Reduction of serum serotonin precursors after veralipride treatment for postmenopausal hot flushes.

OBJECTIVE: The pathogenesis of hot flushes involves several brain neurotransmitter systems, and changes in serotonin turnover have been hypothesized. Veralipride is an anti-dopaminergic agent that relieves hot flushes and putatively also modulates serotonergic neurons. To further elucidate this relationship, in the present study we evaluated whether administration of veralipride for relief of hot flushes is able to affect serum levels of the serotonin precursor tryptophan in postmenopausal women. METHODS: Twenty-four postmenopausal women were randomly assigned to receive veralipride (100 mg/day) or similar placebo tablets for 3 months (n = 12 per group). Free tryptophan and total tryptophan (free + protein-bound) levels were assayed before and monthly by high pressure liquid chromatography. Data were analyzed with repeated measures ANOVA and Student-Newman-Keuls post hoc test. RESULTS: Relief of hot-flushes was achieved with complete suppression of symptoms after veralipride, but not placebo, treatment. In the veralipride group, total tryptophan levels significantly (p < 0.05) decreased from baseline (11.2 +/- 0.4 microg/ml) to 3 months (8.0 +/- 0.3 microg/ml), as well as free tryptophan concentrations (baseline 2.1 +/- 0.1 microg/ml; after 3 months 1.3 +/- 0.1 microg/ml; p < 0.05). No changes were recorded in the placebo group. CONCLUSION: Women treated with veralipride for relief of menopausal symptoms show a decrease in serum levels of serotonin precursors, suggesting that the brain serotonergic system may be involved in the pathogenesis of postmenopausal vasomotor symptoms.

Serum levels of tryptophan, 5-hydroxytryptophan and serotonin in patients affected with different forms of amenorrhea.

Tryptophan (Trp) is present in the serum, partly bound to albumine and in the free form. The unbound portion of circulating tryptophan has the property of crossing the hematoencephalic barrier and being converted within the brain into serotonin (5-HT) through the enzymatic processes of hydroxylation and decarboxylation. The serotoninergic system plays an important role in neuroendocrine control of reproductive hormone secretion, and in particular, it may influence GnRH pulsatility, a function essential for reproductive processes. In this study, we analysed serum levels of tryptophan, serotonin and 5-hydroxytryptophan (5-HTP) in women with three different forms of amenorrhea: 16 patients were diagnosed with anorexia nervosa, 60 patients with functional hypothalamic amenorrhea, and 14 patients with hyperprolactinemia. Data were compared with those of a group of 25 healthy women. Serum Trp levels were significantly (P ≤ 0.05) lower in the anorexic (11.64 ± 0.53 µg/ml, mean ± S.E.) than in the control (12.98 ± 0.37 µg/ml) groups. In addition, in the anorexic group a statistical dispersion of Trp values was shown indicating a bimodal data distribution suggesting the existence of two different subgroups of patients. Regarding 5-HTP, an increase of its serum level was observed in all the groups with amenorrhea with the highest value in hyperprolactinemic patients. On the contrary, no statistical differences in serum 5-HT levels among the four analyzed groups were observed.This study shows that women affected by various forms of amenorrhea present an altered metabolism of tryptophan via serotonin and, in particular, markedly high differences are observed between the two subgroups of anorexic patients.

Menopause alters the metabolism of serum serotonin precursors and their correlation with gonadotropins and estradiol.

OBJECTIVE: Tryptophan, the serotonin (5-HT) precursor, is circulating in blood in both free (FT) and protein-bound forms. The free form crosses the hematoencephalic barrier and is converted into 5-HT. During the fertile years, tryptophan levels are negatively correlated to gonadotropin concentrations. The present study aims to evaluate the correlation between circulating tryptophan, gonadotropin and estradiol (E2) levels postmenopause. METHODS: Serum levels of total tryptophan (TT, free + protein-bound) and FT, and plasma luteinizing hormone (LH), follicle stimulating hormone (FSH), and E2 were determined in 15 postmenopausal women and 15 cycling women during follicular (days 7-10), periovulatory (days 13-16) and luteal (days 21-24) phases of the menstrual cycle. Data were analyzed by ANOVA, linear correlation coefficients and hierarchical cluster analysis of variables. RESULTS: TT, but not FT, levels were significantly (p<0.05) higher in postmenopausal (12.07+/-0.40 microg/ml) than fertile women in the periovulatory period (10.46+/-0.36 microg/ml). In postmenopausal women, there was no significant correlation between TT and FT, nor between these tryptophan forms and gonadotropins, but only between FT and E2. Cluster analysis showed that the main cluster composed by FSH-LH-TT-FT observed in fertile women was absent in postmenopause, since both serum tryptophan forms were distant from gonadotropins. CONCLUSION: High TT levels circulate in postmenopausal women, with lack of correlation between TT and FT, and FT/TT and gonadotropins. Since estrogens play a pivotal role on central 5-HT metabolism, estrogen deprivation may alter the brain tryptophan utilization for 5-HT synthesis and its relation to gonadotropin release.

Serum fluctuations of total and free tryptophan levels during the menstrual cycle are related to gonadotrophins and reflect brain serotonin utilization.

BACKGROUND: Serotoninergic (5-HT) neurons are suggested to regulate estrous cycle in animal models. In the present study we evaluated whether a relationship exists between the serotoninergic precursors in the central nervous system and the gonadotrophin-ovarian cyclic function. METHODS: We measured 5-HT precursors [free (FT) and total (TT) tryptophan] and LH, FSH and 17beta-estradiol (E2) levels in the serum of 15 fertile women with normal menstrual cycles during the follicular (cycle days 1-5, 7-11), mid-cycle (cycle days 14-16) and luteal (cycle days 17-19, 22-24) phases. RESULTS: TT and FT were significantly increased in the 7-11 and 17-19 cycle days and were decreased at mid-cycle (P < 0.01), with a cyclic and opposite behaviour when compared to that of FSH and LH. Indeed, correlation analysis through the matrix of mean values showed that LH was negatively correlated to TT (r = -0.636) and FT (r = -0.574), as well as FSH (TT, r = -0.655; FT, r = -0.663), and that TT and FT were positively correlated to each other (r = 0.801; P < 0.001). Furthermore, whilst the two FT peaks reached approximately the same levels in the follicular and luteal phase, TT levels were approximately 30% higher in the luteal than in the follicular phase of the cycle: thus in the first (follicular) phase FT peak was relatively higher than that of TT, whereas the contrary occurred in the second (luteal) phase of the cycle. CONCLUSIONS: Both TT and FT levels have cyclic variations throughout the menstrual cycle, being lowest at mid-cycle (14-16 cycle days), concomitant with the highest LH and FSH concentrations, and higher before and after mid-cycle phase, coinciding with the lowest circulating LH/FSH levels. Since TT and FT levels in the plasma have cyclic changes, our study: (i) suggests that a consumption of serum serotonin precursors takes place concomitant with gonadotrophin release during menstrual cycle; (ii) may represent an in vivo model to investigate this relationship in women in different physiopathological conditions.

Intravenous iron therapy in pregnancy anemia: hematological response in relation to gestational age.

This study was undertaken to evaluate the response to parenteral administration of iron in 62 pregnant patients with asiderotic anemia and mean initial hemoglobin (Hb) concentrations (Hb1) of 9.91+/-(SD) 1.13 g/dl. Iron (742+/-366 mg) was administered intravenously, and the response to treatment was classified according to the rise in Hb (VarHb; 0.97+/-0.77 g/dl) and evaluated after 19.5+/-14.6 (range 4-57) days. It was found that the VarHb was inversely correlated with the Hb1 value (r = -0.46; p<0.001) and only weakly correlated with the number of vials administered. In addition, two-cluster analysis of patients on the basis of VarHb and gestational age resulted in two significantly different groups (p<0.001): >28 weeks of pregnancy (n = 39, group 1: 1.27+/-0.66, range 0.1-3.3 g/dl) and < or =28 weeks of pregnancy (n = 23, group 2: 0.45+/- 0.69, range 0.4-2.3 g/dl). No difference was found between groups 1 and 2 in relation to Hb1, iron dose, and therapy duration. The number of patients with VarHb >0.8 g/dl was found to be higher in group 2 than in group 1: 31/39 versus 8/23 (p<0.001). These results indicate that the response to intravenous iron therapy in pregnancy anemia is related to Hb1 level and gestational age at the onset of treatment and probably depends on the erythropoietin response to anemia.

Vitamin B12 levels in pregnancy influence erythropoietin response to anemia.

OBJECTIVE: to discover whether vitamin B12 levels influence erythropoietin (EPO) response during pregnancy. STUDY DESIGN: 117 pregnant women after the 27th week were divided into three groups according to log vitamin B12 concentrations. EPO (by enzyme-linked immunosorbent assay), Hemoglobin (Hb) and medium corpuscular Hb concentration (MCHC) were measured in these patients. The tests used were: calculation of simple statistic, regression coefficient and t-independent test with level of significance. An exclusive partitioned cluster method (K-means procedure) was used. RESULTS: For the lowest vitamin B12 levels there is an unexpected lack of difference in plasma EPO levels between anemic and nonanemic patients. In fact EPO levels were high even in nonanemic women. The only parameter of the blood count that seems to change in relation to vitamin B12 concentration is the MCHC. CONCLUSIONS: These results suggest that low vitamin B12 levels inhibit the suppression of EPO response in nonanemic pregnant women probably through MCHC modifications.

Intravenous iron therapy for severe pregnancy anemia with high erythropoietin levels.

BACKGROUND: To demonstrate that intravenous (IV) iron therapy rapidly can secure the physiologic correction of severe nonhemorrhagic anemia more safely than blood component therapy and recombinant erythropoietin treatment. CASE: An 18-year-old woman with beta-thalassemia in her 33rd week of gestation had a hemoglobin level of 4.8 g/dL and an erythropoietin value of 191 mU/mL. After IV iron administration, erythropoietin rapidly decreased and hemoglobin increased to 8.1 g/dL in correlation with estriol elevation. A healthy infant with normal hemoglobin and ferritin levels was delivered at 42 weeks by cesarean. CONCLUSION: Intravenous iron administration rapidly corrected severe nonhemorrhagic anemia in a pregnant patient and may produce an improvement in fetal indices. High erythropoietin levels predict a good response to iron and may obviate the need for blood transfusions and recombinant erythropoietin administration, at least until this therapy is tried.

Relation between erythropoietin and vitamin B12 in normal and anemic pregnant women.

In this cross-sectional study of 178 pregnant women between the 7th and 42nd week of pregnancy, we analyzed correlations between erythropoietin (EPO) and vitamin B12 (B12) in different stages of pregnancy and in relation to hemoglobin (Hb) levels. Patients with hypertension, fetal growth retardation and severe systemic diseases were excluded. EPO (by ELISA), B12 (by RIA) and Hb were assayed in the same blood sample taken on admission. On the basis of weeks of pregnancy, EPO levels and B12 levels, the 178 subjects were found to fall into two clusters, before and after the 27th week of gestation. The correlation coefficient between EPO and B12 was highly significant in the first group but not in the second (R = -0.33; p < 0.01). When the patients were divided on the basis of Hb levels (< or = or > 11 g/dl), a significant correlation was found only in the 88 patients with Hb > 11 g/dl (R = -0.44; p < 0.001) and not in the 72 anemic subjects. Moreover, in the former group the correlation between EPO and B12 was high before and after the 27th week, unlike in the latter group for which no significant correlation was found. These results suggest that EPO and B12 act together to establish normal erythropoiesis in pregnancy.

Pattern of vitamin B12 and folic acid during pregnancy.

The aim of this study was to evaluate folate and vitamin B12 serum concentrations and their reciprocal relationships during pregnancy in relation to gestational age and levels of hemoglobin. Serum levels of vitamin B12 (B12) and folic acid (FA) were assessed by RIA in 213 women between the 6th and 43rd week of pregnancy. For 195 of these subjects, hemoglobin and hematocrit values were available. The logarithm (log) of B12 levels was found to be inversely correlated with weeks of pregnancy (R = -0.261; p < 0.001). A decrease in B12 levels occurred before the 27th week and was significant only in the subgroup of patients having hemoglobin levels above 11 g/dl. The log FA concentrations did not show any significant correlation with weeks of pregnancy irrespective of Hb levels. There was also a highly significant correlation between log B12 and log FA after 27 weeks and in the subgroups divided according to Hb levels (< or = and > 11 g/dl). It is therefore concluded that: (1) the demand for vitamin B12 is high in the first 27 weeks of pregnancy due to increasing maternal and embryo-fetal erythropoiesis and in order to sustain normal maternal Hb levels in the last weeks of pregnancy; (2) vitamin B12 might favor the absorption and utilization of FA after 27 weeks of pregnancy.

The significance of the relationship between serum levels of cobalamin and MCHC during pregnancy.

Cobalamin concentration and mean corpuscular haemoglobin concentration (MCHC) were found to have highly significant inverse correlation with the weeks of pregnancy (respectively -.278 P < .0001 and .342 P < .00001) in 205 pregnant women. Among all haematometric parameters cobalamin concentrations during pregnancy only correlates with MCHC (P < .01). This datum seems to indicate an influence of B12 on erythropoiesis which adequate the concentration of haemoglobin to circulatory modifications of pregnant women.

Erythropoietin and transferrin concentrations during pregnancy in relation to hemoglobin levels.

Serum levels of erythropoietin (EPO) were assayed by ELISA at the same time as red blood cells (RBC), hemoglobin (Hb), hematocrit (Hct), serum iron and transferrin in 136 pregnant women, divided on the basis of hemoglobin values (> or < or = 10.5 g/dl) and weeks of pregnancy (< or > or = 27th week). In the overall population, a parallel increase with weeks of pregnancy was shown by serum concentrations of EPO expressed as a logarithm (multiple R = 0.367, P < 0.0001), and transferrin levels (multiple R = 0.529, P < 0.0001). It was found that EPO levels did not differ significantly between anemic and non-anemic patients before the 27th week, but the difference became highly significant (P < 0.01) after the 27th week in favour of anemic patients. Before the 27th week, the correlations between log EPO and RBC, Hct, Hb and iron were not significant, whereas the correlation between log EPO and transferrin was significant (P < 0.01); after the 27th week, the correlations and significance of the regression found were: log EPO vs Hb (Pearson coefficient = -0.384; P < 0.001), vs Hct (Pearson coefficient = -0.370; P < 0.01), vs transferrin (Pearson coefficient = 0.392; P < 0.0001), vs iron (Pearson coefficient = -0.274, P < 0.05). In the population divided according to Hb levels, the correlation was positive and significant in both groups between log EPO and transferrin (Hb > 10.5 g/dl: Pearson coefficient = 0.524, P < 0.0001; Hb < or = 10.5: Pearson coefficient = 0.614, P < 0.0001), but was inverse and significant only in the group with Hb < or = 10.5 g/dl between log EPO and serum iron (Pearson coefficient = -0.481, P < 0.01). The variations in EPO were related to Hb levels after the 27th week of pregnancy and were closely correlated with transferrin over the whole period. The physiological mechanism of these changes is discussed.

Iron balance in pregnancy in relation to anemia.

Blood levels of iron, transferrin and ferritin varied in the course of pregnancy (6th to 42nd week) in 136 women. Analysis of variance showed that the factor "weeks of pregnancy" (< or = 27 or > 27 weeks) was correlated differently with the variables "ferritin" and "iron" according to the presence or absence of anemia (Hb < or = or > or = 11 g/dl). In anemic women the correlation was significant (F-ratio = 5.90; P = 0.018) for iron (which decreased from initial low level until term) but not ferritin, whereas in non-anemic women the correlation was significant (F-ratio = 13.306; P = 0.0006) for ferritin (which decreased to less than 20 micrograms/ml around the 34th week) but not iron. In both anemic and non anemic subjects, transferrin levels increased with weeks of pregnancy. It is concluded that towards the end of pregnancy, some decrease in ferritin (> or = 15 micrograms/ml) is physiological, and in the absence of anemia (Hb > 11 g/dl) iron supplements are not necessary.

QRS changes in direct fetal electrocardiogram during uterine overstimulation; report of four cases.

Four cases are presented in which increased QRS complex voltages or deviation of the mean electrical axis were observed in the fetus by direct fetal electrocardiogram (ECG) during delivery under anaesthesia. There was transformation of the initial QRS aspect before delivery. These changes were only observed when large doses of oxytocin (20 IU in 500 ml) were used after Pentothal administration in deliveries in which other fetal ECG alterations (bradycardia, ST changes, T inversion) and/or low pH values had been observed. In case 1 there were ST level changes, inversion of the T wave and transformation of the QRS complex from RS to Rs. Case 2 showed a change from RS to QR type complex associated with repolarization defects. In cases 3 and 4, ST level changes, inversion and increased QRS complex voltages were observed. We checked that the modifications observed were not due to changes in position of the fetus during recording. It is thought that the acute redistribution of the fetal blood volume due to oxytocin overstimulation in fetal hearts with hypoxic signs may lead to compensatory mechanisms such as tachycardia, increased contractile activity (higher QRS) and functional predominance of one side of the fetal heart (deviation of the electrical axis) subjected to sudden load.

Total and free tryptophan levels in serum of newborn infants. Relationships with the Serotonin and nicotinic acid pathways.

The levels of total and free serum tryptophan have been determined in a group of newborn babies at birth, one day later and five days after birth. Total and free tryptophan levels are very high in the umbilical cord at birth, decrease quickly and significantly 24 hours after birth and show a slight, but not significant increase five days after birth. The high tryptophan levels at birth and their decrease in the first day after birth recall previous data on tryptophan metabolism "via" serotonin and "via" nicotinic acid. Since the synthesis of cerebral serotonin depends on the availability of tryptophan, and is thus linked to the level of free tryptophan in blood, these data suggest that synthesis of serotonin as well may be elevated at birth and may reach the values of adult soon afterwards. With respect to the nicotinic acid pathway the high levels of tryptophan in blood may be related to the synthesis of tryptophan pyrrolase, which is present in the liver of newborn babies.