Are dietary reports in a case-control study on thyroid cancer biased by risk perception of Chernobyl fallout?

BACKGROUND: In retrospective case-control studies performed following nuclear tests or nuclear accidents, individual thyroid radiation dose reconstructions are based on fallout and meteorological data from the residential area, demographic characteristics, and lifestyle as well as dietary information. Collecting the latter is a controversial step, as dietary declarations may be affected by the subjects' beliefs about their risk behavior. This report analyses the potential for such bias in a case-control study performed in eastern France. METHODS: The study included 765 cases of differentiated thyroid carcinoma matched with 831 controls. Risk perceptions and beliefs of cases and controls were compared using Chi2 tests and differences in dietary reports were analyzed using a two-way ANOVA. RESULTS: In general, atmospheric pollution and living near a nuclear power plant were the two major risks that may influence thyroid cancer occurrence cited by cases and controls. When focusing in particular on the consequences of the Chernobyl accident, cases were more likely to think that the consequences were responsible for thyroid cancer occurrence than controls. Vegetable consumption during the two months after the Chernobyl accident was correlated with the status of subjects, but not to their beliefs. Conversely, consumption of fresh dairy products was not correlated with the status or beliefs of subjects. CONCLUSION: We found no evidence of systematic bias in dietary reports according to the status or beliefs held by subjects about the link between thyroid cancer occurrence and Chernobyl fallout. As such, these dietary reports may be used in further studies involving individual dosimetric reconstructions.

Hürthle cell thyroid carcinoma metastatic to the sigmoid colon.

Prognosis of differentiated thyroid cancer is favorable in the majority of cases. However, distant metastases occur in 10-15% of cases, predominantly in lungs and bones, especially in older patients exhibiting poorly differentiated forms or advanced stages. We report a case history of Hürthle cell thyroid carcinoma metastasized to the sigmoid colon. To the best of our knowledge, this location has never been described before. This case history illustrates the difficulties of diagnosis and treatment in patients whose metastases do not concentrate radioiodine. The interest of different imaging modalities, including fluoro-deoxy-glucose positron emission tomography scan and somatostatin receptor scintigraphy, is discussed.

Familial pituitary adenomas with a heterogeneous functional pattern: clinical and genetic features.

Familial pituitary adenoma is a rare syndrome which may present either as isolated lesions, or in association with other endocrine tumors, for example in the frame of multiple endocrine neoplasia (MEN-1) or Carney complex (CNC). The most frequently described forms of familial isolated pituitary adenoma (FIPA) are familial somatotropinomas or prolactinomas. Recently, some cases of familial isolated somatotropinoma have been associated with germline mutations in the aryl hydrocarbon receptor interacting protein (AIP) gene. The present report shows heterogeneous FIPA with 3 subtypes of tumor in 3 individuals of the same family: somatotropinoma in the proband, giant prolactinoma in a brother, and gonadotroph cell macroadenoma in the father. A prospective survey also suggested the occurrence of a silent microadenoma in the proband's sister. Clinical screening was performed in the 3 affected members, the 4th suspected case, and 9 additional, asymptomatic relatives. They had no clinical evidence of associated endocrine lesion suggesting MEN-1 or CNC. Genetic screening for germline mutation of the MEN-1, the gene encoding the protein kinase A (PKA) type 1 alpha regulatory subunit (R1 alpha) (PRKAR1alpha) and AIP gene was negative in 2 affected members. In conclusion, these data suggest that familial pituitary adenomas can occur with a heterogeneous functional pattern that is distinguished from MEN-1 or CNC. The absence of mutation of the recently described AIP gene suggests the implication of other predisposing gene(s). Collaborative, multicentric studies are needed to further define the location of gene(s) involved in heterogeneous FIPA.

[Role of hospital claims databases from care units for estimating thyroid cancer incidence in the Rhône-Alpes region of France]. / Place du Programme de médicalisation des systèmes d'information (PMSI) dans l'estimation de l'incidence du cancer de la thyroïde dans la région Rhône-Alpes.

BACKGROUND: Incidence measures are essentially based on the data collected by cancer registries. Hospital claims databases from care units (PMSI) can be used as a source of information for registries because they contain standard records of most cancer patients. Regarding thyroid cancer, we have evaluated the PMSI as a source of information for the Rhône-Alpes thyroid cancer registry and usefulness of PMSI as a tool for surveillance of thyroid cancer incidence. METHODS: Patients with incident thyroid cancer in 2002 were identified in the claims data of the Rhône-Alpes region using an algorithm based on DRG codes of thyroidectomy and on diagnosis codes of thyroid cancer in a principal or secondary position. The patients identified were compared to those in thyroid cancer registry of the Rhône-Alpes region regarding sex, age, ZIP code of residence, month of discharge and length of stay versus the diagnosis date. When the percentage of cases of claims data identified in the cancer registry and the percentage of cases of the cancer registry identified in claims data were obtained, the capture-recapture method was applied to estimate the number of missing cases and the total number of incident thyroid cancers in the region. RESULTS: 667 patients were identified in claims data while the cancer registry included 677 patients. 95.2% of patients identified in claims data were in the cancer registry and 82.3% of patients in the cancer registry were identified in claims data. Cases lacking in claims data mostly corresponded to micro-cancers which represented 41% of cases in the cancer registry. Regarding cancer above 1 cm, 92% of the cancer registry cases were identified in claims data. Sensitivity of combining information from cancer registry and claims data was 99.2%. Cases lacking in cancer registry, present in claims data base and considered as true cases after obtaining pathological confirmation represented 2% of the whole thyroid cancer population. CONCLUSION: Claims data obtained from anonymous regional or national bases can be helpful for checking the completeness of thyroid cancer registries and to provide a small amount of unknown cases. They can be considered an acceptable tool for surveillance of thyroid cancer incidence. The significance of the variations in incidence that could be observed from claims data remains to be evaluated in comparison with comparable data obtained from registries.

Clinical and histological correlations in prolactinomas, with special reference to bromocriptine resistance.

BACKGROUND: Prolactinomas usually exhibit a benign course and can be safely and effectively managed by dopamine agonists (DA). However, some are locally invasive and may show resistance to DA therapy, and the management of such cases remains controversial. The aim of the present study was to determine whether histological features and markers of cell proliferation correlated to the clinical behaviour of prolactinomas and with DA resistance. METHOD: This retrospective study included 74 cases (36 men and 38 women) who had monohormonal prolactinomas removed by transsphenoidal surgery. The prolactinomas were categorized on the basis of tumour size (48 macroadenomas), invasion of the cavernous sinus (n = 31), and resistance to bromocriptine (BRC) therapy (n = 14). Group 1 consisted of non-invasive microprolactinomas (n = 24), group 2 of non-invasive macroprolactinomas (n = 19), group 3 of invasive non-BRC-resistant tumours (n = 19), and group 4 of invasive BRC-resistant tumours (n = 12). The later group included one case of carcinoma with bone and lung metastases. Seven additional parameters were studied, these being age, sex, basal prolactin (PRL) levels, the Ki-67 and PCNA labelling indices (LI), mitotic count, and cellular atypia. FINDINGS: Age and preoperative PRL levels did not correlate to the histological parameters studied. Tumour size and invasion were related to cellular atypia and the Ki-67 LI. BRC-resistant tumours were more frequently invasive (12/14) than BRC-responsive tumours (11/30; p = 0.002) and were more frequent in men than in women (33 versus 5%; p = 0.003). BRC-resistant tumours had a higher Ki-67 LI and mitotic count (4.2+/-2.0% and 4+/-1, respectively) than other tumours (0.7+/-0.2% and 1+/-0, respectively; p<0.05). The strongest correlations with tumoural staging were seen with male sex and high mitotic activity. Six out of the 12 invasive BRC-resistant macroprolactinomas, including the PRL secreting carcinoma, exhibited histological features of aggressiveness (a mitotic count >/=3 [i.e. in the fourth quartile] and/or a high Ki-67 LI and cellular atypia). CONCLUSIONS: In this surgical retrospective series, histological signs of aggressiveness are present in 50% of invasive and BRC-resistant prolactinomas, which are more frequent in men than in women. This fits with the behaviour of BRC-resistant prolactinomas, which can continue to grow despite DA treatment. These findings justify the long-term follow up of these tumours, and the use of surgery and/or radiotherapy if there is concern about the control of tumour growth.

Long term effect of incremental doses of the somatostatin analog SMS 201-995 in 58 acromegalic patients. French SMS 201-995 approximately equal to Acromegaly Study Group.

Fifty-eight acromegalic patients were included in a multicenter prospective study of increasing doses (300-1500 micrograms) of SMS 201-995 (octreotide, Sandostatin) administered 3 times daily, sc, during 6 months to determine its effect on signs and symptoms of GH hypersecretion. Subsequently, 34 of the patients were maintained for 12-26 months on the minimal efficacious dose, determined from the previous dose-response study. Some adverse effects were frequently encountered, mostly at the initiation of treatment, and disappeared with time. Asymptomatic gallstones occurred in 5 patients. Minimal changes in carbohydrate tolerance, consisting of a rise in blood glucose and a transient decrease in plasma insulin level after meals, were noted. GH normalized in 22% of the patients, improved in 56%, and remained unchanged in 22% regardless of the dose. The optimal daily dose was 300 micrograms in 50% of the patients and 1500 micrograms in 20%. Pituitary tumor size reduction occurred in 47% of the patients harboring large tumors or tumor remnants. No additional improvement or escape from being controlled occurred with time. These data indicate that SMS 201-995 is an effective treatment for refractory acromegaly and for some de novo patients for whom surgical therapy is not advisable.

Nocturnal continuous infusion of growth hormone (GH)-releasing hormone results in a dose-dependent accentuation of episodic GH secretion in normal men.

Fluctuations in plasma GH levels have been found in patients with acromegaly who have continuously elevated levels of ectopically produced GH-releasing hormone (GHRH). Likewise, plasma GH fluctuations have been found in normal subjects receiving continuous GHRH infusions. We report the effects of two doses of GHRH, administered by constant infusion, on nocturnal GH secretion in six normal young men. Each received, in random order, 2.5 ng/kg X min GHRH, 15 ng/kg X min GHRH, and 0.15 M NaCl. During both GHRH doses, a highly significant increase in total nocturnal GH secretion was found (P less than 0.001) as well as an increase in GH secretion during different periods of the night. Nocturnal GH secretion was episodic during the GHRH infusions, with an increase in the number and magnitude of the peaks compared to those during the NaCl infusion. Plasma immunoreactive GHRH concentrations plateaued at 1 h during the high dose and at 3 h during the low dose GHRH infusion. Sleep parameters, including total sleep time, sleep latency, and duration and timing of the different sleep stages, were not affected by GHRH infusions. We conclude that GHRH, continuously infused, increases nocturnal GH secretion according to the dose, while the episodic pattern of GH secretion is maintained.

Gonadotropin-releasing hormone agonists are unsuccessful in reducing tumoral gonadotropin secretion in two patients with gonadotropin-secreting pituitary adenomas.

Whether GnRH agonist treatment leads to reduced gonadotropin secretion and tumor volume in patients with gonadotropin-secreting pituitary adenomas is controversial. We studied the effect of GnRH analog treatment in two such patients, one with a recurrent FSH- and LH-secreting pituitary adenoma (patient 1) and one with a recurrent FSH- and alpha-subunit-secreting pituitary adenoma (patient 2). Patient 1 was treated with 200 micrograms Buserelin daily for 65 days, and patient 2 received three injections of 3 mg [D-Trp6]-LHRH formulated in microcapsules at 21-day intervals. In both patients, plasma FSH, LH (RIA), and alpha-subunit concentrations increased initially and remained above the pretreatment values throughout the treatment period. Plasma LH, measured by immunoradiometric assay, remained well above the detection limit. Plasma bioactive LH and testosterone became undetectable in patient 2, but did not change in patient 1. In neither patient did pituitary tumor size (determined by computed tomographic scan) change during treatment. We conclude that 1) the overall effect of GnRH analogs in patients with gonadotroph cell adenomas is stimulation of gonadotropin release by the tumor, although LH release varies according to how plasma LH is measured, possibly related to the origin of the hormone (normal or tumor gonadotroph cells), and 2) GnRH analog treatment does not reduce tumor size.

Presence of somatostatin receptors negatively coupled to adenylate cyclase in ectopic growth hormone-releasing hormone- and alpha-subunit-secreting tumors from acromegalic patients responsive to octreotide.

The functional study of SRIH receptors was performed in ectopic GHRH-secreting tumors from two patients with acromegaly; patient 1 presented with multiple endocrine neoplasia type 1 with GHRH- and insulin-secreting pancreatic tumors, and patient 2 presented with a multihormone-secreting carcinoid tumor (including GHRH and alpha-subunit secretion, as demonstrated by clinical and immunohistochemical studies). In both cases, plasma GH levels were responsive to octreotide. In patient 2, plasma GHRH and alpha-subunit levels were responsive to octreotide. In vitro perifusion studies of a tumor fragment from patient 1 also showed inhibition of GHRH secretion by SRIH. A high density of specific SRIH-binding sites was visualized by autoradiography in GHRH tumors from both patients. SRIH specific binding was much higher in the GHRH tumors (6.6-8.4 fmol/surface unit) than in the insulinoma (1.9 fmol/surface unit). The binding inhibition constant (IC50) was in the nanomolar range (0.9-3 nmol/L) in the GHRH tumors. SRIH-14 inhibited forskolin-stimulated adenylate cyclase in the GHRH tumors from both patients, but not in the insulinoma. The functional SRIH receptors negatively coupled to adenylate cyclase present in ectopic GHRH-secreting tumors mediate the inhibitory effect of octreotide on GHRH secretion and on previously underrecognized ectopic alpha-subunit secretion from carcinoid tumors.

Dose-effect study of intranasal administration of growth hormone-releasing hormone-44-NH2 in healthy subjects.

Intranasal (in) administration of GH-releasing hormone-40- (GHRH-40) has been demonstrated to be efficient in stimulating GH secretion at doses equal to or higher than 30 micrograms/kg in man. We performed a dose-response study with GHRH-44-NH2 (GHRH) given by nasal spray and closely monitored local tolerance. Twelve normal young men were given 5 GNRH doses (125, 250, 500, 750, and 1000 micrograms) and placebo in random order according to a latin square design. Mild symptoms of local intolerance, subjective, objective, or both, were noted in the first 20 min after spray in 30 of 72 tests, and a significant difference (P = 0.003) was obtained in their frequency between the group placebo plus the lowest dose and the group of the other doses. The areas under the GH curves were significantly different between the subjects and the doses (by analysis of variance, P = 0.001 and P = 0.025, respectively). Multiple comparison tests showed a significant difference between the 3 highest doses and the placebo (P = 0.005, P = 0.05, and P = 0.02, respectively) and a significant difference between the highest dose and the 2 lowest doses (P = 0.005). By weighted linear regression between GH areas under the curve and GHRH doses the dose-response relationship was established as: y = 1.226x + 457. The magnitude of the GH peaks induced by in GHRH was significantly lower than that induced by iv GHRH. We conclude that in the normal young men tested, who were high responders to GHRH (as demonstrated by iv test), a 500-micrograms dose is sufficient to elicit GH secretion. Local tolerance, although imperfect, appears satisfactory to permit a clinical trial in children.

Effects of a new prolactin inhibitor, CV 205-502, in the treatment of human macroprolactinomas.

The effects of a new PRL inhibitor, CV 205-502 (CV), on human macroprolactinomas were studied in nine patients according to a prospective protocol. Five patients had undergone surgery leaving tumor remnants and persistent hyperprolactinemia. The four others were de novo patients, two of whom had received short term treatment with Parlodel. Plasma PRL levels ranged from 235-6050 micrograms/L before treatment. The doses of CV used in this trial ranged from 0.075-0.600 mg. Plasma PRL normalized in eight of the nine patients during treatment with CV. The time to normalize varied from 2 weeks to 9 months, and the doses from 0.075-0.450 mg. A tumor volume reduction of more than 50% was obtained in all four patients who had not been operated on before CV treatment. Only one of the five patients with postoperative tumor remnants had no reduction in tumor size. The drug was generally well tolerated, and no patient interrupted the treatment. Slight and short-lasting gastrointestinal symptoms were noted in several patients, and a single episode of fainting occurred in one patient when the drug was not taken at bedtime as instructed. A noticeable and persistent weight loss with anorexia was noted in two patients. Since CV 205-502, administered in a single daily dose, has tolerable side-effects and is effective in reducing PRL secretion and tumor size, it can be considered to be a useful treatment for macroprolactinomas.

Effects of the somatostatin analog BIM 23014 on the secretion of growth hormone, thyrotropin, and digestive peptides in normal men.

BIM 23014 (BIM) is a long-acting octapeptide somatostatin analog. We studied the effects of this analog on the secretion of GH, TSH, and gastroenteropancreatic hormones [secretin, motilin, and pancreatic polypeptide (PP)] in normal men. In the first protocol three BIM doses (125, 250, and 500 micrograms) and vehicle were administered sc in random order at 2000 h to eight normal young men. Plasma GH concentrations decreased during the first part of the night only after the highest dose (P less than 0.05). Plasma secretin levels did not change, while plasma motilin decreased after the 250- and 500-micrograms doses (P = 0.05 and P = 0.02, respectively), and plasma PP decreased after all three doses (P less than 0.05, P less than 0.01, and P less than 0.01, respectively) during the first part of the night. In the second protocol, eight men received BIM, administered by constant sc infusion during the night in a dose of 2 mg/12 h, or vehicle, either alone or in association with a 10 ng/kg.min iv GHRH or vehicle infusion. Nocturnal GH secretion was suppressed by the BIM infusion (P less than 0.001). GH secretion, stimulated by GHRH infusion (P less than 0.001), was reduced by concomitant BIM infusion (P less than 0.001) and was pulsatile during the combined infusions. BIM infusion suppressed the physiological nighttime rise in plasma TSH levels. Plasma motilin and PP levels were reduced by BIM, when administered either alone or in combination with GHRH. We conclude that: 1) BIM is capable of reducing GH secretion when administered sc in a dose of 500 micrograms and of abolishing nocturnal GH secretion when constantly infused at a dose of 2 mg/12 h; 2) BIM, constantly infused, reduces the nocturnal rise in TSH secretion; and 3) motilin and PP secretion are more sensitive than that of GH to BIM, as they are reduced by a lower dose.

Effects of human pancreatic tumor growth hormone-releasing hormone (hpGRH1-44-NH2) on immunoreactive and bioactive plasma growth hormone in normal young men.

Synthetic human pancreatic tumor GH-releasing hormone (hpGRH 1-44-NH2) was given by iv bolus injection to 10 normal men at doses of 75, 150, 300, and 600 micrograms. At all doses the plasma GH responses were similar in an individual subject. Among subjects, however, the responses were significantly different, with peak GH concentrations ranging between 9.0 micrograms/liter and 54.9 micrograms/liter. The GH released in response to GRH was bioactive in the Nb2 lymphoma cell multiplication assay. The circulating GH 30 and 60 min after GRH was detected in 3 molecular forms corresponding to little, big, and big-big GH. These forms averaged 50%, 30%, and 20% of the total immunoreactive GH, respectively. The mean rise of plasma somatomedin-C, from 1.86 U/ml to 2.21 U/ml 24 h after GRH, was not statistically significant. A small but statistically significant GRH dose-dependent rise in plasma PRL (mean PRL concentrations 10 min after 600 micrograms GRH, 11.13 micrograms/liter occurred consistently after GRH injection. The evidence that the GH released by GRH is bioactive supports the potential use of GRH for therapeutic applications.

Decrease in carotid intima-media thickness after one year growth hormone (GH) treatment in adults with GH deficiency.

An increased carotid arterial intima-media thickness (IMT) has been reported in hypopituitary adults untreated for GH deficiency. In the present study, the effect of GH replacement on IMT and cardiovascular risk factors was prospectively investigated, in GH deficiency patients treated at a mean dose of 1 UI/day during 1 yr (n = 22) and 2 yr (n = 11). The IMT measurements were performed by the same experienced physician, and the coefficient of variation (calculated in two control groups) was below 6.5%. IMT at baseline was related to conventional risk factors. After 1 yr GH treatment, IMT decreased from 0.78 +/- 0.03 mm to 0.70 +/- 0.03 mm (P < 0.001). The decrement was observed in 21 of 22 patients. After 2 yr GH treatment, IMT had stabilized at 0.70 +/- 0.04 mm and remained significantly different from baseline values (P < 0.003). GH treatment resulted in a moderate decrease in waist circumference and body fat mass and an increase in VO2 max. Conventional cardiovascular risk factors were unmodified except for a transient 10% decrease in low-density lipoprotein cholesterol at 6 months. The contrast between the limited metabolic effect of treatment and the importance and precocity of the changes in IMT suggests that the decrease in IMT was not exclusively attributable to a reversal in the atherosclerotic process. A direct parietal effect of GH replacement on the arterial wall might also be involved. The consequences, in terms of cardiovascular risk, should be established by randomized prospective trials.

A human beta-endorphin pituitary adenoma.

A beta-endorphin (beta END)-containing pituitary adenoma was demonstrated by immunocytochemical, biochemical, and ultrastructural methods in a 43-yr-old man who had impotence, slight testicular atrophy, and an enlarged sella turcica (grade II0), but no manifestations of Cushing's disease. Preoperative hormone data revealed hyperprolactinemia (97 ng/ml), low plasma cortisol levels without circadian rhythm, undetectable plasma ACTH, and normal plasma FSH and LH levels, with an impaired response to LRH. After hypophysectomy, these hormone levels normalized and responded normally to dynamic tests. Immunocytochemically, 30% of the tumor cells reacted only with beta END antiserum. beta END immunoreactivity was the only component revealed by RIA and sodium dodecyl sulfate-polyacrylamide gel electrophoresis. A characteristic ultrastructural aspect is also described. These findings demonstrate dissociation in the secretion of the proopiomelanocortin-derived peptides and suggest a relationship between hyperprolactinemia and tumor secretion of beta END.

Melatonin and jet lag: confirmatory result using a simplified protocol.

This study replicates the alleviation of jet-lag with melatonin in a simplified protocol for eastward flight. At 22-n hr (n is the time-lag between the North American departure point and France), subjects took either melatonin (8 mg, n = 15), or placebo (n = 15) on the day of the return flight and for 3 consecutive days. On day 8, self-ratings significantly discriminated between melatonin and placebo for global treatment efficacy, morning fatigue, and evening sleepiness.

A chronobiological study of melatonin and cortisol secretion in depressed subjects: plasma melatonin, a biochemical marker in major depression.

The temporal organization of plasma melatonin and cortisol secretion was examined in healthy rested controls and in depressed patients: 11 patients suffering from a primary affective disorder (10 female, 1 male) and 8 male controls were studied over a 24-hr period; blood was collected at 2-hr intervals during the day at 1-hr intervals at night. Plasma melatonin and cortisol levels were determined by radioimmunoassay. In addition, melatonin was determined in plasma sampled at 3 AM in older male controls (n = 8) and in females (n = 10) at ovulation. The controls showed low or undetectable (less than 5 pg/ml) diurnal plasma melatonin levels and a very marked nocturnal rhythm (acrophase: 2.27 AM, mesor: 34.4 pg/ml, amplitude: 58.7 pg/ml). For the three control groups, no significant difference was observed in the nocturnal melatonin peak at 3 AM. The depressed patients also showed a significant melatonin rhythm but with lower amplitude (14.5 pg/ml) and mesor (19.1 pg/ml). The latter rhythm was not significantly phase-advanced with respect to the controls (acrophase at 1.18 and 2.34 AM, respectively). In 9 of the 11 patients, nocturnal melatonin secretion was less marked and frequently associated with hypercortisolemia. An additional episodic melatonin secretion was observed in the late afternoon in only two patients. In depressed patients, there was an increase in the mean cortisol secretion level (mesor at 13.6 micrograms/100 ml against 9.1 micrograms/100 ml in the controls), but the amplitude and the acrophase were not significantly modified. These data are discussed in terms of both the hypothalamus-pituitary-adrenal-epiphysis and aminergic abnormalities.

Detection and enzymatic deglycosylation of a glycosylated variant of prolactin in human plasma.

Immunoperoxidase electrophoresis was applied to the plasma of a patient showing a high level of prolactin (PRL) secreted by a pituitary adenoma. Two PRL monomers were detected with an anti-hPRL antiserum: a major 22 kDa form and a minor 25 kDa form. Concanavalin A-Sepharose 4B chromatography revealed that the 25 kDa form was a glycosylated variant of PRL. Incubation of this variant with endoglycosidase F led to its transformation into the 22 kDa form.

Expression of insulin target genes in skeletal muscle and adipose tissue in adult patients with growth hormone deficiency: effect of one year recombinant human growth hormone therapy.

Our aim was to investigate the effects of one year recombinant human growth hormone (rhGH) therapy on the regulation by insulin of gene expression in muscle and adipose tissue in adults with secondary GH deficiency (GHD). Six GHD subjects without upper-body obesity were submitted to a 3-h euglycemic hyperinsulinemic clamp before and after one year of rhGH therapy. Muscle and abdominal subcutaneous adipose tissue biopsies were taken before and at the end of each clamp. The mRNA levels of insulin receptor, p85 alpha-phosphatidylinositol-3 kinase (p85 alpha PI-3K), insulin dependent glucose transporter (Glut4), hexokinase II, glycogen synthase, lipoprotein lipase (LPL) in muscle and in adipose tissue, hormone sensitive lipase and peroxisome proliferator-activated receptor gamma (PPAR gamma) in adipose tissue were quantified by RT-competitive PCR. One year treatment with rhGH (1.25 IU/day) increased plasma IGF-I concentrations (54+/-7 vs 154+/-11 ng/ml, P<0.01) but did not affect insulin-stimulated glucose disposal rate measured during the hyperinsulinemic clamp (74+/-9 vs 85+/-5 micromol/kg free fat mass/min). Insulin significantly increased p85 alpha PI-3K, hexokinase II and Glut4 mRNA levels in muscle both before and after rhGH treatment. One year of GH therapy increased LPL mRNA levels in muscle (38+/-2 vs 70+/-7 amol/microg total RNA, P<0.05) and in adipose tissue (2490+/-260 vs 4860+/-880 amol/microg total RNA, P<0.05), but did not change the expression of the other mRNAs. We conclude from this study that GH therapy did not alter whole body insulin sensitivity and the response of gene expression to insulin in skeletal muscle of adult GHD patients, but it did increase LPL expression in muscle and adipose tissue. This result could be related to the documented beneficial effect of GH therapy on lipid metabolism.

Identification of thyroid hormone residues on serum thyroglobulin: a clue to the source of circulating thyroglobulin in thyroid diseases.

Thyroglobulin (Tg) present in the serum of normal individuals and patients with thyroid disorders could be partly newly synthesized non-iodinated Tg and partly Tg containing iodine and hormone residues originating from the lumen of thyroid follicles. With the aim of examining the contribution of the latter source of Tg to the elevation of serum Tg concentration in thyroid pathophysiological situations, we devised a procedure to identify thyroxine (T4) and tri-iodothyronine (T3) residues on Tg from unfractionated serum. A two-step method, basedon (i)adsorption of Tg on an immobilized anti-human Tg (hTg) monoclonal antibody (mAb) and (ii)recognition of hormone residues on adsorbed Tg by binding of radioiodinated anti-T4 mAb and anti-T3 mAb, was used to analyze serum Tg from patients with either Graves' disease (GD), subacute thyroiditis (ST) or metastatic differentiated thyroid cancer (DTC). Purified hTg preparations with different iodine and hormone contents were used as reference. Adsorption of purified Tg and serum Tg on immobilized anti-hTg mAb ranged between 85 and 90% over a wide concentration range. Labeled anti-T4 and anti-T3 mAbs bound to adsorbed purified Tg in amounts related to its iodine content. Tg adsorbed from six out of six sera from ST exhibited anti-T4 and anti-T3 mAb binding activities. In contrast, significant mAb binding was only observed in one out of eight sera from untreated GD patients and in 1 out of 13 sera from patients with DTC. The patient with DTC, whose serum Tg contained T4 and T3, represented a case of hyperthyroidism caused by a metastatic follicular carcinoma. In conclusion, we have identified, for the first time, T4 and T3 residues on circulating Tg. The presence of Tg with hormone residues in serum is occasional in GD and DTC but is a common and probably distinctive feature of ST.