Responses to corticotropin-releasing hormone and its bound and free forms in pregnant and nonpregnant women

Plasma CRH levels are considerably higher in women during the third trimester of pregnancy than in non-pregnant women. Most of plasma CRH in pregnant women is bound to CRH-binding protein (CRH-BP). To gain further insight into CRH physiology during pregnancy, we measured the responses of plasma ACTH and cortisol and the changes in bound and free forms of CRH in plasma after human CRH administration (2 micrograms/kg) in five pregnant (39-40 weeks of pregnancy) and five nonpregnant women. The mean basal plasma ACTH and cortisol levels in the pregnant women were higher than those in the nonpregnant women. However, the maximum increments in plasma ACTH and cortisol levels and the integrated ACTH and cortisol responses, after subtraction of the basal levels after CRH administration, were similar in the two groups. The plasma CRH half-time in the pregnant group was similar to that in the nonpregnant group. The mean basal plasma CRH level in the nonpregnant women was 1.5 +/- 0.2 (+/- SE) pmol/L, and that in the pregnant women was 360 +/- 35 pmol/L. On gel filtration chromatography, almost all of the CRH in the plasma was protein bound (320 +/- 30 pmol/L) in the pregnant women; no CRH peaks were detected in nonpregnant women because of the low plasma CRH levels. After CRH administration, the level of the bound form of plasma CRH was highest at 5 min, and then declined to a plateau at 15 min and 30 min in the pregnant women. In the nonpregnant women, protein-bound CRH also was highest at 5 min, but it progressively declined thereafter. The disappearance rate of the bound CRH in plasma from the nonpregnant women was similar to that of the second compartment of the plasma decay curves of the free CRH from both groups. We conclude that the plasma ACTH and cortisol responses to exogenous CRH are similar in pregnant and nonpregnant women, the effect of CRH-BP on the disappearance of plasma CRH is minimal, and plasma CRH-BP in pregnant women has the capacity to bind additional CRH.     

The role of serum binding proteins in determining free thyroid hormone concentrations during development in quail

Japanese quail were used as a model for studying the role of binding proteins in determining free T4 (FT4) and free T3 (FT3) concentrations during development. Adults were used to characterize thyroid hormone binding; developmental stages studied were late embryonic, perinatal, hatchling, and juvenile. Total and free hormones were determined directly by RIA, and free hormones were determined indirectly by equilibrium dialysis. Binding proteins were identified by electrophoresis of serum preincubated with labeled hormones. Serum FT4 and FT3 concentrations in adult quail were equivalent to those in humans. T4 bound principally to albumin and secondarily to prealbumin; T3 bound principally to alpha-globulin and secondarily to albumin and gamma-globulin. A specific T4-binding globulin, as in mammals, was not present. The relative affinity of stripped serum was greater for T4 than for T3. In late embryos, FT4 concentrations rise as a result of a marked increase in total T4 (TT4) and modest increases in binding proteins. The perinatal peak in FT4 reflects the perinatal surge of TT4 without a change in binding proteins. From days 1-6 posthatching, FT4 decreases as a consequence of TT4 decreasing faster than the decrease in binding. In juveniles, FT4 concentrations stabilize as increases in TT4 are paralleled by increases in serum binding. T3 binding shows few significant differences from adult values during development, so FT3 concentrations follow closely the pattern of TT3 changes. These results demonstrate that developmental changes in serum binding proteins play a significant role in determining the pattern of free thyroid hormones, especially for FT4, by modulating the total hormone concentrations controlled by the hypothalamic-pituitary axis.     

Glucocorticoid response in amiodarone-induced thyrotoxicosis resulting from destructive thyroiditis is predicted by thyroid volume and serum free thyroid hormone concentrations

CONTEXT: Amiodarone-induced thyrotoxicosis (AIT) resulting from destructive thyroiditis (type 2) is commonly treated with glucocorticoids, but time needed to restore euthyroidism may be unacceptable for patients with underlying cardiac disorders. OBJECTIVE: The objective of this prospective study was to identify factors affecting the response to glucocorticoids in a large cohort of patients with type 2 AIT followed prospectively. SETTING: This study was conducted at university centers. PATIENTS: Sixty-six untreated patients with type 2 AIT were enrolled in the study. INTERVENTION: All patients were treated with prednisone (initial dose, 0.5 mg/kg.d) as long as needed to restore euthyroidism, defined as cure of AIT. MAIN OUTCOME MEASURE: The main outcome measure was cure time. RESULTS: The median cure time was 30 d (95% confidence interval, 23-37 d). Serum free T4 concentration (picograms per milliliter) and thyroid volume (milliliters per square meter) (and, to a lesser extent, serum free T3 concentration) at diagnosis were the main determinants of response to glucocorticoids, with a cure hazard ratio of 0.97 (95% confidence interval, 0.95-0.99; P = 0.005) and 0.84 (95% confidence interval, 0.77-0.91; P = 0.000) for unit of increment, respectively. AIT was cured in all patients with a complete follow-up; euthyroidism was reached in 30 d or less in 60% of patients but in more than 90 d in 16%. A prompt control of thyrotoxicosis (相似文献   

Comparison of thyroid stimulators and thyroid hormone concentrations in the sera of pregnant women.

To clarify the role of various thyroid stimulators in normal human pregnancy, we measured serum TSH, chorionic TSH (hCT), hCG, bioassayable thyroid-stimulating activity, T4, T3, T3 uptake, free T4 and free T3 indexes, free T4, and free T3 by dialysis in 339 serum samples from pregnant women at various intervals of pregnancy and in 40 normal female controls. Serum T4 and T3 and free T4 and free T3 indexes were significantly elevated throughout pregnancy in comparison with controls. Free T4 concentration was elevated after 10 weeks of pregnancy and free T3 concentration was elevated at 13--20 weeks. Bioassayable thyroid-stimulating activity was elevated from 9--16 weeks when serum hCG concentrations were highest. Serum TSH levels were significantly lower at 9--12 weeks compared with the rest of pregnancy. hCT was detected in only 35% of sera tested; the mean detectable value was 0.60 +/- 0.04 (SE) microU/ml; only 15% of the detectable values exceeded 1 microU/ml. The level of hCG correlated with bioassayable thyroid-stimulating activity (P less than 0.01). The data indicate that hCT is not a significant thyroid stimulator. We propose that hCG, as a weak thyroid stimulator, causes a modest rise in free thyroid hormone levels early in pregnancy which in turn causes a modest reduction in pituitary TSH secretion.     

The effect of serum free fatty acid on serum free thyroid hormone fractions in low T3 syndrome

We studied the role of serum free fatty acid (FFA) in the elevation of serum dializable fraction of T4 (DFT4) and evaluated the serum free T4 (FT4) level in low T3 syndrome. Serum DFT4 and DFT3 were measured by equilibrium dialysis method with phosphate buffer, and serum FFA concentration was obtained by gas chromatography. In patients with nonthyroidal systemic illnesses who showed reduced serum total T3 (TT3) and normal total T4 (TT4) (low T3 group, TT3 48 +/- 14 ng/dl, n = 10), mean (+/- SD) DFT4 value (0.032 +/- 0.05%) was significantly higher than that of the group of systemic illnesses with normal TT3 and TT4 (normal T3 group, TT3 79 +/- 7 ng/dl, n = 10). Mean TT4 value of low T3 group (6.5 +/- 1.0 micrograms/dl) was lower than that of normal T3 group (8.6 +/- 2.4 microgram/dl, p less than 0.02). There was no difference in mean absolute FT4 (AFT4) value between the two groups (2.07 +/- 0.46 vs 2.19 +/- 0.53 ng/dl). On the other hand, there was no significant difference in DFT3 value between the groups (0.274 +/- 0.043 vs 0.247 +/- 0.035%), and mean AFT3 of low T3 group (1.29 +/- 0.39 pg/ml) was low than that of normal T3 group (1.92 +/- 0.26 pg/ml, p less than 0.01). In cases of low and normal T3 groups (n = 20), serum thyroxine binding globulin (TBG) concentration had a negative correlation with DFT3 (r = -0.707, p less than 0.001), but not with DFT4. Although there were no significant differences in serum albumin and TBG concentrations between the two groups, the mean serum total FFA concentration and molar ratio of FFA to albumin in low T3 group (579 +/- 249 microM and 1.31 +/- 0.61) were significantly higher than those in normal T3 group (345 +/- 170 microM and 0.75 +/- 0.32, p less than 0.05 and less than 0.025, respectively). All of FFA concentrations in low T3 group, especially oleate, were higher than those in normal T3 group. Moreover, the higher the total FFA concentration was, the greater was the percent fraction of oleate. DFT4 values were significantly increased by the addition of 1 mM oleate to the sera of low T3 group, and this effect was more marked in the sera of the patients with lower albumin concentration.(ABSTRACT TRUNCATED AT 400 WORDS)     

Circulating adiponectin concentrations were related to free thyroxine levels in thyroid cancer patients after thyroid hormone withdrawal

Because it is unclear whether adipose-derived hormones are related to thyroid hormone metabolism, this study evaluated the relationship between adiponectin concentrations and changes in the thyroid hormones in athyreotic patients after thyroid hormone withdrawal. Twenty-eight athyreotic thyroid cancer patients (4 male and 24 female; mean age, 52.2 ± 11.3 years) were analyzed on the final day of levothyroxine treatment and 1 day before serum thyroglobulin and radioiodine scanning examinations after an average of 4 weeks of thyroid hormone withdrawal. Evaluations included analysis of thyroid function test, serum adiponectin, body composition by bioimpedance analysis, and insulin sensitivity index as determined by the homeostasis model assessment of insulin resistance (HOMA-IR). Discontinuation of thyroid hormone treatment resulted in a significant change in thyroid-stimulating hormone (82.1 ± 9.8 vs 1.0 ± 0.4 mL/L, P < .05), free thyroxine (FT4) (5.7 ± 0.4 vs 18.7 ± 2.3 pmol/L, P < .05), and free triiodothyronine levels (1.8 ± 0.2 vs 3.4 ± 0.2 pmol/L, P < .05) as compared with the prewithdrawal values, whereas circulating adiponectin levels (5.7 ± 0.6 vs 5.4 ± 0.6 mg/L), body fat mass (20.3 ± 1.2 vs 19.4 ± 1.2 kg), and insulin sensitivity index (1.8 ± 0.2 vs 2.2 ± 0.3) remained unaltered. A positive correlation between adiponectin and FT4 (r = 0.61, P < .01) independent of age, sex, fat body mass, HOMA-IR, and other potential covariates known to affect thyroid hormone metabolism, such as renal and liver functions, was observed after thyroid hormone withdrawal. In addition, baseline circulating adiponectin levels were correlated with a diminished postwithdrawal reduction of FT4 concentrations after adjusting for baseline FT4 levels and changes in body mass index, fat body mass, and HOMA-IR (r = 0.71, P < .01). In conclusion, adiponectin concentrations were associated with FT4 levels in the athyreotic patients after thyroid hormone withdrawal. The relevant roles of adiponectin in the regulation of thyroid hormone metabolism require further investigation.     

Biosynthesis of estrogens in pregnant and non-pregnant guinea pigs.

Guinea pig ovaries obtained from pregnant and non-pregnant animals, incubated in the presence of a NADPH-generating system, converted [3H]-dehydroepiandrosterone and [14C]testosterone to estradiol. Under the same conditions, no radioactive estrogen could be identified in adrenal and placental incubations. The rate of formation of estradiol from dehydroepiandrosterone was linear during the 30-min incubation. The initial rates of formation for estradiol were 415 X 10(-13) and 10.4 X 10(-13) mol/min/g tissue for the ovaries from pregnant and non-pregnant guinea pigs, respectively. The formation of estrone was shown only in the pregnant animal, and the initial rate of formation was 36.0 X 10(-13) mol/min/g tissue. These in vitro studies suggest that the major site of estrogen formation in both pregnant and non-pregnant guinea pigs is the ovary.     

Relationship between serum free fatty acids and thyroid hormone binding inhibitor in nonthyroid illnesses

We measured the serum concentration and relative distribution of various free fatty acids (FFA) by gas/liquid chromatography in normal subjects and nonthyroid illness (NTI) patients with or without detectable serum thyroid-hormone binding inhibitor (THBI). The mean serum concentration of total FFA was 0.72 +/- 0.08 (SE) mM in eight normal subjects; it was similar (0.63 +/- 0.12) in eight THBI-negative NTI patients, but was significantly higher (3.1 +/- 1.0; P less than 0.05) in eight THBI-positive NTI patients (THBI index, 3.9 +/- 0.3 vs. 1.0 +/- 0.05 in normal subjects). Relative distribution of FFA in THBI-negative patients did not differ significantly from that in normal subjects. In THBI-positive patients, however, serum concentrations of palmitic, palmitoleic, stearic, and oleic acids were significantly above normal. Among fatty acids with appreciable THBI activity, oleic acid was most abundant in THBI-positive patients; its concentration of 1.3 +/- 0.32 mM in patients was about 6-fold higher than the corresponding normal value (0.21 +/- 0.02; P less than 0.005). The serum concentration of THBI correlated significantly with levels of both total FFA (r = 0.69; P less than 0.005) and oleic acid (r = 0.80; P less than 0.001). Addition of 0.33 mM oleic acid to THBI-negative NTI serum or 0.66 mM oleic acid to normal serum increased THBI activity to a level greater than 2 SD above the normal mean, i.e. 1.6. The various data suggest that 1) circulating FFA contribute importantly to THBI activity in sera of NTI patients; 2) oleic acid contributes more to THBI activity of NTI sera than do other FFA.     

Maternal and fetal parathyroid hormone responsiveness in pregnant primates

Maternal and fetal parathyroidd hormone (PTH) responsiveness to hypocalcemia induced by EDTA infusion (50 mg/kg over 2 h) was studied in rhesus monkeys in late pregnancy. Although baseline serum total calcium (Ca) levels in the fetus exceeded those in the mother (4.83 +/- 0.13 vs. 4.28 +/- 0.15 meq/liter; P < 0.001), PTH values were not significantly different (5.62 +/- 0.37 vs. 6.18 +/- 0.33 muleq/ml; P > 0.05). EDTA infusion directly to five fetuses produced significant hypocalcemia (maximal decline averaging 19 +/- 2%) and PTH response (maximal increase averaging 46 +/- 5%). In contrast, in four control studies involving fetal saline infusion, there were no significant changes in fetal Ca or PTH levels. Four maternal control infusions produced no significant changes in either Ca or PTH levels. A comparison of maternal and fetal PTH responses indicated considerable similarity, although fetal PTH levels tended to return to baseline somewhat more gradually after cessation of the hypocalcemic stimulus than did maternal levels. These studies indicate that fetal PTH secretion, both baseline and in response to hypocalcemia, is quantitatively similar to that of the adult, and thus, the fetal parathyroid does not appear to be suppressed by the relative hypercalcemia of late fetal life.     

Changes in serum thyroid hormone, thyrotropin and thyroglobulin concentrations during thyroxine therapy in patients with solitary thyroid nodules

We studied the effect of therapy with 0.1 mg/day T4 for 3 months on goiter size in 49 patients with solitary thyroid nodules. The nodule volume in 18 patients (responders) decreased by more than 50%. In this group the mean serum thyroglobulin (Tg) levels decreased significantly (from 425 to 61 micrograms/L; P less than 0.01). In the nonresponders the mean serum Tg levels did not change significantly (145 vs. 250 micrograms/L). The mean serum T4, free T4, free T3, and rT3 concentrations increased significantly in both groups during T4 therapy, serum T3 levels did not change, and serum TSH decreased. These findings demonstrate that serum Tg levels decrease when T4 therapy is effective. Thus, serum Tg measurements may prove a useful indicator of the efficacy of T4 therapy in patients with solitary nodules.     

Cardiac catheterization dye does not affect serum thyroid hormone concentrations or tsh secretion

The iodinated contrast agents used in oral cholecystography impair peripheral iodo-thyronine-5′-deiodinase activity, resulting in a transient decrease in serum 3,5,3′-triio-dothyronine (triiodothyronine, T₃) and in increases in serum 3,3′,5′-triiodothyronine (reverse T₃ rT₃) and thyroxine (T₄) concentrations. A related iodinated contrast agent, diatrizoate, is employed in coronary angiography. The effect of diatrizoate (Renografin-76®) on serum T₄, rT₃, and thyroid stimulating hormone (thyrotropin, TSH) concentrations and the TSH and T₃, responses to thyrotropin releasing hormone (TRH) were evaluated in seven euthyroid patients before and on the fifth day following coronary angiography. No significant changes were observed. Thus, diatrizoate, in contrast to the oral cholecystographic agents, appears to have little or no clinically important effect on thyroid hormone metabolism in man.     

高糖环境对豚鼠膀胱Cajal样间质细胞内向电流的影响

目的观察高糖环境对豚鼠膀胱Cajal样间质细胞（ICCs）内向电流的影响。方法采用胶原酶消化法,得到原代培养的成年豚鼠膀胱ICCs;采用膜片钳技术,在全细胞记录模式下,记录葡萄糖5（对照组）、15（高糖Ⅰ组）、30mmol／L（高糖Ⅱ组）下ICCs超极化激活时的内向电流值。结果正常对照组膀胱ICCs的内向电流值为（505．75±157．660）pA,高糖Ⅰ组为（349．25±71．087）pA,高糖Ⅱ组为（95．00±33．337）pA。三组间比较,P均〈0．01。结论高糖环境可导致豚鼠膀胱ICCs超极化激活的内向电流值降低,这可能是导致糖尿病膀胱病变的原因之一。     

Components of the total serum thyroid hormone concentrations during pregnancy: high free thyroxine and blunted thyrotropin (TSH) response to TSH-releasing hormone in the first trimester

The distribution of thyroid hormones between free solution and their several protein-binding sites during pregnancy was studied under physiological conditions of temperature and pH. Single serum specimens were obtained from individual women at different stages of pregnancy. During the first 5 weeks of pregnancy, mean serum free T4 and free T3 concentrations were 50% higher than in nonpregnant women or women during the third trimester. Free T4 was increased significantly throughout the first trimester, but because of wide variance, free T3 was significantly above control values only during the first 5 weeks. Free T4 and free T3 concentrations decreased to control levels in the third trimester. These changes in free T4 concentrations are consistent with a weak thyrotropic action of hCG, which attained maximal concentrations early in the first trimester and then decreased markedly in the second and third trimesters. TRH testing of women scheduled for abortion in the first and second trimesters revealed marked inhibition of TSH response to TRH in those first trimester women who had elevated free T4 concentrations. The percent free T4 did not decrease during the first 5 weeks, but then declined progressively to term as T4-binding globulin (TBG) affinity, defined as the product of the capacity and affinity constant, progressively increased. T4 bound to TBG (T4-TBG) increased from early in the first trimester to term, and then decreased in postterm pregnancy and postpartum. T4 bound to prealbumin (T4-PA) and to albumin (T4-Alb) decreased significantly in the third trimester compared with either control or first trimester concentrations. The concentration of free T3 was positively correlated with T4-PA (r = 0.25) and T4-Alb (r = 0.31), but not with free T4 (r = 0.18) or T4-TBG (r = -0.30) concentrations. These results suggest that 1) only the high concentrations of hCG present in the first trimester of pregnancy have a thyrotropic effect in excess of normal levels of TSH, and this can be sufficient to suppress the TSH response to TRH; 2) hepatic TBG secretion continues to respond to the continuously rising estrogen levels throughout pregnancy; and 3) T4-PA and T4-Alb, but not free T4 or T4-TBG, are possible precursors for the extrathyroidal generation of T3.     

Relation between serum interleukin-6 and thyroid hormone concentrations in 270 hospital in-patients with non-thyroidal illness

OBJECTIVES Non-thyroidal illness (NTI) is frequently accompanied by alterations in circulating thyroid hormone concentrations, despite patients remaining clinically euthyroid. The mechanisms accounting for these changes in circulating thyroid hormone concentrations remain unknown. Much attention has focussed on the role of inflammatory cytokines which are known to be important mediators of disease. The aim of this study was to investigate the role of the cytokine interleukin-6 (IL-6) in alterations of thyroid hormone metabolism seen in NTI. DESIGN Longitudinal study of hospital in-patients, correlating serum IL-6 concentrations with circulating thyroid hormone concentrations. PATIENTS Two hundred and seventy in-patients recruited consecutively, excluding those with known or suspected thyroid disorder. The patients were divided into 5 subgroups reflecting the nature of their NTI and comprised 41 patients with liver disease, 99 with renal disease, 19 intensive care (ITU) patients, 22 with cardiac disease and 89 patients with general medical, or surgical conditions. MEASUREMENTS Serum IL-6 concentrations were determined using a commercially obtained immunoassay (IL-6 Quantikine assay, R&D Systems, Abingdon, UK). Serum total T4 and total T3 were measured using chemiluminescent immunometric assays (Kodak Clinical Diagnostics Ltd, Amersham, UK) and serum TSH was measured using a third-generation chemiluminescent immunometric assay (Amerlite TSH 30, Kodak Clinical Diagnostics Ltd, Amersham, UK). RESULTS Ninety-three patients studied (35%) had a serum T3 below the normal range (<1.0 nmol/l), 89 patients (33%) had a serum T4 below the normal range (<65 nmol/l) and in 58 patients (21%) both serum T3 and T4 were below the normal range. There was a significant negative correlation between serum total T3 and IL-6 (r = ?0.219; P<0.001) and total T4 and IL-6 (r = ?0.132; P = 0.032), but not between TSH and IL-6 (r = ?0.075; P = 0.22). The ITU patient subgroup had the highest IL-6 concentrations (229.3 ± 48.1 ng/l, mean ± standard error), whilst also having the lowest T3 (0.93 ± 0.08 nmol/l), TSH (0.79 ± 0.25 mU/l) and T4 concentrations (66.6 ± 7.3 nmol/l). The subgroup of patients under general medical or surgical care had least disturbance of their T3 (low in 19%) and T4 (low in 8%) concentrations, whilst also having the lowest mean IL-6 concentration (39.0 ± 5.3 ng/l). The renal patient subgroup, whilst including a high proportion of patients with low T3 (39%) and T4 (45%) concentration, demonstrated only modest elevation of IL-6 concentrations (mean 41.4 ± 8.5 ng/l). CONCLUSIONS Our data revealed a statistical relation between elevated serum IL-6 concentrations and alterations in circulating thyroid hormone concentrations seen in NTI; however, the findings in patients with renal disease suggest that circulating IL-6 is not the only factor responsible for alteration in thyroid hormone metabolism in NTI.