The ontogenesis of human fetal hormones. III. Prolactin.

The synthesis and release of human prolactin (hPRL) in the human fetus was assessed by radioimmunoassay analysis of the content and concentration of hPRL in 82 pituitary glands and the concentration of serum hPRL in 47 fetuses of gestational age 68 days to term. Fetal hPRL exhibited parallelism with the reference standard (Lewis 203-1). hPRL was detected by 68 days of gestation (10 wk), the earliest fetal pituitary gland studied; 8 out of 33 pituitaries had a prolactin (PRL) content above 2.0 ng between 10-15 wk gestation. The mean ocntent of PRL in the pituitary gland increased sharply from 14.8 plus or minus 4.6 ng at 15-19 wk to 405 plus or minus 142 ng at 20-24 wk and 542 plus or minus ng at 25-29 wk gestation. By term, the mean content was 2,039 plus or minus 459 (range 493-3,689) and the mean concentration 15.9 plus or minus 2.4 ng/mg (range 7-20). There was a significant positive correlation (P less than 0.001) between the hPRL and human growth hormone (hGH) content of fetal pituitary glands; at term the hPRL/hGH ratio was 1/290. The concentration of serum hPRL between 12 and 24 wk ranged from 2.9 to 67 ng/ml, mean 19.5 plus or minus 2.5 ng/ml )n = 21); by 26 wk fetal serum hPRL increased sharply and attained levels of 300-500 ng/ml in late gestation. At delivery, the mean plasma concentration of hPRL was 167 plus or minus 14.2 ng/ml in 36 umbilical venous specimens and 111.8 plus or minus 12.3 ng/ml in the matched maternal venous specimens. No correlation between serum hPRL and the pituitary content or concentration of hPRL was demonstrable in 12 matched fetal specimens. In five anencephalic infants, umbilical venous hPRL levels were between 65 and 283 ng/ml. In two anencephalic infants, thyrotropin releasing factor (TRF) (200 mug IV) evoked a rise in serum hPRL in one patient from 43 to 156 ng/ml at 30 min, and in the other from 65 to 404 ng/ml at 120 min. In both patients, plasma thyroid-stimulating hormone (TSH) rose from undetectable base-line levels to peak levels of 97 and 380 muU/ml, respectively. The pattern of change in serum hPRL in the human fetus contrasts sharply with that of serum hGH, luteinizing hormone, or follicle-stimulating hormone. These observations in the fetus and in anencephalic infants suggest that the striking elevation of serum PRL in the fetus is neither mediated by a putative PRL releasing factor or by TRF, nor is a consequence of suppression or absence of PRL release inhibiting factor alone, as a functional hypothalamus is not required to attain the high PRL concentration at term. Several lines of evidence support the view that high plasma estrogen levels characteristic of gestation act directly on the fetal anterior hypophysis to stimulate PRL secretion or to sensitize the secretory mechanism of the lactotrope, increasing its responsiveness to other stimuli.     

The effect of administration of human growth hormone on the plasma growth hormone, cortisol, glucose, and free fatty acid response to insulin: evidence for growth hormone autoregulation in man

The effect of administration of human growth hormone (HGH) (3 mg every 6 hr for 6 days) on the endogenous GH response to insulin-induced hypoglycemia at 8, 12, 24, and 48 hr posttreatment was studied in 11 healthy male adults. Free fatty acid, cortisol, and glucose responses pre- and posttreatment with HGH were evaluated concurrently. Control subjects received saline injections to evaluate relationship of GH responses to the periodicity of insulin tolerance tests. The data were compared for each subject pre- and posttreatment with HGH as well as by comparison of the results of the saline-treated group with those of the HGH-treated group.The mean maximal GH concentration in response to insulin-induced hypoglycemia for all the subjects (n = 16) was 31.1 +/-3.6 ng/ml (+/-SEM) on day 1 of the control period and 23.4 +/-3.1 (SEM) on day 2, not statistically significant.A significant decrease in the maximal peak GH response (n = 8) after insulin-induced hypoglycemia was observed at 8 and 12 hr after HGH administration was terminated with mean peak values for GH of 4.6 +/-1.3 ng/ml and 10.4 +/-1.9 ng/ml, respectively (P < 0.01). A progressive return to control values was noted between 12 and 24 hr. The GH responsiveness of the saline-treated group (n = 5) was unchanged from that observed during the control period.The fasting glucose values were unchanged in the GH-treated group from those of the control period or of the saline-treated controls. Insulin resistance was apparent at 8 hr posttreatment with HGH. No differences in FFA response after insulin-induced hypoglycemia were observed in GH-treated or saline-treated subjects. The rise in plasma cortisol after insulin-induced hypoglycemia was comparable in the GH-treated and saline-treated group. Diurnal variation in plasma cortisol was maintained during the period of GH suppression.These observations support the concept that GH can modulate its secretion by means of an auto-feedback mechanism.     

Thyroid Hormone Inhibition of the Prolactin Response to Thyrotropin-Releasing Hormone

The influence of serum triiodothyronine (T(3)) and thyroxine (T(4)) concentrations on the release of prolactin in man was studied by determining the prolactin response to synthetic thyrotropin-releasing hormone (TRH) in hypothyroid and hyperthyroid patients before and after correction of their serum thyroid hormone abnormalities. The maximum increment in serum prolactin above the basal level (maximum Delta prolactin) was used as the index of response to TRH.In 12 patients with primary hypothyroidism, the maximum Delta prolactin in response to TRH fell from 100.5+/-29.1 ng/ml (mean +/-SEM) before treatment to 36.1+/-6.0 ng/ml (P < 0.01) during the 4th wk of treatment with 30 mug T(3) + 120 mug T(4) daily. The mean serum T(3) level increased from 57+/-8 to 138+/-10 ng/100 ml, and the mean serum T(4) level increased from 3.0+/-0.4 to 7.2+/-0.4 mug/100 ml during this treatment. In eight normal subjects the maximum Deltaprolactin in response to TRH was not significantly different during the 4th wk of treatment with 30 mug T(3) + 120 mug T(4) daily from the response before treatment. In 10 patients with hyperthyroidism, the maximum Deltaprolactin in response to TRH increased from 14.2+/-2.9 ng/ml before treatment to 46.9+/-6.7 ng/ml (P < 0.001) during antithyroid treatment. The mean serum T(3) level fell from 313+/-47 to 90+/-8 ng/100 ml, and the mean serum T(4) level fell from 20.8+/-2.5 to 6.8+/-0.6 mug/100 ml during this treatment.These results show that changes from normal serum levels of T(3) and T(4) are associated with changes in prolactin responses to TRH; subnormal serum levels of T(3) and T(4) increase TRH-induced prolactin release, whereas substantially higher than normal serum levels of T(3) and T(4) inhibit this release.     

Observations on the maturation of thyroid function in early fetal life

Serum samples were obtained from 21 normal human fetuses after therapeutic abortion for psychiatric indications. Fetal crown-rump length ranged from 5.2 to 22.5 cm, corresponding to the gestational age of 65-168 days.Serum thyroxine, assayed by a modification of the Murphy-Pattee method, was identified in the second smallest fetus examined at 78 days gestation. Thereafter it increased rapidly, maintaining a significant linear correlation with crown-rump length until term (r = 0.800, P < 0.001). Free thyroxine (FT4) also increased in a linear relation to gestational age (r = 0.908, P < 0.001), but reached term levels by 18-20 wk. Radioimmunoassayable thyroid-stimulating hormone (TSH) was detected at 78 days gestation. Levels increased rapidly with advancing gestation, so that by 16 wk almost all were within the range of term infants. After 16 wk gestation, levels were usually greater than 4.0 muU/cc, higher than that seen in normal children.No correlation was demonstrated between the serum TSH levels and total thyroxine. TSH and FT4, however, increased in a parallel manner with a significant positive correlation. This suggested that fetal TSH secretion was responsive to FT4 levels from very early in gestation, possibly as early as 11 wk.Thyroxine-binding globulin (TBG) was detected in a fetus of 78 days gestation (1.4 mug/100 ml). Levels increased rapidly, paralleling the rise in serum thyroxine and maintaining a linear correlation with crownrump length (r = 0.864, P < 0.001). Thyroxine-binding prealbumin binding capacity (TBPA) in fetuses 14-24 wk gestation was comparable with that seen at term.When examining the distribution of tracer amounts of thyroxine-(131)I (T4-(131)I) between the thyroxine-binding proteins, it was found that a major fraction was bound to TBPA and albumin during the early part of gestation. This decreased linearly with maturation of the fetus as the fraction bound to TBG increased. By 20 wk gestation fetal TBG was able to bind 78% of tracer despite a TBG capacity of only 7.7 mug/100 ml. This appeared to be the result of relatively low concentrations of TBPA and albumin during this period of gestation. The theoretical association constant calculated for fetal and newborn TBG was found to be similar to that estimated for normal adult males and females.     

Somatotroph Hyperplasia: SUCCESSFUL TREATMENT OF ACROMEGALY BY REMOVAL OF A PANCREATIC ISLET TUMOR SECRETING A GROWTH HORMONE-RELEASING FACTOR

A 21-yr-old woman with Turner's syndrome presented with signs and symptoms of acromegaly. The serum growth hormone (GH) (95+/-9.4 ng/ml; mean+/-SEM) and somatomedin C (11 U/ml) levels were elevated, and an increase in GH levels after glucose instead of normal suppression, increase after thyrotropin-releasing hormone (TRH) administration instead of no change, and decrease after dopamine administration instead of stimulation were observed. The pituitary fossa volume was greater than normal (1,440 mm(3)) and the presence of a pituitary tumor was assumed. After tissue removal at transsphenoidal surgery, histological study revealed somatotroph hyperplasia rather than a discrete adenoma. Postoperatively, she remained clinically acromegalic and continued to show increased GH and somatomedin levels. A search was made for ectopic source of a growth hormone-releasing factor (GRF). Computer tomographic scan revealed a 5-cm Diam tumor in the tail of the pancreas. Following removal of this tumor, serum GH fell from 70 to 3 ng/ml over 2 h, and remained low for the subsequent 5 mo. Serum somatomedin C levels fell from 7.2 to normal by 6 wk postoperatively. There were no longer paradoxical GH responses to glucose, TRH, and dopamine. Both the medium that held the tumor cells at surgery and extracts of the tumor contained a peptide with GRF activity. The GRF contained in the tumor extract coeluted on Sephadex G-50 chromatography with rat hypothalamic GH-releasing activity. Stimulation of GH from rat somatotrophs in vitro was achieved at the nanomolar range, using the tumor extract.The patient's course demonstrates the importance of careful interpretation of pituitary histology. Elevated serum GH and somatomedin C levels in a patient with an enlarged sella turcica and the characteristic responses seen in acromegaly to TRH, dopamine, and glucose do not occur exclusively in patients with discrete pituitary tumors and acromegaly. This condition can also occur with somatotroph hyperplasia and then revert to normal after removal of the GRF source. Thus, in patients with acromegaly a consideration of ectopic GRF secretion should be made, and therefore, careful pituitary histology is mandatory. Consideration for chest and abdominal computer tomographic scans before pituitary surgery, in spite of their low yield, may be justified.     

Studies on the relationship between plasma free fatty acids and growth hormone secretion in man

The influence of plasma free fatty acid (FFA) concentration on the secretion of human growth hormone (HGH) was investigated. (a) FFA depression was produced by means of a nicotinic acid (NA) infusion for either 1 or 5 hr in the presence of glucose-induced hyperglycemia. Controls received only saline. (b) FFA depression was also produced by a 90 min NA infusion and then rapid FFA elevation by a lipid-plus-heparin (lipid) infusion. This procedure was compared with a similar NA infusion not followed by lipid. (c) FFA elevation was produced either by a lipid or by a norepinephrine (NE) infusion and then HGH secretion was stimulated by insulin-induced hypoglycemia. Each subject in this group received both the lipid and the NE infusion on seperate days as well as two control tests (insulin alone and NE alone).Depression of FFA resulted in an increase of HGH with a lag period of approximately 2 hr. Maximal HGH rise after 1 hr NA infusion was 7.7+/-1.9 ng/ml and with 5 hr NA infusion 14.3+/-3.6 ng/ml (both significantly higher than during saline infusion, P < 0.025 and < 0.005 respectively) and occurred despite continuous hyperglycemia. Lipid infusion just before the expected HGH increase prevented the HGH response to FFA depression. HGH rise during insulin hypoglycemia (32.2+/-6.5 ng/ml) was significantly inhibited by prior FFA elevation whether achieved by lipid infusion (maximum HGH rise 11.4+/-1.6 ng/ml) or by NE infusion (maximum HGH rise 19.0+/-6.2 ng/ml).The results are suggestive of a negative feedback loop between plasma FFA and HGH secretion, of importance for subacute rather than acute changes in the plasma FFA concentration. FFA lack itself seems to be the signal for HGH release despite the lag period between FFA decrease and HGH increase. Glucose and FFA can at least not fully replace each other in their respective influence on HGH release.     

Inhibition of thyrotropin response to thyrotropin-releasing hormone by small quantities of thyroid hormones

Inhibition of thyrotropin (TSH) release by chronic treatment with small quantities of triiodothyronine (T(3)) and thyroxine (T(4)) was evaluated by determining the serum TSH response to thyrotropin-releasing hormone (TRH) in normal subjects and hypothyroid patients. Response to TRH was determined before treatment and after each dosage of a synthetic combination of T(3) + T(4) had been given for 3-4 wk.Treatment of eight normal subjects with 15 mug T(3) + 60 mug T(4) reduced the maximum increase in serum TSH above baseline (maximum DeltaTSH) by 76% in response to 400 mug TRH and by 87% in response to 25 mug TRH. The average serum T(3) level during a 24 hr period in normal subjects who had been taking 15 mug T(3) + 60 mug T(4) for 3-4 wk was 129+/-10 ng/100 ml (mean +/-SEM), well within the normal range, 70-150 ng/100 ml, although higher than the pretreatment level, 98+/-7 ng/100 ml. The average serum T(4) level was unchanged from the pretreatment level. Treatment of the same subjects with 30 mug T(3) + 120 mug T(4) reduced the maximum DeltaTSH further.Six patients with primary hypothyroidism were treated, sequentially, with 15 + 60, 22.5 + 90, and 30 mug T(3) + 120 mug T(4). For each patient there was one increase in dosage of 7.5 mug T(3) + 30 mug T(4) which abruptly converted a maximum DeltaTSH that was greater than, or at the upper limit of, normal to one that was subnormal. Concurrent with these six abrupt changes in TSH response, the mean serum T(3) level increased only from 105+/-5 to 129+/-9 ng/100 ml, and the mean serum T(4) level increased only from 4.9+/-0.8 to 6.3+/-0.5 mug/100 ml.These data demonstrate the extreme sensitivity of TRH-induced TSH release to inhibition by the chronic administration of quantities of T(3) + T(4) which do not raise serum T(3) and T(4) levels above the normal ranges.     

Umbilical cord and maternal blood leptin concentrations in intrauterine growth retardation.

Leptin, the ob gene product, plays an important role in the regulation of body fat mass and weight. In previous studies, it was demonstrated that leptin is detectable in human fetal cord blood as early as at 18 weeks of gestation and that serum leptin concentrations are significantly reduced in small gestational age newborns. In the present study, we investigated whether umbilical and maternal serum leptin concentrations correlate with intrauterine growth retardation (IUGR). In addition, we aimed to determine the relationships between leptin concentration in the maternal and cord blood. We studied 40 newborn infants (21 female and 19 male; gestational age, 38-42 weeks) and their mothers. Of the infants studied, 10 had IUGR. Serum leptin concentrations were measured by radioimmunoassay. All newborns had detectable leptin concentrations. Leptin concentrations were significantly lower in newborns with IUGR and in their mothers (n = 10; 3.53 +/- 1.42 ng/ml, 6.75 +/- 1.47 ng/ml, respectively) than in infants experiencing normal growth and their mothers (n = 30; 5.58 +/- 2.98 ng/ml, 9.85 +/- 6.50 ng/ml, respectively) (p < 0.01 for newborns, p < 0.05 for mothers). There was no significant correlation between umbilical leptin concentration and maternal leptin concentration (r = 0.229; p = 0.155) in all study groups but, significantly, a correlation was observed in the group with IUGR (r = 0.736; p = 0.015). There were no significant correlations between both umbilical and maternal leptin concentrations and parity, delivery type and gestational age. There was a correlation between umbilical leptin concentration and birth weight of newborns (r = 0.383; p = 0.015) but no correlation with body mass index (BMI) of the newborns (r = 0.034; p = 0.834). Maternal leptin concentrations correlated with maternal weight and BMI (r=0.606; p=0.000, r=0.535; p=0.000, respectively). There was no correlation between maternal leptin concentrations and birth weight of the newborns (r=0.179; p=0.269) and with BMI of the newborns (r = 0.146; p = 0.367). There was no gender difference in leptin concentrations in the newborns (n=21; 5.50 +/- 3.37 ng/ml, for females; n = 19; 4.58 +/- 1.98 ng/ml for males) (p = 0.296). In summary, we have shown that IUGR is associated with a decreased leptin concentration in newborns and their mothers. The association between umbilical serum leptin and birth weight in this and other studies suggests a pivotal role of fetal leptin in regulating fetal growth and development.     

Human fetal and adult chondrocytes. Effect of insulinlike growth factors I and II, insulin, and growth hormone on clonal growth.

Clonal proliferation of freshly isolated human fetal chondrocytes and adult chondrocytes in response to human insulinlike growth factors I and II (IGF I, IGF II), human biosynthetic insulin, and human growth hormone (GH) was assessed. IGF I (25 ng/ml) stimulated clonal growth of fetal chondrocytes (54 +/- 12 colonies/1,000 inserted cells, mean +/- 1 SD), but IGF II (25 ng/ml) was significantly more effective (106 +/- 12 colonies/1,000 inserted cells, P less than 0.05, unstimulated control: 14 +/- 4 colonies/1,000 inserted cells). In contrast, IGF I (25 ng/ml) was more effective in adult chondrocytes (42 +/- 6 colonies/1,000 inserted cells) than IGF II (25 ng/ml) (21 +/- 6 colonies/1,000 inserted cells; P less than 0.05, unstimulated control: 6 +/- 3 colonies/1,000 inserted cells). GH and human biosynthetic insulin did not affect clonal growth of fetal or adult chondrocytes. The clonal growth pattern of IGF-stimulated fetal and adult chondrocytes was not significantly changed when chondrocytes were first grown in monolayer culture, harvested, and then inserted in the clonal culture system. However, the adult chondrocytes showed a time-dependent decrease of stimulation of clonal growth by IGF I and II. This was not true for fetal chondrocytes. The results are compatible with the concept that IGF II is a more potent stimulant of clonal growth of chondrocytes during fetal life, whereas IGF I is more effective in stimulating clonal growth of chondrocytes during postnatal life.     

Relationship between the Accumulation of Pituitary Growth Hormone and Nuclear Occupancy by Triiodothyronine in the Rat

Studies were undertaken in hypothyroid rats in an effort to define the kinetics of growth hormone (GH) accumulation in response to i.v. pulse injections of triiodothyronine (T(3)) and to calculate the relationship between nuclear occupancy by T(3) and the instantaneous rate of accumulation of pituitary GH. Results were contrasted to the findings in previous studies of the induction of hepatic mitochondrial alpha-glycerophosphate dehydrogenase (alpha-GPD) and malic enzyme (ME) by T(3). The dose of T(3) required to achieve half-maximal accumulation of GH in 24 h was 0.6 mug/100 g body wt, a value 15-fold less than the half-maximal dose for alpha-GPD and ME induction at a comparable time after injection. Although significant increase in pituitary GH were evident as early as 3 h after injection of maximally effective doses of T(3), the rate of increase became linear only 12 h after injection. After achievement of peak values, the pituitary content of GH decayed with a similar terminal t((1/2)) of 3.9 days and 4.1 days in two groups of animals injected with a single dose of 1.0 and 50 mug T(3)/100 g body wt, respectively. In vivo isotopic displacement studies carried out at the equilibrium time point indicated that the pituitary nuclear binding capacity was 5.5 ng T(3)/g tissue and that the plasma concentration at which one-half of the nuclear sites are occupied is 1.0 ng/ml. Nuclear occupancy as a function of time was calculated from the estimated plasma T(3) concentration after injection of the dose and the half-occupancy plasma concentration. These data were then analyzed by application of the mathematical model previously developed to ascertain the relationship between nuclear occupancy and the rate of hepatic enzyme induction. Results indicated that the pituitary nuclear occupancy-response relationship was generally linear, in marked contrast to the highly amplified relationship between nuclear occupancy and the response of ME and alpha-GPD to T(3) in the liver. In supplementary experiments, euthyroid rats received daily injections of 200 mug of T(3) for 7 days to keep nuclear sites nearly saturated for the duration of the experiment. No significant increase in the pituitary GH content above euthyroid base-line levels was noted. This also contrasts with the marked increase above euthyroid levels in alpha-GPD and ME observed in previous studies. Our findings suggest the existence of major differences between the specific mechanisms which lead to the induction of pituitary GH and the hepatic enzymes by T(3).     

颅咽管瘤患者术后腺垂体生长激素储备功能的初步评价

目的 探讨颅咽管瘤患者手术后腺垂体生长激素储备功能状态.方法 采用胰岛素耐受性试验（insulin tolerance test,ITT）对12例颅咽管瘤术后时间超过6个月以上的患者行动态腺垂体生长激素储备功能试验.结果 本组所有患者ITT各时间点生长激素分泌的水平均低于1 ng/ml,提示本组受试者均存在完全性生长激素缺乏.受试者中4例患者的生长激素水平在ITT试验的各观察时间点波动在0.092 ～0.199 ng/ml,但仍低于1 ng/ml,其余8例患者生长激素水平在ITT激发后各观察时间点较前4例更低,其中4例患者各观察时间点生长激素水平甚至低于0.05 ng/ml.结论 本组颅咽管瘤患者在手术治疗6个月以后均存在严重的腺垂体生长激素储备功能减退.     

Decreased serum insulin-like growth factor-I associated with growth failure in newborn lambs with experimental cyanotic heart disease.

To determine whether chronic hypoxemia results in alterations in endocrine function that may contribute to growth failure, we measured growth hormone (GH), somatomedins (insulin-like growth factors I and II, IGF-I and IGF-2), hepatic growth hormone receptors, and circulating IGF-binding proteins IGFBP-3 and IGFBP-2 in 12 newborn lambs with surgically created pulmonic stenosis and atrial septal defect, and in 10 controls. During chronic hypoxemia (oxygen saturation of 60-74% for 2 wk), weight gain was 60% of control (hypoxemic, 135 +/- 20 vs. control, 216 +/- 26 g/d, P less than 0.02). IGF-I was decreased by 43% (hypoxemic 253.6 +/- 29.3 SE vs. control 448.0 +/- 75.5 ng/ml, P = 0.01), whereas GH was unchanged (19.9 +/- 5.1 vs. 11.9 +/- 3.0 ng/ml, NS). The increase in IGF-1 was associated with a decrease in IGFBP-3 (hypoxemic, 5.09 +/- 1.25 vs. control, 11.2 +/- 1.08 arbitrary absorbency units per mm (Au.mm), P less than 0.01), and increase in IGFBP-2 (0.47 +/- 0.03 vs. 0.19 +/- 0.13 Au.mm, P less than 0.05), but no significant downregulation of hepatic GH receptors (hypoxemic, 106.1 +/- 20.1 vs. control, 147.3 +/- 25.9 fmol/mg, NS). Thus, chronic hypoxemia in the newborn is associated with a decrease in IGF-I and IGFBP-3 in the face of normal GH. This suggests peripheral GH unresponsiveness, similar to protein-calorie malnutrition or GH receptor deficiency dwarfism, but mediated at a level distal to the hepatic GH receptor.     

Metabolic clearance and production rates of human growth hormone

The metabolic clearance rate (MCR) of human growth hormone (HGH) was determined by the constant infusion to equilibrium technique utilizing HGH-(125)I. 22 control subjects had a MCR of 229 +/-52 ml/min (mean +/-SD). No difference was evident between sexes, or between various age groups. Patients with acromegaly demonstrated normal MCR's. Moreover, acute elevations of plasma growth hormone concentrations in normal subjects did not alter the MCR of HGH. The MCR was relatively constant from day to day and within the day when subjects were evaluated in the supine position. In contrast, the assumption of the upright position was associated with a mean 24% decrease in the MCR.These results were contrasted with the MCR of HGH observed in a small number of patients with altered thyroid function or diabetes mellitus. In six patients with hypothyroidism the MCR (131 +/-36 ml/min) was significantly decreased (P < 0.001); whereas the MCR in eight patients with hyperthyroidism (240 +/-57 ml/min) did not differ from control subjects. The MCR in eight patients with insulin-independent diabetes mellitus (IID) (185 +/-41 ml/min) and in eight patients with insulin-dependent diabetes mellitus (IDD) (136 +/-31 ml/min) were significantly different from control subjects (P = < 0.05 and P = < 0.001, respectively).These data were interpreted to indicate that the plasma HGH-removing mechanism(s) is not saturated at physiologic plasma HGH levels, that plasma HGH levels alone may not permit distinction between variations in pituitary release of the hormone and its rate of clearance from the plasma, and that the estimation of the MCR of HGH may help clarify the mechanism of abnormal plasma HGH responses to various stimuli.Production rates of HGH (PR) in control subjects (347 +/-173 mmug/min) were contrasted with hyperthyroid patients (529 +/-242 mmug/min, P < 0.05), hypothyroid patients (160 +/-69 mmug/min, P < 0.02), IID (245 +/-100 mmug/min, NS), and IDD (363 +/-153 mmug/min, NS). Considerable variability in the determination of the concentrations of immunoprecipitable HGH-(125)I and endogenous plasma HGH concentrations was encountered at apparent equilibrium conditions. Since both factors are necessary for the PR calculations, the wide 95% confidence limits of the PR's did not permit a clear interpretation of the significance of these observations.     

Growth hormone response in very short children.

Growth hormone (GH) response to standardized exercise, L-DOPA/propranolol and a 6-h diurnal GH profile (GHP) were evaluated in twenty-three children with very short stature and abnormal growth velocities. Standardized exercise (Jones Stage I) was performed on a cycle ergometer at 53% of the maximum oxygen consumption (VO2max) for 20 min. VO2max was determined by an incremental progressive workload until exhaustion. The mean +/- SEM peak GH concentration (ng/ml) for each test was: exercise, 8.7 +/- 1.3; L-DOPA/P: 12.8 +/- 1.9 and GHP: 3 +/- 0.7. There was no statistical difference between exercise and L-DOPA/P peaks but both peaks were significantly higher than the peak observed during the profile. During exercise 14 of 23 patients had a GH response greater than 8 ng/ml. Two patients were found to be GH deficient. Therefore 16 of 23 patients (86%) had a result concordant with their final diagnosis. During the L-DOPA/P test 17 of 23 patients had a GH response greater than 8 ng/ml. By contrast only 6 of 23 patients had a positive response during GHP. Standardized exercise is as effective as L-DOPA/P as a stimulation test for growth hormone response in very short children with abnormal growth velocities. Exercise has the advantages of being physiological, having minimal side effects, and requiring fewer blood samples. In this population of children, exercise and L-DOPA/propranolol are significantly better than the 6-h growth hormone profile for assessing GH secretion.     

Hyperresponse to Thyrotropin-Releasing Hormone Accompanying Small Decreases in Serum Thyroid Hormone Concentrations

To determine whether pituitary thyrotropin (TSH) responsiveness to thyrotropin-releasing hormone (TRH) is enhanced by small decreases in serum thyroxine (T4) and triiodothyronine (T3), 12 euthyroid volunteers were given 190 mg iodide po daily for 10 days to inhibit T4 and T3 release from the thyroid. Basal serum T4, T3, and TSH concentrations and the serum T4 and TSH responses to 400 mug TRH i.v. were assessed before and at the end of iodide administration. Iodide induced small but highly significant decreases in basal serum T4 (8.0+/-1.6 vs. 6.6+/-1.7 mug/100 ml; mean +/- SD) and T3 (128+/-15 vs. 110+/-22 ng/100 ml) and increases in basal serum TSH (1.3+/-0.9 vs. 2.1+/-1.0 muU/ml). During iodide administration, the TSH response to TRH was significantly increased at each of seven time points up to 120 min. The maximum increment in serum TSH after TRH increased from a control mean of 8.8+/-4.1 to a mean of 13.0+/-2.8 muU/ml during iodide administration. As evidence of the inhibitory effect of iodide on hormonal release, the increment in serum T3 at 120 min after TRH was significantly lessened during iodide administration (61+/-42 vs. 33+/-24 ng/100 ml). These findings demonstrate that small acute decreases in serum T4 and T3 concentrations, resulting in values well within the normal range, are associated both with slight increases in basal TSH concentrations and pronounced increases in the TSH response to TRH. These results demonstrate that a marked sensitivity of TSH secretion and responsiveness to TRH is applicable to decreasing, as well as increasing, concentrations of thyroid hormones.     

Plasma dehydroepiandrosterone in pregnant and nonpregnant women.

From 157 plasma samples taken randomly throughout normal pregnancy and from 42 plasma samples of nonpregnant women, total plasma dehydroepiandrosterone was measured by a method using Amberlite XAD-2 column chromatography at 45degreesC, enzyme hydrolysis, radioactive internal standard, thin-layer chromatography and gas-liquid chromatography after trimethylsilyl ether derivative formation. The following values for dehydroepiandrosterone were obtained: from individual, nonpregnant samples, (n = 25) 69.6 +/- 10.6 mug/100 ml (S.E.M.); from the pool of nonpregnant samples (n = 17) 67.7 mug/100 ml; from individual samples, 6-12 weeks of gestation (n = 32) 48.5 +/- 5.7 mug/100 ml (S.E.M.); from individual samples, 13-18 weeks of gestation (n = 13) 45.9 +/- 7.7 mug/100 ml (S.E.M.); from individual samples, 19-24 weeks of gestation (n = 20) 42.9 +/- 6.9 mug/100 ml (S.E.M.); from individual samples, 25-30 weeks of gestation (n = 22) 41.7 +/- 6.8 mug/100 ml (S.E.M.); from individual samples, 31-36 weeks of gestation (n = 31) 39.5 +/- 6.1 mug/100 ml (S.E.M.); from individual samples, 37-43 weeks of gestation (n = 29) 37.6 +/- 3.6 mug/100 ml (S.E.M.); and from the pool sample, 37-43 weeks of gestation (n = 10) 25.4 mug/100 ml. This study demonstrates a significant decrease of total plasma dehydroepiandrosterone throughout the course of normal pregnancy in individual and pooled plasma samples, thus confirming previous reports. These plasma hormone changes are discussed in relation to production and utilization of this steroid in pregnancy.     

Longitudinal assessment of glycosylated blood protein concentrations in normal pregnancy and gestational diabetes

Longitudinal changes in glycosylated hemoglobin concentration (GlyHb) and glycosylated serum protein concentration (GSP) in both normal pregnancy and pregnancy complicated by gestational diabetes were determined using affinity chromatography, a method in which nonenzymatically glycosylated proteins are specifically measured. At 7-10 wk gestation, GlyHb in women who developed diabetes (N = 21) was higher than GlyHb in normal women (N = 49) (6.7 +/- 0.2% versus 5.7 +/- 0.2%, respectively, P less than 0.001) and remained elevated throughout gestation. In normal pregnancy, GlyHb decreased to a nadir at 23-26 wk and returned to baseline concentration by 31-34 wk. In gestational diabetes, there was an initial increase in GlyHb to 7.1 +/- 0.5% at 11-14 wk followed by a steady decrease. At 7-10 wk, GSP in women who developed diabetes was not elevated compared with normal concentration, although at 11-14 wk there was significant difference between the two groups (P less than 0.02). In normal women, GSP remained constant throughout gestation. In gestational diabetes, GSP decreased to early pregnancy values (P less than 0.02). Glycosylated blood proteins were elevated in early gestation in women who developed gestational diabetes and may have predictive value in identifying women who will develop diabetes in pregnancy.     

Effect of amiodarone on serum triiodothyronine, reverse triiodothyronine, thyroxin, and thyrotropin. A drug influencing peripheral metabolism of thyroid hormones.

2-n-Butyl-3-(4'-diethylaminoethoxy-3',5'-diiodobenzoyl)-benzofurane (amiodarone), a drug used in arrythmias and angina pectoris, contains 75 mg of organic iodine/200 mg active substance. Four studies were performed to test its effect on thyroid hormone metabolism: (a) nine male subjects were treated with 400 mg of amiodarone for 28 days; (b) five male subjects received, for the same period of time, 150 mg of iodine in the form of Lugol's solution; (c) five subjects received 300 mug L-thyroxine (T4) for 16 days; from the 10th to the 16th day, 400 mg of amiodarone was added; and (d) five euthyroid subjects received 300 mug L-T4 for 16 days. The changes in serum thyroid-stimulating hormone (TSH), serum total T4, 3,5,3'-triiodothyronine (T3), free T3, and 3,5',3'-triiodothyronine (reverse T3, rT3) were measured, and the pituitary reserve in TSH was evaluated by a thyrotropin-releasing hormone (TRH) test. The results show that amiodarone induced a decrease in serum T3 (28+/-5.1 ng/100 ml, mean+/-SEM, P less than 0.0S and 82.7+/-9.3 ng rT3/100 ml, P less than 0.01). The control study with an equal amount of inorganic iodine did not induce these opposite changes but slightly lowered serum rT3, T3, and T4. In the third study, serum rT3 increased as under amiodarone treatment, thereby proving that these changes were peripheral. It is suggested that amiodarone changes thyroid hormone metabolism, possibly by reducing deiodination of T4 to T3 and inducing a preferential production of rT3. Amiodarone also increased the response of TSH to TRH. The maximal increment of serum TSH above base line was 32+/-4.5 muU/ml under treatment and 20+/-3 muU/ml before treatment (P less than 0.01). During this test, the serum T3 increase was more pronounced than during the control period (83+/-13 and 47+/-7.4 ng/100 ml, P less than 0.05).     

Early sonographic evaluation for fetal growth delay and congenital malformations in pregnancies complicated by insulin-requiring diabetes. National Institute of Child Health and Human Development Diabetes in Early Pregnancy Study.

OBJECTIVE--It has been reported that early fetal growth retardation may be a useful marker for congenital malformations in diabetic pregnancies. To test this hypothesis, diabetic and nondiabetic women were sonographically evaluated during the first trimester. RESEARCH DESIGN AND METHODS--Fetal crown-rump lengths were measured sonographically at least once during the first 15 wk of pregnancy in 329 nondiabetic and 312 diabetic women. Of these, 289 nondiabetic and 269 diabetic women had sonograms before 10 wk of gestation and 283 nondiabetic and 269 diabetic women had sonograms between 10 and 15 wk of gestation. Early fetal growth delay was defined as a sonographic gestational age of greater than or equal to 6 days less than menstrual gestational age. RESULTS--The mean crown-rump lengths at 8 wk were 17.9 +/- 4.6 mm in the diabetic and 18.7 +/- 4.9 mm in the nondiabetic groups (P = 0.13). At 12 wk, the mean fetal crown-rump length was 58.5 +/- 8.8 mm for diabetic subjects and 60.6 +/- 8.7 mm for nondiabetic subjects (P = 0.04). Between 5 and 9 wk, 28 of 289 (9.7%) fetuses of nondiabetic subjects, 34 of 259 (13.1%) normal fetuses of diabetic subjects, and 2 of 10 (20%) malformed fetuses of diabetic subjects demonstrated growth delay (P = 0.31, normal vs. malformed diabetic). Between 10 and 15 wk of gestation, 28 of 283 (9.9%) fetuses of nondiabetic subjects, 32 of 256 (12.5%) normal fetuses of diabetic subjects, and 4 of 13 (30.8%) malformed fetuses of diabetic subjects demonstrated growth delay (P = 0.06, normal vs. malformed diabetic). Early fetal growth delay did not predict a reduced birth weight at term. CONCLUSIONS--Among insulin-dependent diabetic subjects who were moderately well controlled at conception, statistically significant but mild early fetal growth delay was present but did not appear to be useful clinically in predicting congenital malformations. Recommendations that growth delay demonstrated on early ultrasound be used as a predictor of congenital malformation require careful reexamination.