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The genetic potentials for growth can be fully expressed only under favourable environmental conditions. Excessive physical training may negatively affect growth, especially during puberty. Sports that require a strict control of energy input in the presence of a high energy output are of particular concern. In gymnastics, a different pattern in skeletal maturation was observed, leading to an attenuation of growth potential ins Artistic Gymnasts (AG), more pronounced in males than in females, whereas in female Rhythmic Gymnasts (RG) the genetic predisposition to growth was preserved because of a late catch-up growth phenomenon. In all other sports not requiring strict dietary restrictions, no deterioration of growth has been documented. Intensive physical training and negative energy balance modify the hypothalamic pituitary set point at puberty, prolong the prepubertal stage and delay pubertal development and menarche in a variety of sports. In elite RG and AG the prepubertal stage is prolonged and pubertal development is entirely shifted to a later age, paralleling the bone age rather than the chronological age. Bone formation, and, consequently, BMD are enhanced by physical activity. In athletes, high-impact loading activities have been shown to improve BMD, while in sports requiring a lean somatotype, the delay in skeletal maturation and pubertal development, resulting from hypoestrogenemia, predisposes athletes to osteopenia. In AG, an increase in bone density is observed using the bone age as denominator.

Capecitabine is a tumor-activated oral fluoropyrimidine with established antitumor activity in breast and colorectal cancer. Hypertriglyceridemia associated with this drug has rarely been reported in the literature.This is a report of two patients who developed capecitabine-induced severe hypertriglyceridemia, together with an increase in total cholesterol levels. The first patient developed hyperlipidemia during long-term capecitabine treatment in combination with trastuzumab for metastatic breast carcinoma (triglycerides: from 219 mgldl to 1409 mg/dl, 543% increase; cholesterol: from 239 mg/dl to 363 mg/dl, 52% increase). The second patient developed abnormalities in the lipid profile after the second cycle of chemotherapy with capecitabine and oxaliplatin for metastatic colorectal cancer (triglycerides: from 101 mg/dl to 1510 mg/dl, 1395% increase; cholesterol: from 203 mg/dl to 310 mgldl, 52% increase). An analysis of the possible underlying pathogeneic mechanisms is provided.Physicians should be aware of the possibility of dyslipidemia, particularly hypertriglyceridemia, following treatment with capecitabine.

Parathyroid scintigraphy and high-resolution ultrasonography are frequently used as preoperative localization procedures in primary hyperparathyroidism. However, when thyroid disease coexists, their diagnostic accuracy is probably abated. DESIGN: 56 patients with primary hyperparathyroidism were prospectively evaluated with parathyroid scintigraphy (with either thallium or technetium-99m agents or both) and 44 of them were also evaluated with ultrasonography. RESULTS: 33 patients (59%) had coexistent thyroid disease. Upon operation, 48 patients were found to have a solitary parathyroid adenoma and were all cured. One patient had a carcinoma and 7 had multiglandular parathyroid disease. Regarding solitary lesions, the sensitivity of parathyroid scintigraphy with Tc-agents was 97% and thallium 78%, while that of ultrasonography was 74%. The false positive rate was 2.6%, 18% and 22%, respectively. Concomitant thyroid disease had a non-significant effect on the results of parathyroid scintigraphy and ultrasonography. The efficiency of both modalities in diagnosing multiglandular disease was low (only 3/7 patients, 43%). CONCLUSIONS: Parathyroid scintigraphy, in conjunction with Sestamibi or Tetrofosmin, constitutes the most sensitive localizing technique as regards solitary lesions. Ultrasonography is also useful in confirming scintigraphic findings, offers more precise anatomic information, and is valuable in the evaluation of concomitant thyroid disease. The complementary use of parathyroid scintigraphy and ultrasonography is beneficial and efficacious in areas with high prevalence of thyroid disease. The value of these modalities is considerably lower in multiglandular disease.

Elite gymnasts are subjected to intense training, which may alter pubertal development.The objective of the investigation was to study the impact of gymnastics on pubertal development in rhythmic (RGs) and artistic gymnasts (AGs).Evaluation of somatometric parameters, pubertal stage, and intensity of training in the competition field were studied.The study was conducted at European and world championships of years 1997-2004.Subjects included 433 elite RGs and 427 AGs, aged 11-23 yr.There were no interventions.Mean chronological and bone ages of each pubertal stage and their relation to the intensity of training were measured.AGs and RGs showed a delay in skeletal maturation (Delta age-bone age, 2.13 and 1.28, respectively; P0.001). AGs were subjected to higher levels of physical training. Thelarche occurred at 12.9 yr for RGs and 13.2 yr for AGs (P = 0.003) and pubarche at 12.5 and 12.9 yr, respectively (P = 0.002). Puberty was delayed but normally progressed. AGs entered each pubertal stage later than RGs. The delay was influenced by the amount of energy output. Menarcheal age was 14.6 yr for RGs and 14.9 yr for AGs. Menarche was influenced in AGs by bone age (b = 0.333; t = 2.521; P = 0.020), pubarche (b = 0.322; t = 2.401; P = 0.026), and body fat (b = -0.458; t = -3.412; P = 0.003) and in RGs by bone age (b = 0.378; t = 3.689; P0.001) and pubarche (b = 0.525; t = 6.017; P0.001).In RGs and AGs, pubertal development was shifted to a later age, maintaining a normal rate of progression, which followed the bone age. AGs, who were exposed to a greater and more sustained energy output than RGs, presented a more pronounced delay in both skeletal maturation and pubertal development.

Gonadal dysfunction in adult long-term survivors of hematopoietic stem cell transplantation (HSCT) is an adverse effect of conditioning regimens consisting of chemotherapy and total body irradiation (TBI). The impact of conditioning regimens consisting of chemotherapy alone on the function of the hypothalamic-pituitary-gonadal (HPG) axis was evaluated in a series of 41 female and 31 male patients who had undergone either autologous or allogeneic bone marrow/peripheral blood stem cell transplantation; mean age at transplantation was 32.6 years and mean time interval from transplantation was 1.5 years (range 0.2-9.8 years). Provocative testing of the HPG axis by administration of luteinizing hormone-releasing hormone was included in the first endocrinological evaluation. The follow-up period extended to three consecutive years. Gonadal dysfunction was not reported by any of the patients prior to their underlying illness. Hypergonadotrophic hypogonadism was observed in 97% of female and 19% of male patients. Leydig cell strain (normal testosterone, high luteinizing hormone levels) was evident in 32% and spermatogenesis damage (high follicle-stimulating hormone levels) in 68% of the male population. At the conclusion of the study four women (10%) had regained spontaneous menses and all hypogonadal men had resumed normal testosterone levels. Our results indicate a high incidence of gonadal dysfunction due to target organ failure in HSCT recipients not treated by TBI.

Steroids determination in saliva offers several advantages. The collection of saliva is a noninvasive, less stressful technique than blood withdrawal and reflects the circulating unbound fractions. The suitability of saliva for 17-hydroxyprogesterone and cortisol determinations has been documented in healthy subjects as well as in diseases like Congenital Adrenal Hyperplasia and Cushing syndrome. The aim of the study was to compare the influence of different collection methods on the results of 17-hydroxyprogesterone measurement in saliva collected by different ways, using commercially available RIAs developed for plasma. 17-hydroxyprogesterone was determined in 64 healthy adult volunteers (30 males, 34 females) in serum (Group SE) and in saliva collected before meals at 8-10 p.m. by directly spitting into a plastic tube (Group SP), using a cotton swab (Group SA) and using a polyester swab Salivette (Group SB). We used a commercially available direct radioimmunoassay without separation technique. The 17-hydroxyprogesterone mean values (ng/ml) were 1.16+/-1.3 (Group SE), 0.056+/-0.046 (Group SP), 0.089+/-0.048 (Group SA) and 0.058+/-0.049 (Group SB). The detection limit was 0.010 ng/ml. The correlations between the values in serum (Group SE) and in saliva were: r=0.77, p0.05 (Group SP); r=0.62, p0.05 (Group SA); r=0.70, p0.05 (Group SB). The saliva values corresponding to the serum cut-off point of 3 ng/ml upper limit of normal values were in ng/ml 0.13 (Group SP), 0.16 (Group SA) and 0.11 (Group SB). In conclusion, 17-hydroxyprogesterone determinations in saliva using commercially available RIAs primarily developed for serum, is a reliable and easy to perform procedure. The three different methods of saliva collection showed 17-hydroxyprogesterone concentrations to have good agreement.

We studied 262 athletes who were 13-23 yr old. There were 93 male and 169 female artistic gymnasts (AG). This study is unique in character, because all variables were measured on the field of competition (24th European Championship). Male AG had a higher height SD score than female (P < 0.001), with a higher reported target height SD score (P < 0.001), a higher predicted final height (P = 0.007), a lower Delta height - target height (P < 0.001), a less delayed bone age (P < 0.001), a greater body mass index (BMI) (P < 0.001), a lower mean body fat (P

Physical exercise enhances bone acquisition during adolescence. The aim of the study was to evaluate the influence of intensive physical exercise on bone acquisition in adolescent elite artistic gymnasts. The study included 262 athletes (93 males and 169 females, aged 13-23 yr) participating in the 24th European Championship held in Greece. Bone age compared with chronological age was delayed by 2 yr for females (n = 120) and 1 yr for males (n = 68). For both sexes, the growth chart of bone mineral density (BMD) followed a normal pattern when estimated according to bone age rather than chronological age. For females, BMD was positively correlated with bone age, chronological age, height, body weight, body mass index, body fat, lean body mass, and with age of onset of training, and negatively with duration of exercise and intensity of training (P values range from0.05 to0.0001). Multiple regression analysis revealed that age of onset of training was the major parameter attenuating the effect of exercise on BMD (P0.001). The latter was related to the stage of puberty (P0.05). For males, BMD was correlated positively with bone age, height, body weight, and lean body mass (P values range from0.01 to 0.0001). Multiple regression analysis revealed that the more powerful factor influencing BMD was weight (P0.01). In conclusion, bone acquisition in adolescents under intensive physical training follows the normal pattern only when estimated according to bone age. The age of onset, the duration, and the intensity of exercise attenuate the bone acquisition, at least in female artistic gymnasts.

BACKGROUND: Somatic activating mutations of the thyrotropin (thyroid-stimulating hormone (TSH)) receptor (TSHR) and G(alphas) protein have been detected in solitary toxic adenomas and toxic multinodular goiters, but their role in the pathogenesis of autonomous nodules is debated. The frequency of mutations is highly variable among populations and is inversely proportional to iodine intake. DESIGN AND PATIENTS: We screened 28 clinically and histologically heterogeneous autonomous nodules from 24 Greek patients for the presence of TSHR and G(alphas) mutations. RESULTS: By direct sequencing of genomic DNA, we detected 11 somatic heterozygous gain-of-function mutations in TSHR and one in G(alphas). Forty-three percent (12 of 28) of all nodules and 57% (four of seven) of solitary toxic adenomas harbored an activating mutation. Typical adenomas and hyperplastic nodules did not differ in mutation frequency. Substitutions I568T and T632I were detected in both histological types of nodules. CONCLUSIONS: Our findings indicate that activating somatic mutations in the TSH signaling pathway are frequent in autonomous nodules in Greece. This may be due to earlier exposure of the population to iodine deficiency, which was corrected in Greece only over the past two decades. Gain-of-function mutations are shared by nodules with varying histological and clinical presentations. Thus, they may represent a common molecular mechanism underlying the pathogenesis of non-autoimmune thyroid autonomy.

Aims and Background The objective of the study was to assess the efficacy of surgical resection of solitary brain metastasis in patients with non-small-cell lung cancer. Methods and Study Design We report a retrospective analysis of 32 patients with single brain metastasis surgically excised at our hospital. All but one patient underwent postoperative whole brain radiation therapy. Results The median survival of patients was 12.5 months postoperatively (mean, 17 months), and the overall 1-year survival was 53%. Thirteen patients had recurrence of brain metastasis: 6 of 13 underwent reoperation for the recurrent lesion, and 1 of the 6 patients had a third craniotomy. Baseline characteristics, which significantly influenced survival, included age less than 60 years, tumor histology (ie, adenocarcinoma), and treatment of the primary lung cancer. The analysis did not yield any significant differences between treatment modalities. Conclusions Our findings correspond well with those reported in the literature and suggest that surgical resection of single brain metastasis in patients with non-small cell lung cancer can improve survival over conservative management. Furthermore, surgical treatment of the primary tumor and the single brain metastasis, combined or not with radiotherapy and chemotherapy, represents an approach that merits further investigation with more patients and a prospective longitudinal design.

The sympathetic nervous system participates in the regulation of the basal metabolic rate (BMR) and in the manifestation of the obesity-related metabolic syndrome. A deletion/insertion germline polymorphism of the alpha(2B) adrenergic receptor that is associated with reduced agonist-promoted desensitization has been linked to low BMR in obese subjects and to a predisposition to gain weight. This study investigated an association of the alpha(2B) polymorphism with the BMR and metabolic syndrome-related parameters of morbidly obese patients. Genotype frequencies were similar in patients and in a control group. The patients' BMR, adjusted for fat-free mass, fat mass, sex and age, did not differ between alpha(2B) genotypes. The polymorphism was also not associated with the patients' BMI, systolic and diastolic blood pressure, resting heart rate, total and HDL cholesterol, triglycerides, fasting glucose and uric acid levels. These findings do not support a major functional significance of the alpha(2B) adrenergic receptor polymorphism in the present sample of morbidly obese subjects.

The purpose of this study was to assess whether the administration of recombinant human erythropoietin (rHuEPO) would correct anemia and improve the quality of life (QOL) in cancer patients receiving chemotherapy. One hundred twenty-two patients with hemoglobin/=11.0 g/dl were randomized to receive rHuEPO 10,000 U three times weekly (n = 61) or no additional treatment (n = 61). Response was assessed by measuring changes in hemoglobin level and QOL. QOL was evaluated before each cycle of chemotherapy at baseline, Week 4, and Week 12 using two separate self-report questionnaires. The analyses indicated that the rHuEPO-treated patients experienced significantly less fatigue (P0.05) than their control group counterparts, and reported significantly higher scores on energy level (P0.05), ability to perform daily activities (P0.01), and overall QOL (P0.05). The overall change in hemoglobin level was significantly greater in the rHuEPO group than in the control group (1.7 g/dl versus 0.3 g/dl, P0.001). rHuEPO effectively corrects anemia and significantly improves QOL in patients with solid tumors receiving chemotherapy.

Insulin resistance and loss of glucose-stimulated acute insulin response (AIR) are the two major and earliest defects in the course of type 2 diabetes. We investigated whether weight loss after bariatric surgery in patients with morbid obesity and type 2 diabetes could restore euglycemia and normal AIR to an intravenous glucose tolerance test (IVGTT). We studied 25 morbidly obese patients—12 with type 2 diabetes, 5 with impaired glucose tolerance, and 8 with normal glucose tolerance (NGT)—before and after a biliopancreatic diversion (BPD) with Roux-en-Y gastric bypass (RYGBP). Twelve individuals with normal BMI served as control subjects. Twelve months after surgery, in the diabetes group, BMI decreased from 53.2 ± 2.0 to 29.2 ± 1.7 kg/m2, fasting glucose decreased from 9.5 ± 0.83 to 4.5 ± 0.13 mmol/l, and fasting insulin decreased from 168.4 ± 25.9 to 37.7 ± 4.4 pmol/l (mean ± SE; P < 0.001). AIR, the mean of insulin concentration at 2, 3, and 5 min over basal in the IVGTT, increased by 770 and 935% at 3 and 12 months after surgery, respectively (from 24.0 ± 22.7 to 209 ± 43.4 and 248 ± 33.1 pmol/l, respectively; P < 0,001). Conversely, in the NGT group, the AIR decreased by 40.5% (from 660 ± 60 to 393 ± 93 pmol/l; P = 0.027) 12 months after surgery. BPD with RYGBP performed in morbidly obese patients with type 2 diabetes leads to significant weight loss, euglycemia, and normal insulin sensitivity; but most importantly, it restores a normal β-cell AIR to glucose and a normal relationship of AIR to insulin sensitivity. This is the first study to demonstrate that the lost glucose-induced AIR in patients with type 2 diabetes of mild or moderate severity is a reversible abnormality.

In a toxic thyroid adenoma we identified a novel somatic mutation that constitutively activates the thyrotropin receptor (TSHR). Two heterozygous point mutations at adjacent nucleotides led to a substitution of alanine with asparagine at codon 593 (A593N) in the fifth transmembrane helix of TSHR. This somatic mutation resided on the same TSHR allele with the germline polymorphism D727E. The functional characteristics of the single TSHR mutants A593N and D727E and of the double mutant A593N/D727E were studied in transiently transfected COS-7 cells. The TSHR mutants A593N and A593N/D727E constitutively activated the cAMP cascade, whereas the D727E mutant did not differ from the wild-type TSHR. Surprisingly, the double mutant’s specific constitutive activity was 2.3-fold lower than the A593N mutant. Thus, the polymorphism significantly ameliorates G αs protein activation in the presence of the gain-of-function mutation A593N, although it is functionally inert in the context of the wild-type TSHR.

The mean erythropoietin concentration in the cord blood of neonates whose mothers were smokers was greater than in neonates whose mothers were not smokers. There was a significant positive correlation between erythropoietin and hemoglobin concentrations. The findings suggest that approximately one of five fetuses who are exposed to tobacco smoke are in a state of chronic hypoxia. (J P ediatr 1994;124:480-2)

Splenic infarction in patients with sickle cell trait is usually related to hypoxic conditions, while non-hypoxia-related infarcts are extremely rare. We report on a case of a 17-year-old male patient, living at sea level, who developed a severe left upper quadrant abdominal pain during the course of a febrile episode. On physical examination he had a mildly palpable but extremely painful spleen. A spleen scan revealed 2 areas of impaired radionucleide distribution. Hepatic enzymes were moderately increased and the IgM anti-EBV antibodies positive. Hemoglobin electrophoresis revealed the presence of 42% of hemoglobin S. A probable diagnosis of splenic infarction was established in a patient with sickle cell trait, during the course of infectious mononucleosis. The patient was treated symptomatically. The conditions of splenic congestion induced by the EBV infection and the high-grade fever may have contributed to splenic sequestration and subsequent infarcts.

Optimal growth depends upon both environmental and genetic factors. Among environmental factors that could alter growth and sexual maturation are stress and intensive physical training. The influence of these factors has been documented in a variety of sports, but there is limited information on rhythmic gymnasts, who have entirely different training and performance requirements.The study was conducted during the 13th European Championships in Patras, Greece, and included 255 female rhythmic gymnasts, aged 11–23 yr. The study included measurement of height and weight, assessment of breast and pubic hair development, estimation of body fat and skeletal maturation, and registration of menarcheal age and parental height.Gymnasts were taller than average height for age, with mean height above and mean weight below the 50th percentile. Actual height sd score was positively correlated to weight sd score (P < 0.001), number of competitions (P = 0.01), and body mass index (BMI; P < 0.001). Predicted adult height sd score was positively correlated to weight sd score (P < 0.001) and negatively to body fat (P = 0.004).There was a delay in skeletal maturation of 1.3 yr (P < 0.001). Pubertal development was following bone age rather than chronological age. The mean age of menarche was significantly delayed from that of their mothers and sisters (P = 0.008 and P = 0.05, respectively), was positively correlated to the intensity of training and to the difference between chronological age and bone age (P < 0.001 and P = 0.002, respectively), and was negatively correlated to body fat (P < 0.001).In the elite female rhythmic gymnasts, psychological and somatic efforts have profound effects on growth and sexual development. Despite these aberrations, adult height is not expected to be affected.

Autoimmune cholangitis is a rare chronic cholestatic liver disease. We describe the case of a 65-year-old woman with celiac disease who presented to us with fever, jaundice and weight loss. Serum biochemical study showed marked increase in alkaline phosphatase and γGT levels. Antinuclear antibodies were positive, while antimitochondrial and anti-smooth-muscle antibodies were negative. Liver biopsy was compatible with primary autoimmune cholangitis. The patient was successfully treated with azathioprine and methylprednisolone. We describe here the uncommon association of autoimmune cholangitis with celiac disease and review the prevalence of liver diseases in patients with celiac disease.

Insulin resistance and hyperinsulinemia both in normal persons and those with non- insulin dependent diabetes mellitus (NIDDM) (type 2 diabetes) appears to be related to obesity. It seems also that insulin plays a role in modulating the obesity-related factors (eg, hyperinsulinemia, hyperglycemia, hypertension, hypertriglyceridemia, hypercholes terolemia, low concentrations of high-density lipoprotein cholesterol) and takes its place among the many risk factors for coronary artery disease (CAD) associated with obesity. Insulin resistance and hyperinsulinemia could play the same role in pathogenesis of CAD independently of obesity. The authors determined blood glucose and immunoreactive insulin and plasma triglyceride concentrations in the fasting state at 60 and 120 minutes after a glucose load of 75 g in 68 patients (54 men, 14 women) with angiographic evidence of CAD and in 65 healthy volunteers matched to the patients for age, gender, and body mass index (43 men and 22 women). Patients with CAD and the healthy volunteers were categorized as obese (body mass index ≥ 26 kg/m2) and nonobese (body mass index < 26 kg/m2) . Four groups of subjects were analyzed: Group A included 40 healthy (28 men and 12 women) nonobese volunteers; group B, 25 healthy (15 men and 10 women) obese volunteers; group C, 39 (30 men and 9 women) nonobese patients with CAD; and group D, 29 (24 men and 5 women) obese patients with CAD. Fasting and postchallenged 60- and 120-minute glucose values were similar in groups A and C. However, significantly higher insulin values (mU/L) were observed in group C than in group A during fasting (12.2 ±6.2 vs 91 ±3, p Significantly higher plasma triglyceride concentrations were observed in group C than in group A (149.0 ±64.1 vs 114.6 ±46.6, p < 0.01 ) and in group D compared with group B (229.4 ± 104. 7 vs 144.9 ±65.1, p < 0.001. Plasma triglyceride concentrations were similar in groups B and C. The authors conclude that patients with documented CAD are insulin resistant inde pendently of obesity.

Normal children and adults show diurnal variation of plasma cortisol levels reaching peak values around 08.00 h and lower values around 24.00 h. Despite numerous studies on diurnal variation of plasma cortisol levels in children, the age of appearance of a circadian rhythm has not been definitely established. The purpose of this study was to investigate the development of cortisol circadian rhythm in infancy. In seventy healthy, full-term infants, less than six months old, plasma cortisol was measured at 10.30 h and 22.30 h. The mean +/- SEM values of daytime plasma cortisol at one to four weeks of life were 159 +/- 41, 116 +/- 43, 240 +/- 54 and 456 +/- 95 nmol/l and the night-time values were 129 +/- 40, 99 +/- 44, 131 +/- 78 and 430 +/- 105 nmol/l, respectively. No statistically significant differences were found between daytime and night-time cortisol values during the first four weeks of life. In contrast, the daytime values of plasma cortisol were 295 +/- 62 at the age of 2-3 months, 211 +/- 43 at 4-5 months and 291 +/- 31 nmol/l at 6 months of life, and night-time values were 166 +/- 52, 119 +/- 35 and 109 +/- 21 nmol/l, respectively, which were statistically significant (p < 0.05). These data clearly indicate that cortisol circadian rhythm starts between the second and third month of life.

Coronary artery calcium detected by digital fluoroscopy is closely associated with known risk factors of coronary artery disease in asymptomatic low-risk populations. Even in the absence of significant luminal narrowing, this may not be an innocent finding, and subjects with coronary calcium may be at greater risk for developing obstruction and clinical disease.

Recent studies have shown that full term neonates actively secrete melatonin and that light deprivation during the first 72 h of life significantly increases plasma melatonin levels. In order to evaluate pineal gland activity and responsiveness to light in premature infants, we measured plasma melatonin levels in 23 healthy infants, 33-36 weeks of gestation, during their first week of life. Nine infants (Group A) remained under constant illumination conditions for 48 hour prior to melatonin measurements. Fourteen infants (Group B) were exposed for the same time period to an artificial alternation of day and night cycles by covering the eyes of the infants with eye pads during the night (20.00-08.00 h). Mean +/- SEM plasma melatonin at 20.00 h, 04.00 h, 12.00 h and 20.00 h was 14.8 +/- 1.6, 16.2 +/- 2.8, 18.7 +/- 3.1, 20.9 +/- 3.1 pg/ml in Group A and 20.5 +/- 3.2, 22.3 +/- 2.9, 20.2 +/- 2.2, 18.5 +/- 2.2 pg/ml in Group B respectively. The differences observed between the two groups were not statistically significant. Our results indicate that at this gestational age the pineal gland is actively secreting melatonin but does not respond to the light alternations attempted. Further studies are needed in order to evaluate the developmental maturation of the pineal gland in humans.

Since maternal smoking causes fetal circulatory abnormalities, as well as disturbances of the maternal endocrine equilibrium, we measured the PRL, hGH and insulin-like growth factor-I (IGF-I) concentrations in the cord and venous blood of neonates of smoking mothers to determine whether or not the tobacco smoke affects the endocrine status of the neonate.The above hormones were measured in the cord blood of the newborns of both smoking and non-smoking mothers. Also, PRL and hGH were determined at 24 and 72 hours after birth in newborns of both groups.Fifty-three newborns of smoking and 47 newborns of non-smoking mothers were investigated. Seventeen of the newborns of the smoking and 21 of the non-smoking mothers were preterm. The remainder were full-term.PRL was measured with a solid-phase immunoradiometric assay, hGH with a solid-phase two-site immunoradiometric assay and IGF-I with a solid-phase radioimmunoassay after extraction with acid-ethanol.The median value of PRL in the 17 preterm newborns of smoking mothers was 4941 mU/I (range 1322-7230), whereas in the 21 preterm newborns of non-smoking mothers it was 2013 mU/I (range 243-4740) (P = 0.0002). The median hGH value in the above subjects was 102.0 mU/I (range 35.2-208.4) and 59.8 mU/I (range 11.6-134.2), respectively (P = 0.0039). The median IGF-I was 580.7 U/I (range 253.2-4851.1) and 530.6 U/I (range 239.6-3591.5), respectively (P = 0.429). In the 36 full-term newborns of smoking mothers the median PRL value was 5171 mU/I (range 2074-7530), whereas in the 26 full-term newborns of non-smoking mothers it was 5081 (range 244-6540) (P = 0.048). The median hGH was 69.6 mU/I (range 42.3-280.0) and 32.2 mU/I (range 6.2-200.0), respectively (P = 0.0031). Also, the median IGF-I value was 926.3 U/I (range 348.5-5344.7) and 462.1 U/I (range 250.2-1578.7), respectively (P = 0.0024). On the 3rd day the PRL in the preterm neonates of both smoking and non-smoking mothers showed the same 16.5% drop, and thus the difference between the groups was maintained. A similar reduction in the hormone levels was observed in the full term neonates.The findings indicate that the maternal tobacco-smoking causes disturbances of the endocrine status of the fetus, as shown by the increased levels of PRL, hGH and IGF-I, which are more pronounced between 30 and 37 weeks of gestation than at term.

Growth hormone (hGH), insulin-like growth factor-I (IGF-I) and prolactin (PRL) were measured in the cord and venous blood of small for gestational age (SGA) neonates in order to evaluate their endocrine status during the first 3 days of life. Although there were SGA newborns with both high and normal levels of hGH, the mean ( ± SD) concentration of hGH in the cord blood of the SGA neonates was 72.1 ± 50.6 ng/ml, whereas in the appropriate for gestational age (AGA) newborns it was 37.0 ± 23.5 (p = 0.001). The IGF-I in the cord blood of the SGA and the AGA newborns was 194.2 ± 174.8 ng/ml and 77.3 ± 50.2, respectively (p = 0.013). The PRL in the SGA and AGA newborns was 184.8 ± 62.4 ng/ml and ± 60.5, respectively (p = 0.0005). On the 3rd day the hGH in the SGA babies was 50.7 ± 41.2, whereas in the AGA it was 24.3 ± 12.3 (p = 0.034). On the same day the IGF-I was ± 120.9 and 44.8 ± 31.6, respectively (p > 0.05). Similarly, the PRL was 157.1 ± 52.3 and 90.9 ± 52.5, respectively (p = 0.0008). All neonates with high hGH concentrations had low IGF-I levels, whereas of those with normal hGH half had high and half normal IGF-I levels. There was no difference in the hormone levels between symmetric and asymmetric intrauterine growth-retarded infants. The findings suggest that the SGA neonates are heterogeneous comprising three groups. The neonates with high hGH and low IGF-I may have resistance at the level of the hGH receptor or a defect in IGF-I synthesis, whereas those with normal hGH and high IGF-I may have a post-IGF-I receptor defect, with compensatory increase in IGF-I synthesis independent of hGH control.

We have studied the effects of rifampicin on the overnight 1-mg dexamethasone suppression test usually employed to exclude suspected Cushing's syndrome. Previous observations indicate that in humans, rifampicin profoundly attenuates the biological effects of hydrocortisol and prednisolone, probably by increasing the metabolism of these drugs in the liver. The study was carried out in 16 normal volunteers. All subjects had a normal overnight 1-mg dexamethasone suppression test (468 +/- 86 vs. 32 +/- 21 nmol/L; mean +/- SD). In 8 subjects treated with rifampicin (600 mg) for 10 days, the inhibitory effect of dexamethasone on serum cortisol was completely prevented (575 +/- 114 vs. 434 +/- 82). In the remaining 8 rifampicin-treated subjects, the inhibitory effect of 1, 2, or 3 mg dexamethasone on serum cortisol was not observed. When 4 mg dexamethasone were administered, the serum cortisol level was 193 nmol/L, above the expected normal suppression value. The plasma dexamethasone concentration was very low after rifampicin treatment (range, 1.2-4.8 nmol/L). We conclude that when patients are treated with rifampicin, the standard overnight dexamethasone suppression test not only has no diagnostic value, but can be very misleading.

Normal children and adults show a similar pattern of diurnal variation of TSH secretion with lower values at 1100 h and higher around 2300 h. The purpose of this study was to investigate the age of appearance of TSH circadian rhythm. In 57 fullterm infants 0-6 months old and in 37 premature infants 1-4 weeks old TSH was measured at 1030, 1100, 1130 h and 2230, 2300, and 2330 h. No diurnal rhythm was detected in both premature and fullterm infants less than 4 weeks of life. After the first month of life a significant difference between AM and PM values was observed in fullterm infants. In infants 1-2 months old mean +/- SEM AM and PM values were 2.8 +/- 0.2 and 3.5 +/- 0.4 mU/L, respectively (P less than 0.025), in infants 3-4 months old 3.0 +/- 0.6 and 4.1 +/- 0.8 (P less than 0.01) and in infants 5-6 months old 1.8 +/- 0.2 and 2.6 +/- 0.3 (P less than 0.0005). These data clearly indicate that the development of TSH circadian rhythm starts after the first month of life.

In 33 normal infants, divided into 3 age groups (less than 1 month, 1-3 months, and 3-6 months) plasma cortisol was measured at 2230, 2300, and 2330 h. Baseline plasma cortisol at 2230 h. was, as expected, low in all infants, with mean +/- SEM values of 41 +/- 5, 72 +/- 14, and 97 +/- 17 nmol/L in each group, respectively. Thirty and 60 min after the painful stimulus of the venipuncture, plasma cortisol increased significantly (P less than 0.0005), reaching a maximum increase up to 458 +/- 50, 392 +/- 66, and 455 +/- 97 nmol/L in each age group, respectively. We conclude that in these infants the hypothalamic-pituitary-adrenal axis was functionally intact and responded to the painful stimulus of the venipuncture by a significant increase in plasma cortisol. This test may be used as a simple procedure for the evaluation of the integrity of the hypothalamic-pituitary-adrenal axis without the administration of pharmacological agents. Its usefulness, however, should be validated with patients having a disorder of the system.

The role of nonprotein sulfhydryl groups (NPSH) in the decreased in vitro hepatic 3',3,5-triiodothyronine (T(3)) generation from thyroxine (T(4)) in the starved, hypothyroid, fetal and 1- to 4-d-old neonatal rat and dwarf mouse was assessed. NPSH were measured in fresh 25% liver homogenates prepared in 0.1 M PO(4)/10 mM EDTA buffer. As compared with values in adult male rats, NPSH concentration was decreased in the 2-d-starved (1.1+/-0.04 (mean+/-SE) vs. 2.2+/-0.15 mmol/250 g wet liver weight, P0.001), fetal (1.0+/-0.04 vs. 3.2+/-0.08, P0.001), 1-d-old neonatal (1.1+/-0.03 vs. 2.1+/-0.04, P0.001), and hypothyroid (thyroidectomized 60 d) (1.4+/-0.06 vs. 2.2+/-0.15 P0.001) rat. NPSH were also decreased in the hypothyroid, hypopituitary dwarf mouse as compared with values in their normal litter mates (1.3+/-0.03 vs. 2.0+/-0.2, P0.01). Chronic administration of T(3) (0.5 mug/100 g body wt per d) markedly increased hepatic T(3) generation from T(4) in the thyroidectomized rat and in the dwarf mouse to values similar to those observed in the normal rodent without affecting NPSH concentration. In contrast, T(3) administration to the starved rat did not alter either hepatic T(3) generation from T(4) or NPSH. Reduced glutathione concentration was also markedly decreased in the starved rat (fed; 1.05+/-0.075 mmol/250 g wet tissue vs. starved 0.38+/-0.02, P0.001). Dithiothreitol (DTT), a thiol reducing agent, increased hepatic T(3) generation from T(4) in the normal adult male rat by 45+/-5% in six experiments. When compared to DTT-stimulated control homogenates, the addition of DTT completely restored hepatic T(3) generation in starved rats, partially restored T(3) generation in 1- and 4-d-old neonates, but had little or no effect in the fetal and hypothyroid rat and dwarf mouse. Liver homogenates stored for 6 mo at -20 degrees C lost their capacity to generate T(3) from T(4). NPSH concentrations in the frozen homogenates decreased progressively with increasing storage and were absent by 6 mo. 5'-Deiodinase activity correlated with NPSH concentration in the stored homogenates (r = 0.95, P0.005). Addition of DTT partially restored hepatic T(3) generation in the frozen homogenate. It is concluded that NPSH are important for the action of the liver 5'-deiodinase. The decreased hepatic T(3) generation in the starved rat is associated with decreased NPSH but not with a decrease in the absolute quantity of 5'-deiodinase because provision of sulfhydryl groups restored hepatic T(3) generation to normal. In contrast, the decreased hepatic T(3) generation in the adult hypothyroid rodent and in the fetal rat is probably due to a decrease in the enzyme concentration per se. In the 1- and 4-d neonatal rat, the decrease in hepatic T(3) generation is secondary to a decrease in NPSH and the deiodinating enzyme.

Reverse T3 (3,3',5'-triiodothyronine, rT3), a major product of the peripheral monodeiodination of thyroxine (T4), was administered to normal male volunteers in doses sufficient to sustain an elevated serum rT3 concentration similar to that frequently observed in patients with nonthyroidal illness. No changes in basal serum T4, T3, TSH and prolactin concentrations, nor in the T3, TSH and prolactin responses to iv TRH were observed during rT3 administration. These findings suggest that physiologic increases in serum rT3 concentration probably do not inhibit T4 to T3 conversion or the anterior pituitary TSH and prolactin responses to thyrotropin-releasing hormone (TRH).

To determine the role of thyrotropin-releasing hormone (TRH) in the regulation of thyroid-stimulating hormone (TSH) secretion in the perinatal period, a physiological approach of neutralizing circulating TRH in the fetal and early neonatal rat was employed. TRH-antiserum (TRH-AS) raised in rabbits and administered daily to low iodine-propylthiouracil (LID-PTU)-fed pregnant rats from days 12 to 19 of gestation markedly impaired the rise in serum TSH to LID-PTU when compared with normal rabbit serum-treated controls. In contrast, fetal serum TSH was unaffected by TRH-AS. The binding capacity of TRH-AS in the fetal serum (111 ng/ml) far exceeded circulating TRH in the fetus. Similarly, acute TRH-AS administration to the pregnant rat fed LID-PTU markedly decreased the serum TSH concentration in the mother, but not in the fetus, 60 min after TRH-AS administration. Chronic TRH-AS administration to neonatal rats whose nursing mothers were fed LID-PTU was in-effective in decreasing the elevated serum TSH in the neonate through day 8 of life, whereas a slight but significant decrease in serum TSH was observed on day 10. Chronic daily TRH-AS administration to neonatal rats through day 10 of life had no effect on the later development of the hypothalamic-pituitary-thyroid axis. These findings suggest that TRH does not participate in TSH regulation during the perinatal life in the rat and that thyroid hormones are probably the main regulators of TSH secretion during this period. Placental TRH is not important in regulating TSH secretion in the fetal rat. Furthermore, TRH “deprivation” during neonatal life does not prevent normal later development of the hypothalamic-pituitary-thyroid axis.

To develop a test of pituitary-thyroid responsiveness to thyrotropin-releasing hormone that would obviate the need for measuring serum thyrotropin, we determined serum thyrotropin, thyroxine, and tri-iodothyronine concentrations before and at frequent intervals after the intramuscular administration of 2 mg of thyrotropin-releasing hormone in normal subjects and in patients with a variety of thyroid disorders. In specimens obtained four and five hours after administration of the hormone to normal subjects, serum thyroxine concentration increased 2.4 plus or minus 0.7 mug per 100 ml (mean plus or minus S.D.) over base-line values, the magnitude of increase being greater than 1.5 mug per 100 ml in 32 of 34 subjects. Serum thyroxine concentrations after administration of thyrotropin-releasing hormone did not increase in 11 hyperthyroid patients. Of 13 with hypothyroidism, increases in 12 were 0 to 0.7 mug per 100 ml; in one the increment was 1.2 mug per 100 ml. Measurement of the serum thyroxine response to intramuscular thyrotropin-releasing hormone will usually suffice to determine the integrity of the hypothalamic-pituitary-thyroid complex.

Chronic diphenylhydantoin (DPH) administration (5 mg x 100 g body wt-1 x day-1) to the normal rat is associated with a decrease in the serum thyroxine (T4) and triiodothyronine (T3) concentrations without an appropriate rise in the serum thyrotropin (TSH) concentration, suggesting a possible direct effect of DPH on TSH secretion. To further study this possibility, DPH was administered chronically to thyroidectomized, hypothyroid rats. In the hypothyroid rats treated chronically with DPH, serum TSH did not increase, pituitary TSH content was significantly decreased, and the serum TSH response to thyrotropin-releasing hormone (TRH) was decreased compared to that of diluent-treated, hypothyroid rats. Hypothalamic TRH content was similar in DPH and diluent-treated rats. These findings suggest that DPH suppresses pituitary TSH secretion, probably as a thyroid hormone agonist. The effect of a single large dose of DPH (20 mg/100 g body wt) administered to thyroidectomized rats also decreased serum tSH but, in contrast to the findings in chronically treated rats, hypothalamic TRH and pituitary TSH content and the serum TSH responses to TRH were increased. These differences may be due to the acute inhibitory effect of a large dose of DPH on hypothalamic TRH release. Furthermore, because the effect of thyroid hormone on regulating pituitary TSH synthesis and release is dose and time dependent, the effect of DPH as a thyroid hormone agonist on pituitary TSH dynamics may also be variable.

The physiological role of thyrotropin-releasing hormone (TRH) in the regulation of thyrotropin (thyroid-stimulating hormone, TSH) and prolactin (Prl) secretion has been assumed but not proven. Stimulation of their release requires pharmacologic doses of TRH. Lesions of the hypothalamus usually induce an inhibition of TSH secretion and an increase in Prl. To determine whether TRH is essential for TSH and Prl secretion in the rat, 0.1 ml of TRH antiserum (TRH-Ab) or normal rabbit serum was administered to normal, thyroidectomized, cold-exposed, and proestrus rats through indwelling atrial catheter. Serum samples were obtained before and at frequent intervals thereafter. Serum TSH concentrations in normal, thyroidectomized, cold-exposed, and proestrus rats were not depressed in specimens obtained up to 24 h after injection of normal rabbit serum. In contrast, serum TSH was significantly decreased after the administration of TRH-Ab in all normal (basal, 41+/-8 muU/ml [mean+/-SE]; 30 min, 6+/-2; 45 min, 8+/-3; 75 min, 4+/-2); thyroidectomized (basal, 642+/-32 muU/ml; 30 min, 418+/-32; 60 min, 426+/-36; 120 min, 516+/-146); coldstressed (basal, 68+/-19 muU/ml; 30 min, 4+/-3; 180 min, 16+/-8); and proestrus (basal, 11 a.m., 57+/-10 muU/ml; 1 p.m., 20+/-3; 3 p.m., 13+/-4; 5 p.m., 19+/-3) rats. However, 0.1 ml of TRH-Ab had no effect on basal Prl concentrations in normal or thyroidectomized rats and did not prevent the Prl rise in rats exposed to cold (basal, 68+/-7 ng/ml; 15 min, 387+/-121; 30 min, 212+/-132; 60 min, 154+/-114), or the Prl surge observed on the afternoon of proestrus (basal 11 a.m., 23+/-2 ng/ml; 1 p.m., 189+/-55; 3 p.m., 1,490+/-260; 5 p.m., 1,570+/-286). These studies demonstrate that TRH is required for TSH secretion in the normal, cold-exposed and proestrus rat and contributes, at least in part, to TSH secretion in the hypothyroid rat, but is not required for Prl secretion in these states.

In 9 euthyroid obese volunteers, 4 weeks of total caloric deprivation resulted in striking decreases in both total and free triiodothyronine (T3) concentrations in serum together with a slight increase in free thyroxine (T4) concentration. These changes were not associated with alterations in the basal serum TSH concentration or in the TSH or T3 responses to exogenous TRH. It is suggested that the decrease in serum T3 concentration that occurs during starvation results from decreased peripheral conversion of T4 to T3 and may explain, at least partially, the decreased serum T3 seen in clinical states associated with inanition.

To evaluate the effect of starvation, oral and i.v. nutriments, and hypothyroidism on the peripheral conversion of thyroxine (T4) to 3,3', 5-triiodothyronine (T3) in the rat and mouse, an in vitro system for assessing T4 conversion to T3 by fresh liver homogenates was used. A 2-day starvation in the rat reduced hepatic T3 generation from T4 by 47% +/- 3.5% (mean +/- SE) in six separate experiments and also impaired the metabolism of 125I-r-T3. Administration of carbohydrate (CHO) and amino acids (P), but not lipid (L), significantly increased T3 generation above values observed in the starved rat. The mean serum glucose concentration was similar in all nutriment-infused groups, but serum insulin was significantly greater in the CHO- and P-infused as compared to the L-infused rats. These findings suggest that CHO and P, but not L, are important modulators of hepatic outer ring thyronine deiodination in the rat, perhaps due to increased intracellular glucose. Hypothyroidism in the rat induced by thyroidectomy and congenital secondary hypothyroidism in the dwarf mouse resulted in a striking decrease in hepatic conversion of T4 to T3. This decrease was restored to normal by the daily s.c. administration of physiologic doses of T4 (1.5 microgram/100 g) or T3 (0.5 microgram/100 g) for 14 days, and was increased above normal following treatment of normal rate with greater than physiologic doses of T4 (3microgram/100 g) or T3 (1 microgram/100g). In vitro hepatic conversion of T4 to T3 is, therefore, dependent upon thyroid function. Since 2-days starvation in the rat was associated with decreased serum concentrations of T4, T3, and TSH, and hypothyroidism resulted in decreased conversion of T4 to T3, the effect of a constant 2-day infusion of physiologic doses of T4 or T3 in the starved rat on the in vitro deiodination of T4 was assessed. Thyroid hormone replacement did not enhance the conversion of T4 to T3 in the starved rat. These observations suggest that the starvation-induced decrease in hepatic generation of T3 from T4 is not due to hypothyroidism and that the mechanism(s) of the decreased T3 production observed in starvation and hypothyroidism is different.

Studies were carried out on various aspects of hypothalamic-pituitary-thyroid function in normal and gonadectomized adult male and female rats. Consistent increases in the serum TSH concentration and the serum TSH response to TRH were observed in the male rat compared to values in the female. Orchiectomy induced a decrease in the serum TSH concentration and the serum TSH response to TRH, and these functions were equal in gonadectomized male and female rats. Oophorectomy did not affect basal and TRH-stimulated serum TSH concentrations. Replacement doses of testosterone (0.33 mg/day) to orchiectomized rats increased and restored these values to those observed in the normal male rat, while replacement doses of estradiol (0.33 microgram/day) to the oophorectomized rat had no effect on basal or TRH-stimulated TSH concentrations. No sex-related differences in pituitary TSH and hypothalamic TRH contents or in serum T4 and T3 concentrations were observed. The present studies strongly suggest that the increased TSH responsiveness observed in male compared to female rats is due to the presence of testosterone. (Endocrinology 108: 529, 1981)

The metabolic effects of rT3 and its role in regulating the metabolic activity of T4 by altering the peripheral monodeiodination of T4 to T3 was studied in normal and thyroidectomized (Tx) rats constantly infused through indwelling atrial catheters. The infusion of 100 μg rT3/100 g BW in normal rats decreased the conversion of T4 to T3 by liver homogenates by 50% (P < 0.001), decreased serum T3 by 21% (P < 0.001), increased serum T4 by 21% (P < 0.001) and had no effect on serum and pituitary GH concentrations. Tx rats were infused with saline, rT3 (100 μg/100 g BW), T4 (2–5 μg/100 g BW), T3 (1 μg/100 g BW), T4 plus rT3, and T3 plus rT3. The infusion of rT3 had no effect on serum and pituitary TSH and GH concentrations. T4 infusion in the Tx rat increased the low in vitro hepatic T3 generation observed in hypothyroidism, decreased serum TSH, increased serum and pituitary GH, and restored the metabolic effect of GH on the epididymal fat pad. The simultaneous infusion of rT3 and T4 partially blocked the meta...