 mg/dl after hemorrhage. At the end of hemorrhage maternal mean arterial pressures were 63% +/- 4%, 82% +/- 2%, and 79% +/- 6% of baseline in the magnesium sulfate, ritodrine, and control groups, respectively. The maternal mean arterial pressure response in the magnesium sulfate group differed significantly from the maternal mean arterial pressure responses in the ritodrine and control groups (p less than 0.01). Fetal pH was decreased significantly only in the magnesium sulfate group (p = 0.0001). Fetal PO2 was decreased significantly in the magnesium sulfate and ritodrine groups (p less than 0.001) but not in the control group. We conclude that magnesium sulfate but not ritodrine, worsened the maternal hypotensive response to hemorrhage in gravid ewes.     

The effect of prenatal administration of dexamethasone and ritodrine on cord blood cortisol and glucose concentrations in premature infants with respiratory distress syndrome.

The influence of maternal dexamethasone and ritodrine administration during pregnancy on cord blood cortisol and capillary serum glucose concentrations and on the incidence of respiratory distress syndrome (RDS) was studied in 30 premature infants (gestational age 27-36 weeks), and compared with a matched control group of 37 premature infants where no such medications were administered. RDS occurred less often in the treated group of infants (13.3%) than in the controls (35.1%, p < 0.01). The healthy treated infants had a significantly lower mean umbilical cord plasma cortisol concentration (5.5 +/- 1.8 ug/dl, mean +/- SD) than that observed in the controls (11.2 +/- 3.9 ug/dl, p < 0.01). Mean cord plasma cortisol concentrations increased with duration of pregnancy. No significant difference in the capillary serum glucose at 30 minutes post-delivery was found between the healthy, RDS, treated and non-treated infants. No adverse effects of steroid and ritodrine therapy were observed.     

Hemodynamic and metabolic effects after nifedipine and ritodrine tocolysis.

OBJECTIVES: The purpose of this study is to compare the hemodynamic and metabolic changes after ritodrine and nifedipine tocolysis. METHODS: For an open randomized study, patients with preterm labor (N=185) were allocated to groups to receive ritodrine intravenously (N=90) or nifedipine orally (N=95). RESULTS: The mean diastolic blood pressure was significantly lower in the ritodrine group 24 h (65+/-12 vs. 70+/-8, P=0.001) and 48 h (65+/-12 vs. 71+/-8, P=0.004) after starting tocolysis compared with the nifedipine group. Mean maternal heart rate was significantly higher in the ritodrine group 24 h (105+/-17 vs. 86+/-13, P<0.0001) and 48 h (100+/-21 vs. 85+/-12, P<0.0001) after starting tocolysis compared with the nifedipine group. Mean fasting glucose levels were higher (6.68+/-2.53 vs. 4.93+/-1.23, P=0.0016), while mean potassium levels were lower (3.52+/-0.84 vs. 3.81+/-0.45, P=0.04) in the ritodrine group 48 h after starting tocolysis compared with the nifedipine group. CONCLUSIONS: Use of nifedipine for preterm labor is associated with a lower incidence of adverse hemodynamic and metabolic changes compared with ritodrine after 24 and 48 h of tocolysis. In our opinion nifedipine is the preferred drug of choice for the treatment of preterm labor.     

Oral nifedipine maintenance therapy after acute intravenous tocolysis in preterm labor

AIMS: Our aim was to evaluate the efficacy of maintenance oral nifedipine in pregnant women initially treated with intravenous ritodrine plus verapamil for preterm labor. METHODS: The study included 73 patients with preterm labor with intact membranes. Patients were randomized to receive either maintenance oral nifedipine therapy (n=37) administered 20 mg every six hours or no treatment (controls, n=36) after discontinuation of acute intravenous tocolysis. RESULTS: Compared to the control group, the mean +/- SD time gained from initiation of maintenance therapy to delivery (26.65 +/- 18.89 vs. 16.14 +/- 12.91 days, p=0.007) and the gestational age at delivery (37.03 +/- 2.06 vs. 35.1 +/- 3 weeks, p=0.003) were higher in the nifedipine maintenance therapy group. The proportion of patients who required one or more courses of subsequent intravenous therapy and perinatal outcomes were similar in the maintenance therapy and control groups. CONCLUSIONS: The gestational age and time gained from initiation of maintenance therapy to delivery were longer in women receiving oral maintenance tocolysis with nifedipine. However, maintenance therapy did not decrease the recurrence of preterm labor episodes or improve perinatal outcomes.     

A double-blind study comparing ritodrine and terbutaline in the treatment of preterm labor

One hundred women in preterm labor were randomly treated with ritodrine or terbutaline in a double-blind fashion. The drugs were comparably effective during intravenous therapy but, in women with intact membranes, an oral dose of terbutaline, 30 mg daily, was significantly more effective than ritodrine, 120 mg daily, in preventing recurrent labor during a 5-day course of oral therapy (one of 19 versus 12 of 23, p less than 0.001). In women with intact membranes, pregnancy was prolonged 40 +/- 25 days (mean +/- SD) in women receiving terbutaline orally and only 22 +/- 24 days in women receiving ritodrine orally (p less than 0.01). In women with intact membranes, a heart rate greater than or equal to 130 bpm occurred in in a higher proportion of women receiving intravenous treatment with ritodrine than among those receiving terbutaline (20 of 31 versus 8 of 27, p less than 0.05). Terbutaline-treated women, however, were significantly more likely to have a serum glucose level in excess of 140 mg/dl than were women treated with ritodrine (13 of 26 versus 6 of 29, p less than 0.05). Side effects commonly observed during intravenous therapy included nausea (22%), chest pain (15%), and shortness of breath (15%). Side effects were significantly (p less than 0.025) more likely to occur during periods when the infusion rate was being increased rather than during periods when the infusion rate was constant.     

Effects of chronic hyperglycemia on electrocortical activity states in unanesthetized fetal lambs

Electrocortical activity (ECoG), tracheal pressure and nuchal muscle activity were recorded in utero in 8 chronically hyperglycemic and 10 control unanesthetized fetal lambs to investigate the effects of chronic hyperglycemia on fetal electrocortical activity states. The chronically hyperglycemic state, induced by alloxan administered to the ewes, existed for at least 40 days prior to the experiments. The mean duration of episodes of high voltage (HV) ECoG was significantly increased in the hyperglycemic group (mean +/- SD: 21.8 +/- 9.2 min) compared with the control group (14.8 +/- 3.3 min), but the incidence of low voltage (LV) ECoG was not different between the groups. ECoG power spectra were not different between the groups. During LV ECoG, the proportions of time with neck movements were significantly less in the hyperglycemic than in the control group. No difference in percentages of time with long neck muscle activity was seen during the HV state in both groups. The incidence of breathing movements was equal in both groups, during HV as well as LV ECoG. No differences in breathing interval were observed.     

Pharmacokinetics and pharmacodynamics of ritodrine after intramuscular administration to pregnant women

To define the pharmacokinetics and pharmacodynamics of ritodrine after intramuscular injection, we administered 5 or 10 mg ritodrine into the gluteus or deltoid muscles of 12 pregnant volunteers. Six women received 5 mg and six received 10 mg into each muscle group on different days. We withdrew blood samples before and 12 times in the 6 hours after ritodrine injection. Blood pressure and heart rate were recorded at each time. Ritodrine was measured by high-performance liquid chromatography. Peak ritodrine concentrations (mean +/- SD) after a single 5 mg injection in the deltoid or gluteus were 38 +/- 13 and 26 +/- 8 ng/ml, respectively. After a 10 mg dose in the deltoid or gluteus, peak concentrations were 59 +/- 30 and 47 +/- 22 ng/ml, respectively. Although higher, the peak plasma concentrations after injections into the deltoid were not significantly greater than those after injection into the gluteus. None of the pharmacokinetic parameters differed according to dose or injection site. The pharmacodynamic effects of ritodrine were unaffected by injection site, but ritodrine caused a dose-related increase in heart rate and systolic blood pressure and a dose-related decrease in diastolic blood pressure. After a 10 mg injection, the maximal changes in heart rate, systolic, and diastolic blood pressure were 22%, 10%, and 19%, respectively. However, mean blood pressure was not altered by either the 5 or 10 mg dose. These findings indicate that there are few differences in pharmacokinetic parameters between deltoid and gluteal injection of ritodrine. The single intramuscular injection of 5 or 10 mg ritodrine results in labor-inhibiting concentrations with clinically insignificant cardiovascular effects.     

Pharmacokinetics of ritodrine administered intravenously: recommendations for changes in the current regimen

We define the pharmacokinetics of ritodrine in 13 pregnant women who received the drug intravenously. With constant infusion of 50 micrograms/minute, steady state ritodrine concentrations reached 28 +/- 11 ng/ml (SD) with a range of 15 to 45 ng/ml. This wide variation is a result of differences in plasma clearance, which ranged from 1.0 to 3.3 L/min, mean 1.94 +/- 0.71 L/min. The apparent volume of distribution was 6.95 +/- 3.54 L/kg, indicating that ritodrine is extensively bound to extravascular tissue. When an infusion of ritodrine is stopped, plasma concentrations fall rapidly initially with a distribution half-life of 5.9 +/- 6.0 minutes. After the initial rapid fall, plasma concentrations decrease more slowly with a mean disposition half-life of 156 +/- 51 minutes. On the basis of the pharmacokinetic parameters defined, we recommend that the current infusion regimen for ritodrine be changed. The infusion rate of ritodrine should start at 50 micrograms/minute rather than 100 micrograms/minute. The maximal infusion rate of 350 micrograms/minute should be increased and once labor is inhibited, the infusion rate should be reduced.     

Comparison of outcome of clomiphene citrate/human menopausal gonadotropin/cetrorelix protocol and buserelin long protocol--a randomized study.

This study evaluates the efficacy of a stimulation protocol with clomiphene citrate (CC)/human menopausal gonadotropin (hMG)/cetrorelix and its effects on oocyte quality and endometrium. One hundred and twenty couples with male-factor infertility who were about to undergo their first intracytoplasmic sperm injection cycles were randomized into two groups. Sixty women were stimulated with the CC/hMG/cetrorelix protocol (cetrorelix group) and 60 received the buserelin long protocol (buserelin group). Fewer oocytes were recovered in the cetrorelix group than in the buserelin group (mean +/- standard deviation (SD): 11.1 +/- 4.0 vs. 17.3 +/- 5.8, p < 0.001); however, the percentages of metaphase II, metaphase I and germinal vesicle oocytes were similar between the two groups. Serum estradiol level was significantly lower in the cetrorelix than in the buserelin group (mean +/- SD: 2600.58 +/- 1189.11 vs. 3293.46 +/- 1221.49 pg/ml, p = 0.006), but the endometrial thickness was similar. The implantation rates (19.2% vs. 17.7%) and the pregnancy rates (41.7% vs. 40.0%) were similar between groups. The ampoules (mean +/- SD: 18.9 +/- 3.0 vs. 38.9 +/- 12.2, p < 0.001) and injections (mean +/- SD: 6.8 +/- 1.1 vs. 15.7 +/- 3.1, p < 0.001) of gonadotropin used were significantly lower in the cetrorelix group than in the buserelin group. No patients in either group developed a premature luteinizing hormone surge. The present study found no statistically significant difference between the two treatment modalities with regard to pregnancy rates.     

Effects of gonadotropin on the growth of malignant ovarian neoplasms assessed by subrenal capsule assay

In the present study 18 cases of malignant ovarian neoplasm were studied to determine the possible role of sex steroid hormones and gonadotropins on tumor development. Twelve cases of serous cystadenocarcinoma, 2 of mucinous cystadenocarcinoma, 2 of endometrioid carcinoma, one malignant Brenner tumor, and one yolk sac tumor were examined with respect to their response to estradiol (E2), [D-Ser(But)6]-LHRH (1-9) nonapeptide-etylamide (Buserelin), human menopausal gonadotropin (HMG), RU 38486 (RU), and pure FSH by subrenal capsule assay (SRCA). Also 125I-FSH binding assay and the protein kinase C (CK) activity were studied in vitro. The results showed; 1) Seventy-three% cases showed a significant increase (p less than 0.05) in size due to SRCA. 2) In the FSH, HMG, and Buserelin treated groups, the size of xenografts increased (p less than 0.05) and the highest response was obtained with FSH. 3) Ninety-one% of cases demonstrated in vitro FSH specific binding which was significantly higher (p less than 0.05) in the cases which responded to gonadotropins in SRCA (42,288 +/- 25,454 vs 6,980 +/- 1,952, mean +/- SD, cpm/mg tissue). 4) CK activity was increased significantly (p less than 0.05) by gonadotropin (204.5 +/- 2.4 vs 363.9 +/- 7.2, mean +/- SD, cpm/mg tissue). These results suggest that gonadotropins possibly play a role in prompting the tumorigenesis of the malignant ovarian neoplasms through specific receptors and this mechanism may modify the CK system in malignant ovarian neoplasms.     

Arterial blood flow velocity waveforms of the pelvis and lower extremities in normal and growth-retarded fetuses.

Serial measurements of femoral artery flow velocity waveforms were made at specified intervals of 3 to 4 weeks from 15 to 20 weeks of gestational age to 35 weeks and 1- to 3-week intervals thereafter until delivery in 12 normal fetuses (group 1A) with pulsed Doppler ultrasonography. The pulsatility index of the femoral artery increased linearly with advancing gestation in all 12 fetuses; this was associated with reverse diastolic flow velocity waveforms. In 30 other normal fetuses (group 1B) whose gestational ages ranged between 16 and 38 weeks (mean +/- SD, 29.5 +/- 5.6 weeks), the femoral artery flow velocity waveforms were analyzed with the external iliac artery, internal iliac artery, and umbilical artery waveforms. No significant difference was observed between the pulsatility index of the external iliac artery and that of the femoral artery (mean +/- SD, 3.7 +/- 1.1 vs 3.7 +/- 1.1). The pulsatility index of the internal iliac artery was significantly higher than that observed in the umbilical artery (mean +/- SD, 1.27 +/- 0.28 vs 1.12 +/- 0.23). The femoral and umbilical artery velocity waveforms also were determined in 20 fetuses with intrauterine growth retardation (group 2), whose gestational ages ranged between 24 and 36 weeks (mean +/- SD, 31 +/- 3.4 weeks). Abnormal femoral artery pulsatility index was recorded in two fetuses who died. Absent or reverse flow of the umbilical artery was recorded in 10 fetuses; four of them died, and four others manifested fetal distress or required admission to the neonatal intensive care unit or both. These preliminary data suggest that the femoral artery pulsatility index cannot be used as an indicator of adverse fetal outcome, whereas absent or reverse flow of the umbilical artery seems to be better correlated with adverse fetal outcome.     

Evaluation of creatine kinase level during long-term tocolysis

OBJECTIVE: This study was performed to evaluate serum creatine kinase (CK) levels during tocolytic therapy. METHODS: A retrospective study was performed in 27 patients who were treated with intravenous tocolytic agents for more than one week. The first-line tocolytic agent was ritodrine hydrochloride, followed by concomitant magnesium sulfate (MgSO4). The serum CK level was measured on admission and every week thereafter. The patients were divided into the normal CK (group 1) and abnormal CK (> 150 IU/L) (group 2) groups. RESULTS: Seventeen patients received both ritodrine hydrochloride and MgSO4. The CK levels in all patients rose significantly from 58.4 +/- 30.8 IU/L on admission to 116.0 +/- 68.7 IU/L on day 7 (p = 0.002). Abnormal elevation of CK occurred in 7 (25.9%) of the 27 patients. Significant differences were found between groups 1 and 2 in the total doses of ritodrine and MgSO4 (p = 0.046 and p = 0.0028, respectively). All patients in group 2 received ritodrine in combination with MgSO4 (p = 0.018). CONCLUSION: When tocolytic therapy continued for more than 1 week, nearly one-fourth of patients showed an increase in CK level above the normal range.     

Atosiban vs ritodrine used prophylactically with cerclage in ICSI pregnancies to prevent pre-term birth in women identified as being at high risk on the basis of transvaginal ultrasound scan.

Our objective was to compare the effectiveness and safety of atosiban and ritodrine, in pregnancies obtained by intracytoplasmic sperm injection (ICSI) undergoing cervical cerclage. Data from a prospective study were compared with those from a retrospective study. Sixteen ICSI pregnant women, 20-24 weeks' gestation and maternal age >18 years, received atosiban (bolus dose 6.75 mg i.v., followed by 300 microg/min i.v. for 3 h and 100 microg/min i.v. for 45 h). Cervical cerclage was performed 3 h after starting atosiban. The control group (group B) of 16 ICSI pregnant women were matched and received ritodrine hydrochloride (100-350 microg/min) for 48 h. Cervical cerclage was performed after 24 h. Pre-term rupture of membranes occurred within 48 h of cervical cerclage in one woman receiving atosiban and in four women receiving ritodrine. There was no significant difference in terms of pregnancies not delivered at 48 h (short-term tocolysis) and at 7 days (long-term tocolysis). However, there was a significantly higher incidence of maternal tachycardia with ritodrine compared with atosiban (p < 0.001). The mean gestational age at delivery was significantly higher for atosiban compared with ritodrine (36 vs 33 weeks; p < 0.001). The neonatal outcome was poorer for ritodrine than atosiban, as there were very low birth weight infants (p = 0.008), resulting in lower Apgar scores (p = 0.005) and there were more neonates requiring a long stay in the neonatal intensive care unit (p = 0.005). We conclude that atosiban is associated with a significantly lower incidence of maternal tachycardia and improved neonatal outcome compared with ritodrine.     

Management of women with one abnormal oral glucose tolerance test value reduces adverse outcome in pregnancy

In this study we sought to test the hypothesis that treatment of women with one abnormal oral glucose tolerance test value will result in reduction of adverse outcome. One hundred twenty-six women with one abnormal oral glucose tolerance test value and 146 women in the control group (normal oral glucose tolerance test values) participated in a prospective study during the third trimester of pregnancy. The subjects with one abnormal test result were randomized into treated (group 1) and untreated groups (group II). Group 1 subjects were treated with a strict diabetic protocol to maintain tight glycemic control by means of diet and insulin therapy. Group 2 subjects tested their capillary blood glucose for a baseline period. The study revealed that the level of glycemic control was similar before initiation of therapy (mean capillary blood glucose 118 +/- 14 vs. 119 +/- 15 mg/dl, p = NS) for groups 1 and 2, respectively. There was a significant difference in mean capillary blood glucose (95 +/- 10 vs. 119 +/- 15 mg/dl, p less than 0.0001), preprandial, and postprandial determinations between the treated and untreated groups. The overall incidence of neonatal metabolic complications (4% vs. 14%, p less than 0.05) and large infants (6% vs. 24%, p less than 0.03) was significantly lower in the treated group. Comparison between the control (normal oral glucose tolerance test) and the untreated groups showed a significantly higher incidence of large infants and metabolic complications. No difference was found between the normal and treated groups. Thus we conclude that treatment of individuals with one abnormal oral glucose tolerance test value will result in significant reduction in adverse outcome in pregnancy.     

The concentration of nitrite in seminal plasma does not correlate with sperm concentration, sperm motility, leukocytospermia, or sperm culture

OBJECTIVE: To compare the clinical efficacy and safety of the combination of Diane 35 (2 mg of cyproterone acetate, and 35 microg of ethinyl estradiol) plus finasteride (5 mg), and Diane 35 alone in the treatment of hirsutism. DESIGN: Prospective randomized clinical study. SETTING: Outpatients in Erciyes University Medical School. PATIENT(S): Forty women with hirsutism were selected. INTERVENTION(S): For 1 year, group 1 patients (n = 20) were treated with Diane 35 alone (2 mg of cyproterone acetate and 35 microg of ethinyl estradiol) daily on days 5 to 25 of the menstrual cycle and group 2 patients (n = 20) with Diane 35 plus finasteride (5 mg daily). MAIN OUTCOME MEASURE(S): Hirsutism was graded at 6-month intervals using the Ferriman-Gallwey method. The basal hormone levels of total and free testosterone (T), androstenedione, DHEAS, and sex-hormone-binding globulin (SHBG) were measured by radioimmunoassay before the study. Total T, free T, SHBG, and DHEAS were also measured at 6-month intervals for 1 year. Multiscreen blood chemistry and side effects were evaluated during the treatment. RESULT(S): Thirty-four patients completed the 12-month study period. A significant decrease in the hirsutism score as compared to baseline was observed after 12 months with both Diane 35 treatment (mean +/- SD, 15.62 +/- 4.89 vs. 9.75 +/- 3.97) and Diane 35 plus finasteride treatment (16.27 +/- 6.90 vs. 8.38 +/- 4.44). The percentage decreases in the hirsutism score (mean percent +/- SD) were 30.26 +/- 14.56 vs. 34.70 +/- 11.60 at 6 months, 38.09 +/- 11.46 vs. 48.14 +/- 14.27 at 12 months in the Diane 35 and the Diane 35 plus finasteride groups, respectively. The percentage reduction in the hirsutism score in the Diane 35 plus finasteride group at 12 months was greater than in the Diane 35 group (P <.05). CONCLUSION(S): The percentage decrease in the hirsutism score at 12 months was higher in the Diane 35 plus finasteride group than in the Diane 35 group. We believe that Diane 35 plus finasteride is an effective and safe combination for the treatment of hirsutism.     

Ritodrine in the management of fetal distress

Summary. The potential value of a bolus injection of ritodrine in the management of fetal distress was examined in 24 patients. Following the injection of ritodrine, uterine activity measured over a period of 14·7±6·3 (SD) min was reduced to 22 (±12·4 SD)% of the pre-existing values. The cardiotocographic tracings showed a reversion to a normal or less ominous pattern in 14 of the 16 patients where this could be evaluated. The infants in the ritodrine group took less time to establish regular respirations. The perinatal neurobehaviour in the ritodrine and control groups did not differ. Two mothers who were given ritodrine and who received atropine premedication developed tachycardia and marked systolic hypertension. The administration of a bolus of ritodrine may have a place in the management of fetal distress when caesarean section is unavoidably delayed, but atropine premedication must be avoided as the combination can lead to potentially serious cardiovascular complications.     

Placental transfer of ritodrine hydrochloride in sheep

The purpose of this study was to examine the placental passage of ritodrine hydrochloride in relation to the drug's effects on the fetal circulation. Studies were carried out on nine nulliparous pregnant (120-140 days) ewes with chronically implanted cannulae for measurements of maternal and fetal arterial pressures and for blood sampling. One group of animals received sequential infusions of doses ranging from 0.1 to 30 micrograms/kg per min for 30 min (group 1). A second group was given a constant infusion of the drug at a dose of 3.0 micrograms/kg per min for 4 h (group 2). The peak concentrations of ritodrine in maternal and fetal blood were determined by radioimmunoassay. In group 1 they were 313.4 +/- 24.1 ng/ml (mean +/- S.E.) and 12.6 +/- 3.7 ng/ml at the finish of 30.0 micrograms/kg per min infusion for maternal and fetal blood, respectively. In group 2, maternal drug levels were 81.3 +/- 20.4 ng/ml after 30 min and 95.9 +/- 17.1 ng/ml after 4 h of the infusion. Fetal plasma concentrations increased slowly from trace levels at 30 min to 3.3 +/- 0.7 ng/ml at 4 h. Fetal blood pressure and heart rate did not show any significant changes during and after the infusion of ritodrine in both treatment groups. Our findings demonstrate the maternal administration of ritodrine produces no significant effects on the circulatory system of the fetal lamb because of the low transplacental passage of this drug.     

Comparison of gonadotropin-releasing hormone and gonadotropin therapy in male patients with idiopathic hypothalamic hypogonadism.

OBJECTIVE: To compare pulsatile gonadotropin-releasing hormone (GnRH) therapy with gonadotropin therapy in male patients with idiopathic hypothalamic hypogonadism. DESIGN: Prospective study. Patients had free choice between the two forms of therapy. SETTING: Patients were treated on an outpatient basis in our department. PATIENTS: Eighteen patients of matched age (mean [+/- SD] age: 21.1 +/- 3.0 years and 23.6 +/- 7.3 years) and similar testicular volume were treated in each group. INTERVENTIONS: Pulsatile GnRH therapy was started with 4 micrograms GnRH subcutaneously every 2 hours using a portable pump and gonadotropin therapy with 3 x 2,500 IU human chorionic gonadotropin (hCG) weekly injected intramuscularly. After 8 to 12 weeks of hCG treatment, 150 IU human menopausal gonadotropin two to four times weekly were added. RESULTS: Testosterone (T) and estradiol (E2) levels increased significantly higher (T: P less than 0.03; E2; P less than 0.001) in the gonadotropin group than in the GnRH group (T: 22.5 +/- 8.1 versus 16.8 +/- 5.5 nmol/L; E2: 150 +/- 70 versus 88. +/- 59 pmol/L). Five patients developed gynecomastia during gonadotropin therapy. The rise of testicular volume was significantly more pronounced (P less than 0.001) in the GnRH group (delta testicular volume = 8.1 +/- 2.0 mL) than in the gonadotropin group (delta testicular volume = 4.8 +/- 1.8 mL). Ten patients of the GnRH and 8 of the gonadotropin group had positive sperm counts, ranging from 1.5 to 26 x 10(6) spermatozoa/mL. The latter was achieved more rapidly in the GnRH group (12 +/- 1.6 versus 20 +/- 2.3 months: P less than 0.02). CONCLUSIONS: Endocrine and exocrine testicular function can be normalized by both forms of therapy. Gonadotropin therapy has more side effects. Gonadotropin-releasing hormone leads to a higher testicular volume and a more rapid initiation of spermatogenesis compared with gonadotropin therapy.     

Hormonal profile and endometrial morphology in letrozole-controlled ovarian hyperstimulation in ovulatory infertile patients

OBJECTIVE: To evaluate the clinical response and endometrial morphology during the implantation window on ovarian hyperstimulation with the aromatase inhibitor letrozole in infertile ovulatory women. DESIGN: Prospective trial in infertile patients. SETTING: Tertiary care hospital. PATIENT(S): Eight ovulatory infertile patient candidates for ovarian superovulation. INTERVENTION(S): Subjects were monitored in one control cycle. In the next cycle, they received letrozole 5.0 mg daily on days 3 through 7 after menses. MAIN OUTCOME MEASURE(S): Number of ovulatory follicles; dominant follicle diameter; endometrial thickness; hormonal profile of FSH, LH, E(2), A, T, and P; endometrial histological dating; and pinopode formation assessed by scanning electron microscopy. RESULT(S): Cycles stimulated with letrozole resulted in more ovulatory follicles than did natural cycles (mean +/- SD 2.0 +/- 0.9 vs. 1.0 +/- 0.0), which attained a greater preovulatory diameter (mean +/- SD 23.8 +/- 2.7 vs. 19.3 +/- 2.1 mm), with similar endometrial thickness at midcycle compared with spontaneous cycles. Endocrine profile of medicated cycles was characterized on day 7 by increased levels of LH (5.9 +/- 0.8 vs. 3.5 +/- 0.4 IU/mL), reduced E(2) (98.4 +/- 11.4 vs. 161.5 +/- 14.7 pmol/L), and elevated androgens. Preovulatory and midsecretory E(2) were similar to spontaneous cycle, and P levels during midluteal phase were significantly elevated (44.2 +/- 4.6 vs. 27.7 +/- 4.6 pmol/L). Endometrial morphology during the implantation window in letrozole-stimulated cycles was characterized by in-phase histological dating and pinopode expression on scanning electron microscopy. CONCLUSION(S): Letrozole induces moderate ovarian hyperstimulation in ovulatory infertile patients with E(2) levels similar to spontaneous cycles and higher midluteal P, leading to both a normal endometrial histology and development of pinopodes, considered to be relevant markers of endometrial receptivity.     

Prolonged in utero meconium exposure impairs spatial learning in the adult rat. Central Prize Award

OBJECTIVE: The purpose of this study was to examine the effects of prolonged in utero meconium exposure on adult learning and memory, as measured by the Morris water maze. STUDY DESIGN: Timed pregnant Long-Evans rats were studied. On gestational day 20 (term, 21 days of gestation), laparotomy was performed, and each maternal animal received an injection of clear amniotic fluid or meconium-stained amniotic fluid into each gestational sac. The laparotomy incision was closed, and the animals received postoperative monitoring through delivery. On postnatal days 145 to 148, the offspring underwent Morris water maze testing. The mean (+/-SEM) for the latency time was reported for each day's trial and compared between groups. RESULTS: There were significant differences between meconium-stained amniotic fluid group and clear amniotic fluid group in the mean time to platform on day 1 (82.7 +/- 1.8 seconds vs 75.9 +/- 3.0 seconds; P=.04), day 2 (60.5 +/- 3.5 seconds vs 47. 8 +/- 4.6 seconds; P=.03), and day 3 (56.5 +/- 4.5 seconds vs 34.7 +/- 4.4 seconds; P=.001). However, there were no differences on days 4 and 5. There were also no differences between recall and response learning trials that were done after a 12-day retention period. CONCLUSION: In the absence of hypoxia or infection, prolonged in utero meconium exposure is associated with a delay of spatial learning in the adult rat.