Calcium metabolism and calcium-regulating hormones during normal pregnancy

Dynamic changes in maternal and fetal calcium metabolism during pregnancy were investigated by simultaneously measuring serum or urinary concentrations of calcium and calcium regulating hormones. Serum concentrations of total calcium in maternal serum decreased significantly, but those of ionized calcium decreased slightly but not significantly late in pregnancy. Maternal serum levels of parathyroid hormone (PTH) were almost the same as non-pregnant values throughout pregnancy, but those of 1 alpha, 25-(OH)2 vitamin D3 increased as pregnancy progressed. Serum levels of calcitonin (CT) in maternal serum increased late in pregnancy but were statistically not significant. Calcium concentrations in maternal urine during pregnancy showed a slight decrease. It is suggested that calcium absorption in the maternal intestine might be increased by the action of increased serum 1 alpha, 25-(OH)2 vitamin D3, and the maternal bone during pregnancy might be kept at the same density as in non-pregnant women because increased CT protects the maternal skeleton by resisting the bone-resorbing activities of 1 alpha, 25-(OH)2 vitamin D3. The concentrations of ionized calcium and CT in umbilical cord blood were higher, but those of PTH and 1 alpha, 25-(OH)2 vitamin D3 were significantly lower than those of the maternal blood at term. It is considered that an active transport mechanism may be involved in the transplacental supply of calcium, and calcium transport from mother to fetus results in a decrease in the calcium concentrations of the maternal serum. Calcium transported into the fetus may be used as fetal body composition such as accumulation in the bone mainly by the action of serum CT.     

Correlation of hormones with lipid and lipoprotein levels during normal pregnancy and postpartum

In a comprehensive study the concentrations of plasma lipids and lipo- and apolipoproteins were measured in 24 nonpregnant women (control) and longitudinally in 42 women throughout gestation and postpartum. The results were correlated with hCG, 17 beta-estradiol (E2), progesterone (PG), human placental lactogen (hPL), and insulin levels by time series analysis. Insulin concentrations were constant until week 25 and increased thereafter. Plasma E2, PG, and hPL as well as plasma lipid levels rose continuously during gestation. Apolipoproteins AI, AII, and B concentrations increased until weeks 25, 28, and 32, respectively, and remained constant until term. Low density lipoprotein cholesterol reached maximum levels at week 36. High density lipoprotein cholesterol exhibited a triphasic behavior, with maximum levels at week 25, a fall until week 32, and maintenance of the level until term. Time series analysis revealed positive correlations with E2, PG, and hPL. These results provide evidence that apoprotein concentrations undergo pronounced serial changes during gestation, which in part might be due to the effect of E2. Furthermore, the importance of hPL as a determinant of the plasma levels of total and free cholesterol, triglycerides, and phospholipids is now documented.     

Malaria and pregnancy: placental cytokine expression and its relationship to intrauterine growth retardation

Malaria infections during pregnancy can lead to the delivery of low-birth-weight infants. In this study, cytokine mRNA was measured in placentas from 23 malaria-infected and 21 uninfected primigravid women who had delivered in Mangochi, Malawi, a region with a high rate of transmission of falciparum malaria. Significantly increased expression of interleukin (IL)-1beta, IL-8, and tumor necrosis factor (TNF)-alpha and decreased expression of IL-6 and transforming growth factor-beta1 were found in malaria-infected compared with uninfected placentas. TNF-alpha and IL-8 were produced by maternally derived hemozoin-laden placental macrophages. Increased TNF-alpha expression was associated with increased placental hemozoin concentrations. Increased TNF-alpha or IL-8 expression in the placenta was associated with intrauterine growth retardation but not with preterm delivery. The results suggest that malaria infections induce a potentially harmful proinflammatory response in the placenta.     

Changes of serum melatonin level and its relationship to feto-placental unit during pregnancy

Serum melatonin concentrations were studied in normal pregnant women and in women with several types of pathologic pregnancies, e.g., twins, preeclampsia or intrauterine growth retardation (IUGR). Blood samples were collected from the maternal antecubital vein at 14:00 hr (daytime) and 02:00 hr (nighttime) during pregnancy, and also from the umbilical vein and artery immediately after delivery. Serum melatonin concentrations were measured by radioimmunoassay. Daytime serum melatonin levels in normal (single fetus; singleton) pregnancies were low. While the levels showed an increasing tendency toward the end of pregnancy, no statistically significant changes occurred. On the other hand, the nighttime serum melatonin levels increased after 24 weeks of gestation, with significantly (P < 0.01) high levels after 32 weeks; these values decreased to non-pregnant levels on the 2nd day of puerperium. Nighttime serum melatonin levels were significantly (P < 0.05) higher in twin pregnancies after 28 weeks of gestation than in singleton pregnancies, whereas the patients with severe preeclampsia showed significantly (P < 0.05) lower serum melatonin levels than the mild preeclampsia or the normal pregnant women after 32 weeks of gestation. Melatonin concentrations in umbilical vessels showed a higher tendency in neonates who were born during at night compared with the other neonates; moreover, those in the umbilical artery were generally higher than those in the umbilical vein. The present results indicate that in humans, the maternal serum melatonin levels show a diurnal rhythm, which increases until the end of pregnancy, reflecting some pathologic states of the feto-placental unit. Fetuses may produce melatonin with a circadian rhythm.     

Gastroenteropancreatic hormones in normal and gestational-diabetic pregnancy: response to oral lipid

The effect of normal and gestational-diabetic pregnancy on the gastroenteropancreatic (GEP) hormone response to lipid ingestion was studied in 17 women, 8 normal and 9 with gestational diabetes, by determination of the plasma concentrations of gastric inhibitory polypeptide (GIP), gut glucagon-like immunoreactivity (gut GLI), insulin, glucagon, and pancreatic polypeptide (PP) following the ingestion of 67 g of triglyceride in late pregnancy and postpartum. Also, the plasma concentrations of free fatty acids (FFA), triglyceride, and glucose were determined. In both groups fasting plasma triglyceride and insulin were increased and PP was decreased. Fasting plasma glucose and gut GLI were decreased in normal pregnancy, but were unaltered in gestational-diabetic pregnancy. Fasting plasma glucagon were unaltered in normal but increased in gestational diabetic pregnancy. In both groups of women the GIP response to triglycerides was impaired in pregnancy. Postpartum, the GIP response was greater in the gestational diabetics than in normal women whereas no difference was found in pregnancy. The other hormones and metabolites responded similarly in pregnancy and postpartum and no difference between normal women and women with gestational diabetes was found. It is concluded that the GIP response to triglycerides is impaired in pregnancy.     

Ghrelin与消化系统的关系研究进展

Ghrelin是新近发现的一种脑肠肽,1999年由日本科学家Kojima从大鼠胃中分离出来,是生长激素促分泌素受体(GHSR)的天然配体,故又称生长素。Ghrelin可调节生长激素(GH)和其他激素的释放,调节能量代谢,抑制肿瘤细胞增殖,影响心血管功能。近来研究发现,Ghrelin与胃动素(motilin)及消化系统关系密切,此文就这方面的研究进展作一综述。     

Glucose-alanine relationship in normal human pregnancy

In order to quantify the glucose-alanine relationship in normal human pregnancy, the turnover rates of alanine and the incorporation of alanine carbon into glucose were quantified in 15 pregnant women during the last 4 weeks of gestation following a ten-hour fast. Eight nonpregnant women of similar age group were studied as controls. l-[2,3-¹³C₂]Alanine and d[6,6-²H₂]glucose were infused as tracers. The ¹³C enrichment of alanine, lactate, and glucose and the deuterium enrichment of glucose were measured by gas chromatography-mass spectrometry. In five pregnant and five nonpregnant women, the contribution of alanine carbon to expired CO₂ directly and via glucose was estimated by combining indirect respiratory calorimetry with the tracer infusions. The alanine turnover rates in the pregnant and nonpregnant women were similar (pregnant, 4.43 ± 0.82 μmol/kg × min; nonpregnant, 4.11 ± 1.08 μmol/kg × min, mean ± SD). However, the fraction of alanine incorporated into glucose was significantly lower during pregnancy (23.5 ± 8.3% v 30.8 ± 8.2%, P < .04). In pregnant women, 20% of lactate pool was derived from alanine as compared with 28% in nonpregnant subjects (P < .02). Twenty-four percent of alanine turnover was converted to CO₂ in both pregnant and nonpregnant women. The plasma insulin concentration was increased significantly during pregnancy (P < .05). These data suggest that gluconeogenesis from alanine is attenuated during pregnancy. This decrease in gluconeogenesis is not the result of decreased alanine flux, but due to intrinsic intrahepatic mechanism such as decreased deamination of alanine mediated by the predominant insulin effect or a decreased hepatic uptake of alanine. These unique adaptive responses in human pregnancy result in conservation of maternal nitrogen for new maternal and fetal protein synthesis.     

正常孕妇早中晚孕期的甲状腺激素参考值范围

目的 建立正常孕妇早、中、晚孕期的甲状腺激素参考值范围,为诊断、治疗、监测(或筛查)孕妇甲状腺疾病以及相关研究提供参考.方法 在碘营养充足地区一次性横断面调查孕妇及非妊娠妇女,通过统一设计的调查表和实验室检测结果严格筛选出505名不同孕期的正常孕妇和153名正常非妊娠妇女(作为对照),建立甲状腺激素参考值范围;甲状腺激素测定采用化学发光免疫测定方法,参考值范围采用中位数(P50)及双侧限值(P2.5和P97.5)表示.结果 进入本研究的所有妇女家庭均食用加碘盐,她们的尿碘中位数均达到了适宜水平,表明这些妇女不存在碘缺乏或碘过量.孕妇的TSH水平在孕早期明显低于非妊娠妇女(P<0.01),孕中期开始回升,但到孕晚期时仍未完全恢复到非妊娠水平;孕妇的FT4和FT3,随妊娠时间逐渐下降,孕中期和孕晚期均明显低于非妊娠妇女(P<0.01);孕妇的TT4和TT3自孕早期开始即明显升高(P<0.01),至孕中期达峰值,大约是非妊娠的1.5倍.结论 孕妇的甲状腺激素水平不同于非妊娠妇女,早、中、晚孕期之间也存在明显差异.因此,建立正常孕妇早、中、晚孕期的甲状腺激素参考值范围具有临床意义.     

Hemostasis during normal pregnancy and puerperium

During normal pregnancy the hemostatic balance changes in the direction of hypercoagulability, thus decreasing bleeding complications in connection with delivery. The most important initial factor for acute hemostasis at delivery is, however, uterine muscle contractions, which interrupt blood flow. Global tests such as Sonoclot signature, the Thromboelastogram, and a new method analyzing overall plasma hemostasis, all show changes representative of hypercoagulability during pregnancy. Increased endogenous thrombin generation, acquired activated protein C resistance, slightly decreased activated partial thromboplastin time (aPTT) and increased prothrombin complex level (PT) measured as international normalized ratio (INR) of less than 0.9 have been reported as well. In normal pregnancy, the platelet count is within normal range except during the third trimester when benign gestational thrombocytopenia, 80 to 150 x 10 9/L, can be observed. Platelet turnover is usually normal. Activation of platelets and release of beta-thromboglobulin and platelet factor 4 are reported. The bleeding time is unchanged during normal pregnancy. Most blood coagulation factors and fibrinogen increase during pregnancy. Factor (F) XI is the only blood coagulation factor that decreases. Blood coagulation inhibitors are mainly unchanged but the level of free protein S decreases markedly and the level of tissue factor pathway inhibitor increases. Thrombomodulin levels increase during pregnancy. Fibrinolytic capacity is diminished during pregnancy, mainly because of markedly increased levels of plasminogen activator inhibitor-1 (PAI-1) from endothelial cells and plasminogen activator inhibitor-2 (PAI-2) from the placenta. Thrombin-activated fibrinolysis inhibitor is reported to be unaffected. The total hemostatic balance has been studied by analyses of prothrombin fragment 1+2, thrombin-antithrombin complex, fibrinopeptide A, soluble fibrin, D-dimer, and plasmin-antiplasmin complex. There is activation of blood coagulation and a simultaneous increase in fibrinolysis without signs of organ dysfunction during normal pregnancy. These changes increase as pregnancy progresses. During delivery, there is consumption of platelets and blood coagulation factors, including fibrinogen. Fibrinolysis improves and increases fast following childbirth and expulsion of the placenta, resulting in increased D-dimer levels. These changes are self-limiting at normal delivery. The hemostatic changes, noted during pregnancy, normalize after delivery within 4 to 6 weeks. Platelet count and free protein S, however, can be abnormal longer. Hemostasis should not be tested earlier than 3 months following delivery and after terminating lactation to rule out influences of pregnancy. PAI-1 and PAI-2 levels decrease fast postpartum, but PAI 2 has been detected up to 8 weeks postpartum. alpha 2 -antiplasmin, urokinase, and kallikrein inhibitor levels have been reported to be increased 6 weeks postpartum.     

Haemoglobin during pregnancy: relationship to erythropoietin and haematinic status

OBJECTIVE: To investigate the effect of haematinic status on erythropoietin throughout pregnancy in order to assess whether haematinic supplementation is appropriate for all pregnant women or should be reserved for individuals in whom deficiency has been identified. METHODS: A prospective, repeated-measures, longitudinal study of 263 women enrolled at an antenatal clinic in a district general hospital who received standard obstetric management including haematinic supplements. Haematological indices, iron status, folate and B12 status, and erythropoietin levels were measured by standard methods at scheduled intervals throughout pregnancy. The relationships between the measurements were analysed using statistical models which took into account the serial correlation between repeated measurements on the same individuals. RESULTS: Erythropoietin levels rose throughout pregnancy from a mean of 22.8 mU/mL at booking to 43.7 mU/mL at 38 wk. There was a significant relationship between erythropoietin levels and haemoglobin, ferritin, TIBC and folate. The relationship was strongest between erythropoietin and haemoglobin. Erythropoietin levels were influenced by parity but not maternal age. CONCLUSION: Haematinic levels, particularly iron are related to the rise in serum EPO which occurs during pregnancy. Therefore, haematinic deficiency in pregnancy will result in increased stimulation of erythroid progenitor cells by erythropoietin. While haematinic supplementation is not always prescribed throughout pregnancy, haematinic status must be assessed on an individual basis and supplementation provided as required.     

Leptin during and after preeclamptic or normal pregnancy: its relation to serum insulin and insulin sensitivity

Hyperleptinemia may be part of the insulin resistance syndrome. We studied serum leptin in preeclampsia, which is an insulin-resistant state, and sought associations between leptin and insulin or insulin sensitivity during and after pregnancy. Twenty-two proteinuric preeclamptic women and 16 normotensive controls were studied during the third trimester. Leptin was higher in preeclampsia (mean +/- SE, 34.6 +/- 3.9 v 20.0 +/- 3.3 microg/L, P = .002) and correlated directly with the level of proteinuria (r = .47, P = .03) and normal pregnancy (r = .52, P = .04), whereas insulin sensitivity as assessed by an intravenous glucose tolerance test showed no relationship to leptin. Leptin was 19.0 +/- 3.6 microg/L in 14 preeclamptic women and 10.1 +/- 2.0 microg/L (P = .11) in 11 controls 3 months after delivery. Leptin correlated directly with insulin both in preeclamptic puerperal women (r = .63, P = .02) and in controls (r = .81, P = .003). Leptin and insulin sensitivity correlated only in preeclamptic puerperal women (r = -.59, P = .02). In conclusion, (1) serum leptin is elevated in preeclampsia, (2) insulin is an important determinant of serum leptin in preeclamptic and normotensive women both during pregnancy and in the puerperium, and (3) hyperleptinemia may be part of the insulin resistance syndrome also in women with prior preeclampsia.     

What happens to the normal thyroid during pregnancy?

Hormonal changes and metabolic demands during pregnancy result in profound alterations in the biochemical parameters of thyroid function. For the thyroidal economy, the main events occurring during pregnancy are: a marked increase in serum thyroxine-binding globulin levels; a marginal decrease in free hormone concentrations (in iodine-sufficient conditions) that is significantly amplified when there is iodine restriction or overt iodine deficiency; a frequent trend toward a slight increase in basal thyrotropin (TSH) values between the first trimester and term; a direct stimulation of the maternal thyroid gland by elevated levels of human chorionic gonadotropin (hCG), which occurs mainly near the end of the first trimester and can be associated with a transient lowering in serum TSH; and finally, modifications of the peripheral metabolism of maternal thyroid hormones. Together, metabolic changes associated with the progression of gestation in its first half constitute a transient phase from a preconception steady-state to the pregnancy steady-state. In order to be met, these metabolic changes require an increased hormonal output by the maternal thyroid gland. Once the new equilibrium is reached, increased hormonal demands are maintained until term, probably through transplacental passage of thyroid hormones and increased turnover of maternal thyroxine (T4), presumably under the influence of the placental (type III) deiodinase. For healthy pregnant women with iodine sufficiency, the challenge of the maternal thyroid gland is to adjust the hormonal output in order to achieve the new equilibrium state, and thereafter maintain the equilibrium until term. In contrast, the metabolic adjustment cannot easily be reached when the functional capacity of the thyroid gland is impaired (such as in autoimmune thyroid disease and hypothyroidism) or when pregnancy takes place in healthy women residing in areas with a deficient iodine intake. The ideal dietary allowance of iodine recommended by the World Health Organization (WHO) is 200 microg iodine per day for pregnant women. In conditions with iodine restriction, enhanced thyroidal stimulation is revealed by relative hypothyroxinemia and goitrogenesis. Goiters formed during gestation may only partially regress after parturition. Pregnancy, therefore, represents one of the environmental factors that may explain the higher prevalence of goiter and thyroid disorders in the female population. An iodine-deficient status in the mother also leads to goiter formation in the progeny. When adequate iodine supplementation is given early during pregnancy, it allows for the correction and almost complete prevention of maternal and neonatal goitrogenesis. In summary, pregnancy is accompanied by profound alterations in the thyroidal economy, resulting from a complex combination of factors specific to the pregnant state, which together concur to stimulate the maternal thyroid machinery. Increased thyroidal stimulation induces, in turn, a sequence of events leading from physiological adaptation of the thyroidal economy observed in healthy iodine-sufficient pregnant women, to pathological alterations, affecting both thyroid function and the anatomical integrity of the thyroid gland, when gestation takes place in conditions with iodine restriction or deficiency: the more severe the iodine deficiency, the more obvious, frequent, and profound the potential maternal and fetal repercussions.     

Physiologic changes during normal pregnancy and delivery

The major adaptations of the maternal cardiovascular system that progress throughout gestation may unmask previously unrecognized heart disease and result in significant morbidity and mortality. Most of these changes are almost fully reversed in the weeks and months after delivery. Hemodynamic changes during pregnancy include increased blood volume, cardiac output (CO), and maternal heart rate; decreased arterial blood pressure; decreased systemic vascular resistance. CO increases up to 30% in the first stage of labor, primarily because of increased stroke volume; maternal pushing efforts in the second stage of labor can increase CO by as much as 50%.     

Serum osteoprotegerin/osteoclastogenesis-inhibitory factor during pregnancy and lactation and the relationship with calcium-regulating hormones and bone turnover markers

Pregnancy and lactation induce dynamic changes in maternal bone and calcium metabolism. A novel cytokine termed osteoprotegerin (OPG)/osteoclastogenesis-inhibitory factor (OCIF) was recently isolated; this cytokine inhibits osteoclast maturation. To define the effects of pregnancy and lactation on circulating OPG/OCIF in mothers, we studied the changes in the levels of OPG/ OCIF as well as those of calcium-regulating hormones and biochemical markers of bone turnover in the maternal circulation during pregnancy (at 8-11 weeks, at 22-30 weeks, at 35-36 weeks and immediately before delivery) and lactation (at 4 days and at 1 month postpartum). Serum intact parathyroid hormone levels did not change and were almost within the normal range in this period. In contrast, serum 1,25-dihydroxyvitamin D levels increased with gestational age and were above the normal range during pregnancy. After delivery, they fell rapidly and significantly (P<0.01) to the normal range. The levels of serum bone-specific alkaline phosphatase, one of the markers of bone formation, increased with gestational age. After delivery, these levels were further increased at 1 month postpartum. The levels at 1 month postpartum were significantly higher than those at 8-11 and 22-30 weeks of pregnancy (P<0.01 and P<0.05 respectively). The levels of serum C-terminal telopeptides of type I collagen, one of the markers of bone resorption, did not change during pregnancy. After delivery, they rapidly and significantly (P<0.01) rose at 4 days postpartum, and had then fallen by 1 month postpartum. Circulating OPG/OCIF levels gradually increased with gestational age and significantly (P<0.01) increased immediately before delivery to 1.40+/-0.53 ng/ml (means+/-S.D.) compared with those in the non-pregnant, non-lactating controls (0.58+/-0.11 ng/ml). After delivery, they fell rapidly to 0.87+/-0.27 ng/ml at 4 days postpartum and had fallen further by 1 month postpartum. These results suggest that the fall in OPG/OCIF levels may be partially connected with the marked acceleration of bone resorption after delivery.     

Ghrelin and growth hormone secretagogue receptor expression in mice during aging

In well-nourished humans, GH and IGF-I decline during aging, and the responsiveness of the GH axis to exogenous ghrelin is attenuated with age. Intriguingly, the GH/IGF-I axis is rejuvenated by chronic treatment with the ghrelin mimetic MK-0677, resulting in improvements in body composition, suggesting that frail elderly subjects might benefit from treatment with ghrelin and ghrelin mimetics. Mouse models are widely used to study the effects of ghrelin, but the impact of age on the ghrelin pathway is unclear. In this study, total and active ghrelin peptides were measured in plasma, and ghrelin mRNA was quantitated in brain tissue from different aged C57BL/6J mice. Surprisingly, plasma levels of ghrelin peptide slightly increased with age; ghrelin mRNA levels were similar in brains from mice aged 2, 6, 12, and 28 months but higher in mice aged 18 and 24 months. The tissue distribution of Ghsr1a mRNA (ghrelin receptor) was also characterized, and pituitary and brain exhibited the highest levels of expression. In the pituitary gland, the highest concentration of Ghsr1a mRNA was observed at age 1-2 months, it was lower at 6 months, and remained unchanged for up to 30 months of age. This result is consistent with the finding that GH release in response to exogenous ghrelin was not significantly different in mice aged 7-30 months. In the brain, Ghsr1a mRNA levels remained stable during aging. Hence, in C57BL/6J male mice, aging is not associated with changes in circulating ghrelin levels or changes in ghrelin receptor expression in the pituitary gland and brain.     

Prolactin and gonadal hormones during pregnancy in systemic lupus erythematosus

We performed prospective hormonal studies in 9 patients (5 active and 4 inactive) with systemic lupus erythematosus (SLE) during pregnancy (Weeks 10 to 37). Nine healthy pregnant women and 5 patients with rheumatoid arthritis (RA) were used for comparison. Serum prolactin (PRL), testosterone and estradiol (E2) levels were determined by RIA. The patients with SLE showed higher serum PRL levels, the difference being statistically significant at Week 20, and reaching the highest levels at Weeks 30 to 40 (p = 0.05 when compared to healthy pregnant women). The 5 patients with active SLE had the highest serum PRL levels; one of these had fetal wastage. In active SLE the serum testosterone and E2 levels were decreased significantly from Weeks 10 to 30 compared with controls (p = 0.001). In patients with RA serum PRL levels, although higher than in controls, did not differ significantly, nor did the lower testosterone and E2 levels. We conclude that gonadal hormones and PRL changes observed in SLE are present also during pregnancy and may be related to fetal wastage and reactivation of disease.     

Red cell aggregation during normal pregnancy

Red cell aggregation (RCA) is responsible for the increase in whole blood viscosity at lower shear rates. RCA depends on the concentrations of red cells and plasma proteins with a high molecular weight and a large and asymmetrical spatial structure such as fibrinogen, immunoglobulin M and alpha 2-macroglobulin. During normal pregnancy, changes occur in all these concentrations. In a prospective study these changes and their influence on the resulting RCA were investigated in 24 healthy women with normal pregnancies. RCA was determined by light reflection measurement (syllectometry). RCA considerably increased during normal pregnancy in spite of the physiological haemodilution. The aggregation half time, used as a measure for RCA, decreased from an average non-pregnant value of 5.6 s to 3.3 s at 37 weeks. Multiple regression analysis showed that the increase in RCA could be mainly attributed to the raised fibrinogen concentration. However, at 37 weeks other factors, in addition to fibrinogen, contribute significantly to the increase in RCA.