Diurnal variations in plasma arginine vasotocin (AVT) concentrations in the ovine fetus.

Previously we have demonstrated the presence of AVT in the blood of fetal sheep. The source is not clear, but AVT has been identified in fetal pineal and pituitary glands. In view of the circadian secretory pattern of the pineal gland, we questioned whether fetal plasma AVT levels might vary diurnally. Plasma samples from five chronically catheterized ovine maternal ewes and fetal lambs 129-135 days' gestation were obtained at 3-19 hourly intervals for 1-2 days (mean +/- S.E.M. = 35 +/- 6 hours. Plasma AVT levels were determined by radioimmunoassay. Results were analyzed by nonlinear curve fitting procedures to relate hormone levels with time of day. Plasma AVT values for maternal ewes did not vary during the day in response to light/dark periods. The curve for mean fetal plasma AVT plotted against time showed oscillations with a period of about 25 hours (p less than 0.05). Peak fetal AVT levels were observed at 1600 hours and minimal levels at 0400 hours. These results indicate that ovine fetal AVT secretion varies diurnally. The site of AVT secretion may be the pineal gland; however, confirmation of this and identification of the physiological stimuli for secretion of fetal plasma AVT require further information.

Catecholamine physiology in the ovine fetus. I. Gestational age variation in basal plasma concentrations.

Fifty-five ewes with chronically catheterized singleton gestations were studied to assess changes in basal concentrations of fetal catecholamines with increasing gestational age. All pregnancies were time dated, and measurements of catecholamines were conducted at least 5 days after placement of fetal catheters when fetal metabolic parameters had normalized. Plasma concentrations of catecholamines were measured by radioenzymatic assay. Additionally, fetal heart rate (FHR) and corrected mean blood pressure were analyzed in 32 of the fetuses for correlation with plasma levels of catecholamines. Multiple regression analysis revealed significant inverse correlations of fetal plasma concentrations of catecholamines with gestational age, as follows: norepinephrine (p less than 0.001), epinephrine (p less than 0.05), and dopamine (p less than 0.01). FHR correlated inversely with gestational age (p less than 0.001) and positively with circulating levels of norepinephrine (p less than 0.001).

Fetal catecholamine release in response to labor and delivery.

Umbilical arterial plasma norepinephrine and epinephrine were measured using a sensitive, specific radioenzymatic assay. Plasma catecholamines were correlated with umbilical arterial blood gases, durations of the first and second stages of labor, duration of rupture of the membranes, fetal heart rate tracings, and fetal sex. Significant correlations were observed for plasma norepinephrine versus fetal pH and PO2 and plasma epinephrine versus pH but not PO2. The majority of the fetal heart rate tracings demonstrated either a normal baseline or mild variable decelerations. The plasma catecholamines and blood gases were similar in these 2 groups. Significant elevations of both plasma catecholamines were observed with those tracings commonly associated with fetal distress; however, the number of infants was small. No sex differences were observed in plasma norepinephrine or epinephrine or in responsiveness. The results suggest that the human fetus at term responds to acidosis and hypoxia with a graded catecholamine release. This may be an important adaptive mechanism.

Developmental changes in pituitary-thyroid function in the human fetus and newborn.

Maturation of the hypothalamic pituitary thyroid axis as reflected in cord serum thyroid hormone concentrations was assessed in premature and full term infants born between 26 and 43 weeks gestation. Measurements of thyroxine (T4), free T4 (FT4), thyrotropin (TSH) and thyroxine binding globulin (TBG) in cord sera were correlated with gestational age, sex and birthweight and compared to similar measurements in well two month old infants and adults. There were significant increases in T4, FT4, and TBG with increasing gestational age (GA) between 26 and 33-35 weeks (P less than 0.001). After 34 weeks, none of these parameters varied with GA. When the infants were separated on the basis of sex the linear regression curves describing the relationships between hormone and TBG concentrations and GA were not different from the curves in the total population. The mean FT4/TSH ratio increased significantly with age throughout gestation (P less than 0.01) and was significantly lower in cord blood samples than in blood samples from the 2-month-old infants or the adults. The results suggest that the set point for negative feedback control of TSH secretion at the pituitary level is changing between 26 weeks GA and 2 months of life. Thyroid gland sensitivity to TSH stimulation also appears to be increasing between 26 and 33 weeks GA.

Characterization of the daily oxytocin rhythm in primate cerebrospinal fluid.

The circadian characteristics of the daily rhythm in oxytocin (OT) concentrations in cerebrospinal fluid (CSF) were studied in the rhesus monkey. Monkeys subjected to constant light or constant dark for periods of 3 to 6 days manifested persistence of the CSF OT rhythm. A 12-hr phase shift in the light-dark cycle resulted in a resynchronization of the rhythm to the new lighting schedule within 3 to 4 days. Altering the daily feeding and care schedule during a period of constant darkness did not alter the expression or timing of the CSF OT rhythm significantly. These results suggest that the OT rhythm is endogenously generated and that the daily light-dark cycle normally synchronizes the rhythm to the 24-hr cycle.

Amniotic fluid thyroid hormone concentrations during human gestation.

AFT4, AFT3, and AFrT3 concentrations were measured in samples from pregnant women between 10 and 43 weeks' gestation. During the first half of pregnancy, AFT4 and AFrT3 concentrations increased progressively, reaching peak levels at 25 to 30 and 17 to 20 weeks, respectively. AFT3 concentrations were low and increased slowly during this stage of pregnancy. During the last half of pregnancy, AFT4 and AFrT3 levels decreased while AFT3 continued to increase. This pattern of change is most likely explained by an increase in 5'-iodothyronine monodeiodinase activity in the fetal compartment. Normal values of amniotic fluid thyroid hormone concentrations as standards of reference for possible prenatal diagnosis of fetal thyroid abnormalities are provided.

Iodothyronine kinetic studies in the newborn lamb.

Metabolic clearance rates and production rates for thyroxine (T4), triiodothyronine (T3) and reverse T3 (rT3) were determined by pulse injection kinetic techniques in newborn sheep between 7 and 14 days of age. The mean metabolic clearance rate for T3 (39.6 +/- 4.5 l/m2 per day) was significantly greater than that for T4 (7.25 l/m2 per day, P < 0.001). The mean value for rT3 (27.5 +/- 2.8 l/m2 per day) also exceeded that for T4 (P < 0.001) but did not differ from that for T3. The mean production rate for T3 (95.6 +/- 5.8 micrograms/m2 per day) was significantly less than that for T4 (511.4 +/- 71.7 micrograms/m2 per day, P < 0.01). The mean value for rT3 (28.6 +/- 1.7 micrograms/m2 per day) was significantly less than respective values for T4 (P < 0.01) and T3 (P < 0.001). Calculated thyroid gland secretion accounted for 42.3 micrograms/m2 per day of T3 production and 4.7 micrograms/m2 per day of rT3 production. Calculated peripheral conversion from T4 accounted for 53.3 micrograms/m2 per day (56%) of the production of T3 and 23.9 micrograms/m2 per day (84%) of that of rT3. The metabolic clearance rate for T4 and the production rate for T4 and T3 in the newborn were greater than those measured earlier (Chopra, Sack & Fisher, 1975) in the fetus or adult ewe. The metabolic clearance rate of T3 in the newborn was less that the fetal value but similar to that measured in adult animals. The newborn value for rT3 was greater than that in the fetus and similar to that in the adult ewe. The production rate of rT3 was lower than that previously measured in the fetus but similar to that in adult ewes. Our results suggest that the transient chemical thyrotoxic state characteristic of the newborn is accountable on the basis of increased thyroid gland secretion of T4 and T3 as well as increased T3 production from T4 via peripheral monodeiodination.

Effect of osmolality on arginine vasopressin and renin release after hemorrhage.

The effects of alterations of plasma osmolality on plasma arginine vasopressin (AVP) and renin activity (PRA) following graded hemorrhage were studied in conscious dogs who were either euhydrated, dehydrated, water loaded, or infused with hypertonic saline. Base-line plasma osmolality and AVP were significantly different in the four treatment groups; however, following hemorrhage the increases in log AVP did not significantly differ. An unexpected finding was that water loading resulted in significant elevations in PRA and plasma aldosterone concentrations, whereas plasma osmolality and AVP were reduced. Prior to hemorrhage, PRA was significantly greater in the water-loaded and dehydrated groups than in the euhydrated or saline-infused groups; following hemorrhage the increases in log PRA were not significantly different in all four treatment groups. The data suggest that, although alterations in osmolality influence base-line levels of AVP, they have no effect on relative (logarithmic) rises in AVP following hemorrhage. Similarly, alterations in AVP may influence base-line PRA, but do not influence relative rises in PRA following hemorrhage.

Comparison of T4, T3, rT3 and TSH concentrations in cord blood and serum of infants up to 3 months of age.

T4, T3, TSH and rT3 concentrations were measured by radioimmunoassay in cord and postnatal (8--94 days of age) serum samples from randomly selected normal newborn infants (Group I). T4 and TSH levels also were determined in cord and postnatal sera from an additional group of apparently healthy infants 8--260 days of age, whose cord serum T4 levels were in the upper or lower 10% of the normal range of values (Group II). Postnatal T4, T3 and TSH concentrations were stable over this age range; there were no significant differences between male and female infant samples. However, there was a significant decrease in serum rT3 concentrations from 8 to 50 days of age. For the Group I infants, there were significant positive correlations between cord serum T4 and postnatal serum T4 levels, cord serum TSH and postnatal serum TSH levels, and cord serum rT3 and postnatal serum rT3 concentrations. For Group II infants, a significant positive correlation was found for cord T4--postnatal T4 serum concentrations.

Variation in values for iodothyronine hormones, thyrotropin, and thyroxine-binding globulin in normal umbilical-cord serum with season and duration of storage.

We measured concentrations of thyroxine, triiodothyronine, reverse triiodothyronine, thyroxine-binding globulin, and thyrotropin in pooled samples of cord sera from normal newborns. Sera collected in winter contain significantly (p less than 0.05) higher concentrations of the first tour--14.9, 13.4, 9k9, and 7.5%, respectively--than do sera collected in summer; thyrotropin concentrations are similar in samples collected during winter and summer (p greater than 0.05). With storage, the values for the thyronines and thyrotropin decreased progressively at rates between 0.9 and 5.3% per year; those for thyroxine-binding globulin did not change significantly.

Oscillations in reverse triiodothyronine levels in serum of healthy infants aged 0 to 130 hours.

rT3 was measured by RIA in sera from 273 normal healthy infants between 0--130 h of age. The curve for the mean rT3 level plotted against age was polyexponential in shape and showed superimposed oscillations with a period of about 16 h, similar to the curves for T4, T3, and TSH previously found for the same group of subjects (J Clin Endocrinol Metab 47: 61, 1978). The ratio of concentrations of rT3 to T4 remained approximately constant, with a mean value of 0.016 over the age range of 3--130 h. These observations suggest that the variations in rT3 levels in newborn serum during the first few days of life are largely accountable by variations in T4 substrate concentrations.

Free metanephrine in human amniotic fluid as an index of fetal sympathetic nervous system maturation.

Free metanephrine, a major metabolite of catecholamines, was measured in the amniotic fluid of 113 pregnant patients at various gestational ages. The results indicate that prior to 30 weeks the levels of free metanephrine are below the level of assay sensitivity. After 30 weeks' gestation there is a positive correlation of free metanephrine concentrations in amniotic fluid with gestational age. In addition there is a further increase in free metanephrine levels in amniotic fluid with labor.

Effect of parturition on serum iodothyronine concentrations in fetal sheep.

T4, T3, and rT3 were determined by RIA on daily serum samples collected from five catheterized fetal sheep during the 2-week period before spontaneous vaginal delivery (PTD). Samples were also available from three newborn lambs during the first 4 h of life. T3 concentrations began to increase 4-6 days before spontaneous vaginal delivery, from a stable geometric mean concentration of 30 ng/dl to a mean concentration of 131 ng/dl on the day of delivery (day 0). T4 concentrations decreased in four of the animals and remained unchanged in one during this time interval. rT3 concentrations decreased from a stable mean of 472 to 249 ng/dl on day 0. The prenatal increase in serum T3 levels correlated temporally with increasing fetal serum cortisol concentrations. The mean T3 concentration increased further after delivery to a level of 487 ng/dl at 1 h of age without significant changes in T4 or rT3 levels. The following conclusions were reached: 1) fetal serum T3 concentrations increase while T4 and rT3 concentrations decrease during the 4-6 days preceding spontaneous labor, and 2) T3 concentrations increase further after delivery. Available evidence suggests that the prenatal increase in fetal serum T3 levels is mediated by a cortisol-induced increase in T4 to T3 conversion in fetal tissues. The mechanism(s) of the postnatal increase in serum T3 concentrations in the newborn is not clear.

Damped oscillations in serum thyroid hormone levels of normal newborn infants.

Exposure to the extrauterine environment is associated with marked stimulation of the hypothalamic-pituitary-thyroid system after which, pituitary-thyroid equilibrium must be reestablished. This marked endogenous perturbation offers the opportunity to study the manner in which the pituitary-thyroid axis is reequilibrated. T4, T3 and TSH concentrations have been measured by RIA in sera from 440 healthy newborn infants, whose ages ranged from birth to 236 h. Results were analyzed by nonlinear curve-fitting procedures to assess the changes in mean hormone concentrations with age (t). Equations have been derived by Danziger and Elmergreen to allow assessment of oscillatory behavior during hormone equilibration. Applying these equations to the present data, we observed the presence of an oscillatory cosine term in the equation for each hormone. This indicates significant oscillations in serum T4, T3, and TSH concentrations during the first 5 days of life. The period of the oscillations approximates 16 h. The oscillations in T4, lag 1/2 to 3/4 cycle behind TSH; T3 lags behind T4. Thus, disturbances in hypothalamic-pituitary-thyroid equilibrium seem to be followed by periodic oscillations in hormone concentrations; these oscillations decrease in amplitude as the negative feedback system establishes new equilibrium conditions.

Correlation between gestational age, weight, or ponderosity and serum thyroxine concentration at birth.

Thyroxine levels were measured in cord blood sera from 2,1800 healthy infants born of "low-risk" mothers in Los Angeles. Variations of T4 with gestational age, birth weight, ponderosity (size related to weight), sex, and race were studied, as well as the variation of W and P with GA. Over the range of GA 30 to 47 weeks, serum T4 concentrations, W, and P each increase with GA, leveling off to approximately constant values from 42 to 47 weeks; the increases are 12, 66, and 20%, respectively. For a fixed GA, T4 increases with increasing W but is not correlated with P; W, GA, and their product are useful measurements for predicting T4, but P is not. Formulas for predicting cord T4 are given for possible use in improving computer-assisted screening programs for congenital hypothyroidism; mean T4 values (+/- I SD) are tabulated against W and GA.

Thyroid function at birth in infants of 30 to 45 weeks' gestation.

Serum T4 was measured in cord blood of 2,683 infants of gestational ages 30 to 45 weeks and birth weights of 1,460 to 5,250 gm. In addition, serum TBG was measured in 180, and serum TSH in 125 of these infants. Mean serum T4 increased with gestational age from 9.4 microng/dl at 30 weeks to 11.7 at 45 weeks. TBG varied from 3.1 to 11.4 mg/dl but showed no correlation with gestational age. There was a positive correlation between T4 and TBG. Serum TSH levels showed a significant negative correlation with gestational age, decreasing from 15 micronU/ml at 30 weeks to 7 micronU/ml at 45 weeks, while the serum T4/TSH ratio increased from 0.6 to 1.6. The results indicate that cord, T4 varies mainly with TBG, and to a lesser extent with gestational age.

Evaluation of serum triiodothyronine and adjusted triiodothyronine (free triiodothyronine index) in pregnancy.

We measured serum thyroxine (free and total), triiodothyronine (free and total), thyroxine-binding globulin, and triiodothyronine uptake by talc in 97 normal men and 50 pregnant women. Mean serum thyroxine and triiodothyronine concentrations were higher in the pregnant subjects (104 vs. 78 mug/liter and 1.69 vs. 1.30 mug/liter) because of a higher mean thyroxine-binding globulin concentration (70 vs. 38 mg/liter). Mean triiodothyronine uptake by talc was lower in the pregnant subjects (0.82 vs. 1.03). Mean free thyroxine concentrations were similar in the two groups, but mean free triiodothyronine concentrations were 10% lower in the pregnant subjects. Triiodothyronine uptake by talc and the diayzable thyroxine and triiodothyronine fractions were highly correlated (r = 0.85 and r = 0.82, P less than 0.001). Calculated free thyroxine index and free triiodothyronine index values (hyroxine and triiodothyronine indirectly adjusted, using triiodothyronine talc uptake to compensate for differences in thyroxine-binding globulin concentration), were statistically similar (84 vs. 82 and 1.38 vs. 1.34) in pregnant and male subjects. The results indicate that the total triiodothyronine concentration can be normalized on the basis of the triiodothyronine uptake by talc to correct for variations in thyroxine-binding globulin concentration.

The diagnosis of Hashimoto's thyroiditis.

Computer methods were used to estimate the usefulness of several clinical signs and laboratory tests in the diagnosis of chronic lymphocytic (Hashimoto's) thyroiditis. Information was drawn from the records of 217 patients with this disease seen at two hospitals in Southern California. The parameters studied included the physical characteristics of the thyroid gland; the appearance of the radioisotope thyroid scan; the response to a perchlorate discharge test; the serum antithyroglobulin antibody titer; the serum TSH concentration measured by radioimmunoassay; the thyroid radioiodine uptake response to exogenous TSH stimulation; and the serum PBI-T4I difference. Of the above, the PBI-T4I difference was deleted, being of limited value. The TSH stimulation test and serum TSH measurement were considered as alternative ways to evaluate thyroid reserve. Therefore, five diagnostic markers remained, all useful but not definitive. Computer and rule-of-thumb methods (two or more of the five markers positive) were tested for successful diagnosis of 145 patients with Hashimoto's thyroiditis proven by pathological examination of biopsied tissue; 23 of these were patients not used in the original pool of data. As a rule of thumb, it was found that Hashimoto's thyroiditis is the likely diagnosis if two or more out of the five useful markers are in its favor. For best results, four and preferably all of the five criteria should be tested. If this is done, the expected diagnostic accuracy for patients with Hashimoto's disease is by the rule-of-thumb method 67% correct, 21% indecisive, and 12% false negative; by computer methods it is 88% correct, 4% indecisive, and 8% false negative. By each method the number of false positive diagnoses was equivalent to 25% of the total number of patients with this disease. The false positive results nearly all occurred in patients with goiter associated with a defect in thyroid hormone synthesis.