- Email: [email protected]
Changes in platelet intracellular free calcium in normal pregnancy
Citations from the Literature
distinct effects occurring in subgroups 3 and 5. Highly elevated T and free T levels were observed in subgroup 5 and in overweight patients (subgroup 6). Estrone (Et) serum concentrations were highest in those subgroups (3 and 5) in which acceleration of LH pulse frequency and increments in LH pulse amplitude were most pronounced; these parameters correlated significantly with Et levels. Conclusions: Changes in pulsatile LH release in patients with hyperandrogenemic chronic anovulation correlate primarily with elevated Et levels, rather than with T or A serum concentrations.
Premature ovarian failure-The prognostic application of sutoimmunity on conception after ovulation induction Blumenfeld Z.; Halachmi S.; Peretz B.A.; Shmuel Z.; Golan D.; Makler A.; Brandes J.M. ISR FERTJL STERIL 1993 5914 (750-755) 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, I5 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 I5 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 folhcular 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 C, 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 I5 patients with autoimmune activity who have undergone ovulation induction using hMG/hCG. I4 pregnancies were achieved in 8 patients. Two of the pregnancies were spontaneous, and I2 were generated by hMG/hCG and fluocortolone, with or without pretreatment with GnRH-a. Twelve healthy babies were generated by IO gestations, 3 ended in spontaneous abortions (23X1), and I 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.
95
Induction of follicular growth using recombinant human folliclestimulating hormone in two volunteer women with hypogonadotropic hypogonadism Shoham Z.; Mannaerts B.; lnsler V.; Coelingh-Bennink H. ISR FERTIL STERIL 1993 5914 (738-742) Objective: To examine the safety, tolerance, pharmacokinetics, follicular growth, and steroidogenesis after the administration of recombinant human FSH (Org 32489; Organon International, Oss, The Netherlands) in women with isolated hypogonadotropic hypogonadism. Design: An open phase I multiple rising dose study with recombinant FSH in two hypogonadotropic but otherwise healthy women. The drug was administered intramuscularly one time per day for a maximum of 21 days, i.e., 75 IU for the first 7 days. I50 IU for the next 7 days, and 225 IU during the last 7 days. Treatment was discontinued if serum E, was > 1,100 pmolil and/or one or more growing follicle > I4 mm in diameter was observed. After the last recombinant FSH injection, subjects were monitored for another 3 weeks. Setting: Specialist Reproductive Endocrinology and Infertility Unit. Volunteers: Two women with isolated hypogonadotropic hypogonadism who did not want to get pregnant anymore. Main Outcome Measures: Serum FSH, androstenedione (A), T, P, LH, follicular growth, and endometrial thickness. Safety parameters: blood pressure, heart rate, urinalysis, hematology. blood biochemistry, and antirecombinant FSH antibodies. Results: Treatment with recombinant FSH resulted in dose-related increases of serum FSH. Both women showed follicular growth (diameter, I7 mm), whereas serum A concentrations were very low, and serum Ez concentrations rose to only 76.7 and 139.5 pmol/L, respectively. No antirecombinant FSH antibody formation or changes of safety variables were noted. Conclusion: This study in two women with hypogonadotropic hypogonadism is consistent with the two-cell theory that FSH alone can induce follicular growth. The low concentrations of A and E, indicate the need for LH to induce appropriate steroidogenesis. It was also found that recombinant FSH is well absorbed, safe, and well tolerated after daily treatment for up to 21 days.
PREGNANCY
AND DELIVERY
Changes in platelet intracellular free calcium in normal pregnancy Kilby M.D.; Broughton Pipkin F.; Symonds E.M. GBR BR J OBSTET GYNAECOL 1993 lOtI/4 (375-379) Objective - To determine if platelet intracellular free calcium concentration (p.(Ca*‘)i) changes with gestation in normotensive, uncomplicated pregnancy. Design ~ A prospective, longitudinal study of primigravid pregnant women compared to a large control group consisting of nulhparous nonpregnant volunteers. Setting - The antenatal clinic at University Hospital, Queen’s Medical Centre, Nottingham. Subjects - Two groups of women were studied. Thirty-one nulliparous. nonpregnant women not using oral contraception were investigated
Inr J Grnrcol
Ohste~ 44
96
Citations from the Literature
in the early follicular phase of their menstrual cycles. Also, 24 primigravid women with normotensive, uncomplicated pregnancies were investigated on eight separate occasions during their pregnancies. Results - A significant increase in mean p.(Ca2+)i was demonstrated by 28 weeks gestation in the pregnant women as compared to the nonpregnant control group and the same individuals when investigated at I2 weeks postpartum (P < 0.05; ANOVA). This change was maximal at 36 weeks gestation (P < 0.001; ANOVA); concentrations had returned to those not significantly different from nonpregnant women by six weeks postpartum. Conclusions - Basal platelet (Ca*‘)i increases significantly by the third trimester of normal, primigravid pregnancy as compared to prepregnancy values and postnatal values. These data mirror the previously described observations of platelet behavior noting increased activity at this gestation of pregnancy. It may be that the increased basal p.(Cazc)i indicates that smaller transient signals have to be generated to induce platelet activity, such as shape change, aggregation and exocytosis. The effect of acetaminophenon prostacyclin productionin pregnant women O’Brien W.F.; Krammer J.; O’Leary T.D.; Mastrogiannis D.S. USA AM J OBSTET GYNECOL 1993 168/4 (1164-1169) Objective: The purpose of this study was to determine if acetaminophen decreased prostacyclin production by endothelial cells in culture and by pregnant women. Study design: The effect of acetaminophen on endothelial cells in culture was determined by the addition of acetaminophen in concentrations of IO and 100 pplml with comparison to control and indomethacin at 10 &ml. Prostacyclin production was estimated in 24 and thromboxane A, production in six third-trimester pregnant women by measurement of excretion of urinary metabolites before and after ingestion of either 1000 mg of acetaminophen or placebo. Results: Compared with control (549 f 61 pg/well, mean f SD), production of prostacyclin in vitro was significantly inhibited by acetaminophen at IO &ml (321 * 25) and 100 &ml (257 f 14). This inhibition is similar to inhibition by IO &ml of indomethacin (228 f I I). Excretion of prostacyclin metabolite was significantly lower after ingestion of acetaminophen (2233 * 446 vs. 1246 f 199 pg/mg creatinine, mean f S.E.M.) but unchanged after ingestion of placebo (I 745 * 304 vs. I7 I2 * 2 I I). There was no difference in response between normal and hypertensive women, and there was no effect of acetaminophen on thromboxane metabolite excretion. Conclusion: Acetaminophen in typical oral doses results in reduced production of prostacyclin by endothelial cells in culture and in a reduction in prostacyclin, but not thromboxane, production in pregnant women. Plasminogen activator inhibitors (PAL1 and PAL2) in normal pregnancies, pre-eclampsia and hydatidiform mole Reith A.; Booth N.A.; Moore N.R.; Cruickshank D.J.; Bennett B. GBR BR J OBSTET GYNAECOL 1993 100/4 (370-374) Objective-To examine the behavior of the major inhibitors Int J Gynecol Obstet 44
of tibrinoysis (PAI-I and PAI-2) in normal pregnancy and pregnancy complicated by either pre-eclampsia or hydatidiform mole. Design - Prospective study. Setting - Antenatal Clinic and Maternity Hospital. Subjects - Eleven women with established pre-eclampsia and eleven women, matched by age, parity, and duration of pregnancy who were undergoing uncomplicated pregnancy. Two women having surgery for hydatidiform mole. Main outcome measure - Plasma levels of PAI-I and PA1-2 antigens determined by sensitive specific ELISA. Functional identification of PAI- by nondenaturing gel electrophoresis with overlay zymography. Results - In preeclampsia PAI- antigen was significantly lower than in normal pregnancy (105.3 f 34.9 vs. 187.1 f 67.9 ng/ml; P < 0.001). In contrait PAI-I antigen was significantly higher in preeclampsia than in normal pregnancy (170.7 f 71.2 vs. 113.8 f 35.6 &ml; P < 0.05). In consequence the ratio of PAI-I/PAI-2 increased markedly in pre-eclampsia (2.5 versus 0.6). No PAI- was detected in plasma of women with hydatidiform moles. Conclusions PA1-2 levels fell significantly in pre-eclampsia probably as a result of decreased placental mass or function. The raised PAI-I level in preeclampsia may reflect a response to hypertension or renal damage that is not specific to pregnancy or may reflect altered placental function. The use of the ratio of PAI-l/PAI-2 assists in separating normal from abnormal pregnancies. Cord blood erythropoietinin relation to different markers of fetal hypoxia Maier R.F.; Bohme K.; Dudenhausen J.W.; Obladen M. DELI OBSTET GYNECOL 1993 81/4 (575-580) Objective: To investigate the relationship between erythropoietin concentration in umbilical venous blood and clinical signs of fetal hypoxia. Methods: We measured erythropoietin concentrations in umbilical venous blood from 200 consecutively born neonates using an enzyme-linked immunosorbent assay (ELISA) with two monoclonal antibodies. Results were available within 6 h. Inter-assay variation was 8.5% and the mean intra-assay variation was 14.2%. Results: Using a multiple regression analysis, we found that the erythropoietin concentration correlated significantly (P < 0.01) with fetal growth retardation and umbilical acidosis but not with gestational age, meconium-stained amniotic fluid (AP), abnormal fetal heart rate (FHR) pattern, or Apgar score at 5 min. Median erythropoietin concentrations were 25.1 mu/ml in infants with no risk factors or complications during pregnancy and delivery (n = l9), 25.8 mu/ml after complicated pregnancy (n = 95), 50.6 mu/ml with meconium-stained AF (n = l2), 44.7 mU abnormal FHR pattern (n = IO), and 72.6 mu/ml with umbilical acidosis (n = 24). The median erythropoietin concentration increased significantly with decreasing pH and with increasing base deficit in umbilical arterial blood. The erythropoietin concentration in umbilical venous blood (cutoff value 50 mu/ml) discriminated between infants with no clinical signs of fetal hypoxia and those with umbilical acidosis with a sensitivity of 75% and a specificity of 90%. Conclusions: Elevated erythropoietin concentrations in umbilical venous blood indicate prolonged fetal hypoxia. The ELISA technique might be a useful
distinct effects occurring in subgroups 3 and 5. Highly elevated T and free T levels were observed in subgroup 5 and in overweight patients (subgroup 6). Estrone (Et) serum concentrations were highest in those subgroups (3 and 5) in which acceleration of LH pulse frequency and increments in LH pulse amplitude were most pronounced; these parameters correlated significantly with Et levels. Conclusions: Changes in pulsatile LH release in patients with hyperandrogenemic chronic anovulation correlate primarily with elevated Et levels, rather than with T or A serum concentrations.
Premature ovarian failure-The prognostic application of sutoimmunity on conception after ovulation induction Blumenfeld Z.; Halachmi S.; Peretz B.A.; Shmuel Z.; Golan D.; Makler A.; Brandes J.M. ISR FERTJL STERIL 1993 5914 (750-755) 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, I5 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 I5 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 folhcular 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 C, 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 I5 patients with autoimmune activity who have undergone ovulation induction using hMG/hCG. I4 pregnancies were achieved in 8 patients. Two of the pregnancies were spontaneous, and I2 were generated by hMG/hCG and fluocortolone, with or without pretreatment with GnRH-a. Twelve healthy babies were generated by IO gestations, 3 ended in spontaneous abortions (23X1), and I 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.
95
Induction of follicular growth using recombinant human folliclestimulating hormone in two volunteer women with hypogonadotropic hypogonadism Shoham Z.; Mannaerts B.; lnsler V.; Coelingh-Bennink H. ISR FERTIL STERIL 1993 5914 (738-742) Objective: To examine the safety, tolerance, pharmacokinetics, follicular growth, and steroidogenesis after the administration of recombinant human FSH (Org 32489; Organon International, Oss, The Netherlands) in women with isolated hypogonadotropic hypogonadism. Design: An open phase I multiple rising dose study with recombinant FSH in two hypogonadotropic but otherwise healthy women. The drug was administered intramuscularly one time per day for a maximum of 21 days, i.e., 75 IU for the first 7 days. I50 IU for the next 7 days, and 225 IU during the last 7 days. Treatment was discontinued if serum E, was > 1,100 pmolil and/or one or more growing follicle > I4 mm in diameter was observed. After the last recombinant FSH injection, subjects were monitored for another 3 weeks. Setting: Specialist Reproductive Endocrinology and Infertility Unit. Volunteers: Two women with isolated hypogonadotropic hypogonadism who did not want to get pregnant anymore. Main Outcome Measures: Serum FSH, androstenedione (A), T, P, LH, follicular growth, and endometrial thickness. Safety parameters: blood pressure, heart rate, urinalysis, hematology. blood biochemistry, and antirecombinant FSH antibodies. Results: Treatment with recombinant FSH resulted in dose-related increases of serum FSH. Both women showed follicular growth (diameter, I7 mm), whereas serum A concentrations were very low, and serum Ez concentrations rose to only 76.7 and 139.5 pmol/L, respectively. No antirecombinant FSH antibody formation or changes of safety variables were noted. Conclusion: This study in two women with hypogonadotropic hypogonadism is consistent with the two-cell theory that FSH alone can induce follicular growth. The low concentrations of A and E, indicate the need for LH to induce appropriate steroidogenesis. It was also found that recombinant FSH is well absorbed, safe, and well tolerated after daily treatment for up to 21 days.
PREGNANCY
AND DELIVERY
Changes in platelet intracellular free calcium in normal pregnancy Kilby M.D.; Broughton Pipkin F.; Symonds E.M. GBR BR J OBSTET GYNAECOL 1993 lOtI/4 (375-379) Objective - To determine if platelet intracellular free calcium concentration (p.(Ca*‘)i) changes with gestation in normotensive, uncomplicated pregnancy. Design ~ A prospective, longitudinal study of primigravid pregnant women compared to a large control group consisting of nulhparous nonpregnant volunteers. Setting - The antenatal clinic at University Hospital, Queen’s Medical Centre, Nottingham. Subjects - Two groups of women were studied. Thirty-one nulliparous. nonpregnant women not using oral contraception were investigated
Inr J Grnrcol
Ohste~ 44
96
Citations from the Literature
in the early follicular phase of their menstrual cycles. Also, 24 primigravid women with normotensive, uncomplicated pregnancies were investigated on eight separate occasions during their pregnancies. Results - A significant increase in mean p.(Ca2+)i was demonstrated by 28 weeks gestation in the pregnant women as compared to the nonpregnant control group and the same individuals when investigated at I2 weeks postpartum (P < 0.05; ANOVA). This change was maximal at 36 weeks gestation (P < 0.001; ANOVA); concentrations had returned to those not significantly different from nonpregnant women by six weeks postpartum. Conclusions - Basal platelet (Ca*‘)i increases significantly by the third trimester of normal, primigravid pregnancy as compared to prepregnancy values and postnatal values. These data mirror the previously described observations of platelet behavior noting increased activity at this gestation of pregnancy. It may be that the increased basal p.(Cazc)i indicates that smaller transient signals have to be generated to induce platelet activity, such as shape change, aggregation and exocytosis. The effect of acetaminophenon prostacyclin productionin pregnant women O’Brien W.F.; Krammer J.; O’Leary T.D.; Mastrogiannis D.S. USA AM J OBSTET GYNECOL 1993 168/4 (1164-1169) Objective: The purpose of this study was to determine if acetaminophen decreased prostacyclin production by endothelial cells in culture and by pregnant women. Study design: The effect of acetaminophen on endothelial cells in culture was determined by the addition of acetaminophen in concentrations of IO and 100 pplml with comparison to control and indomethacin at 10 &ml. Prostacyclin production was estimated in 24 and thromboxane A, production in six third-trimester pregnant women by measurement of excretion of urinary metabolites before and after ingestion of either 1000 mg of acetaminophen or placebo. Results: Compared with control (549 f 61 pg/well, mean f SD), production of prostacyclin in vitro was significantly inhibited by acetaminophen at IO &ml (321 * 25) and 100 &ml (257 f 14). This inhibition is similar to inhibition by IO &ml of indomethacin (228 f I I). Excretion of prostacyclin metabolite was significantly lower after ingestion of acetaminophen (2233 * 446 vs. 1246 f 199 pg/mg creatinine, mean f S.E.M.) but unchanged after ingestion of placebo (I 745 * 304 vs. I7 I2 * 2 I I). There was no difference in response between normal and hypertensive women, and there was no effect of acetaminophen on thromboxane metabolite excretion. Conclusion: Acetaminophen in typical oral doses results in reduced production of prostacyclin by endothelial cells in culture and in a reduction in prostacyclin, but not thromboxane, production in pregnant women. Plasminogen activator inhibitors (PAL1 and PAL2) in normal pregnancies, pre-eclampsia and hydatidiform mole Reith A.; Booth N.A.; Moore N.R.; Cruickshank D.J.; Bennett B. GBR BR J OBSTET GYNAECOL 1993 100/4 (370-374) Objective-To examine the behavior of the major inhibitors Int J Gynecol Obstet 44
of tibrinoysis (PAI-I and PAI-2) in normal pregnancy and pregnancy complicated by either pre-eclampsia or hydatidiform mole. Design - Prospective study. Setting - Antenatal Clinic and Maternity Hospital. Subjects - Eleven women with established pre-eclampsia and eleven women, matched by age, parity, and duration of pregnancy who were undergoing uncomplicated pregnancy. Two women having surgery for hydatidiform mole. Main outcome measure - Plasma levels of PAI-I and PA1-2 antigens determined by sensitive specific ELISA. Functional identification of PAI- by nondenaturing gel electrophoresis with overlay zymography. Results - In preeclampsia PAI- antigen was significantly lower than in normal pregnancy (105.3 f 34.9 vs. 187.1 f 67.9 ng/ml; P < 0.001). In contrait PAI-I antigen was significantly higher in preeclampsia than in normal pregnancy (170.7 f 71.2 vs. 113.8 f 35.6 &ml; P < 0.05). In consequence the ratio of PAI-I/PAI-2 increased markedly in pre-eclampsia (2.5 versus 0.6). No PAI- was detected in plasma of women with hydatidiform moles. Conclusions PA1-2 levels fell significantly in pre-eclampsia probably as a result of decreased placental mass or function. The raised PAI-I level in preeclampsia may reflect a response to hypertension or renal damage that is not specific to pregnancy or may reflect altered placental function. The use of the ratio of PAI-l/PAI-2 assists in separating normal from abnormal pregnancies. Cord blood erythropoietinin relation to different markers of fetal hypoxia Maier R.F.; Bohme K.; Dudenhausen J.W.; Obladen M. DELI OBSTET GYNECOL 1993 81/4 (575-580) Objective: To investigate the relationship between erythropoietin concentration in umbilical venous blood and clinical signs of fetal hypoxia. Methods: We measured erythropoietin concentrations in umbilical venous blood from 200 consecutively born neonates using an enzyme-linked immunosorbent assay (ELISA) with two monoclonal antibodies. Results were available within 6 h. Inter-assay variation was 8.5% and the mean intra-assay variation was 14.2%. Results: Using a multiple regression analysis, we found that the erythropoietin concentration correlated significantly (P < 0.01) with fetal growth retardation and umbilical acidosis but not with gestational age, meconium-stained amniotic fluid (AP), abnormal fetal heart rate (FHR) pattern, or Apgar score at 5 min. Median erythropoietin concentrations were 25.1 mu/ml in infants with no risk factors or complications during pregnancy and delivery (n = l9), 25.8 mu/ml after complicated pregnancy (n = 95), 50.6 mu/ml with meconium-stained AF (n = l2), 44.7 mU abnormal FHR pattern (n = IO), and 72.6 mu/ml with umbilical acidosis (n = 24). The median erythropoietin concentration increased significantly with decreasing pH and with increasing base deficit in umbilical arterial blood. The erythropoietin concentration in umbilical venous blood (cutoff value 50 mu/ml) discriminated between infants with no clinical signs of fetal hypoxia and those with umbilical acidosis with a sensitivity of 75% and a specificity of 90%. Conclusions: Elevated erythropoietin concentrations in umbilical venous blood indicate prolonged fetal hypoxia. The ELISA technique might be a useful