The effect of strength training on muscle cellular stress in prostate cancer patients on ADT.

BACKGROUND: Androgen deprivation therapy (ADT) for prostate cancer (PCa) is associated with several side effects, including loss of muscle mass. Muscle atrophy is associated with reduced mitochondrial function and increased muscle cellular stress that may be counteracted by strength training. Thus, the aim of this study was to investigate the effect of strength training on mitochondrial proteins and indicators of muscle cellular stress in PCa patients on ADT. METHODS: Men diagnosed with locally advanced PCa receiving ADT were randomised to a strength training group (STG) (n=16) or a control group (CG) (n=15) for 16 weeks. Muscle biopsies were collected pre- and post-intervention from the vastus lateralis muscle, and analysed for mitochondrial proteins (citrate synthase, cytochrome c oxidase subunit IV (COXIV), HSP60) and indicators of muscle cellular stress (heat shock protein (HSP) 70, alpha B-crystallin, HSP27, free ubiquitin, and total ubiquitinated proteins) using Western blot and ELISA. RESULTS: No significant intervention effects were observed in any of the mitochondrial proteins or indicators of muscle cellular stress. However, within-group analysis revealed that the level of HSP70 was reduced in the STG and a tendency towards a reduction in citrate synthase levels was observed in the CG. Levels of total ubiquitinated proteins were unchanged in both groups. CONCLUSION: Although reduced HSP70 levels indicated reduced muscle cellular stress in the STG, the lack of an intervention effect precluded any clear conclusions.

Effects of strength training on muscle cellular outcomes in prostate cancer patients on androgen deprivation therapy.

Androgen deprivation therapy (ADT) improves life expectancy in prostate cancer (PCa) patients, but is associated with adverse effects on muscle mass. Here, we investigated the effects of strength training during ADT on muscle fiber cross-sectional area (CSA) and regulators of muscle mass. PCa patients on ADT were randomized to 16 weeks of strength training (STG) (n = 12) or a control group (CG; n = 11). Muscle biopsies were obtained from m. vastus lateralis and analyzed by immunohistochemistry and western blot. Muscle fiber CSA increased with strength training (898 µm(2) , P = 0.04), with the only significant increase observed in type II fibers (1076 µm(2) , P = 0.03). There was a trend toward a difference in mean change between groups myonuclei number (0.33 nuclei/fiber, P = 0.06), with the only significant increase observed in type I fibers, which decreased the myonuclear domain size of type I fibers (P = 0.05). Satellite cell numbers and the content of androgen receptor and myostatin remained unchanged. Sixteen weeks of strength training during ADT increased type II fiber CSA and reduced myonuclear domain in type I fibers in PCa patients. The increased number of satellite cells normally seen following strength training was not observed.

Relationship between serum TSH and the responsiveness of toxic solitary autonomous thyroid nodules to radioiodine therapy.

OBJECTIVE: To investigate if serum TSH at the time of 131I therapy influences the outcome. DESIGN: A retrospective analysis of data on 39 consecutive patients with toxic solitary autonomous thyroid nodules treated with 131I during a 4 year period. METHODS: Serum TSH was determined by an ultrasensitive RIA with a functional sensitivity of 0.03 mU/l. The 131I dose was calculated blind to the actual serum TSH according to a model compensating for thyroid size estimated by palpation as well as 24 h 131I uptake. RESULTS: After a mean follow-up period of 30 months, 34 patients (87% of all patients) were euthyroid, three (8%) had responded insufficiently and required further antithyroid therapy, and two (5%) had developed hypothyroidism. No significant difference in the response pattern between patients with suppressed or detectable serum TSH could be demonstrated. The two patients who developed hypothyroidism both had detectable serum TSH at the time of 131I treatment. No other clinical parameter seemed to influence the outcome. CONCLUSION: There is no clinically significant effect of circulating TSH on the response of toxic solitary autonomous thyroid nodules to 131I therapy. However, keeping the patients subclinically hyperthyroid when receiving 131I treatment may possibly result in a reduced frequency of hypothyroidism.

Serum TSH and the response to radioiodine treatment of toxic multinodular goitre.

A retrospective analysis of data from 73 consecutive patients with toxic multinodular goitre treated with iodine-131 (131I) during a 2-year period was performed to investigate if serum TSH at the time of 131I treatment influences the outcome. The dose of 131I was calculated according to a model compensating for thyroid size estimated by palpation and 24-h 131I uptake. Serum TSH was determined by a third-generation assay with a functional sensitivity of 0.03 mU/l. A significantly more pronounced response to 131I treatment was observed in patients with TSH > 0.0 mU/l than in patients with TSH = 0.0 mU/l (P = 0.0006. This difference resulted in a threefold lower frequency of non-responders and a fivefold higher rate of early hypothyroidism in the group with detectable serum TSH. While the high frequency of hypothyroidism among patients with measurable serum TSH can be explained by destruction of normal thyroid tissue, the high frequency of treatment failure in the group with serum TSH = 0.0 mU/l suggests that autonomous thyroid tissue may also be sensitized to a deleterious effect of 131I through stimulation by TSH. We conclude that serum TSH has a significant influence on the outcome of 131I treatment of toxic multinodular goitre. The results of 131I treatment may be improved by adjustment of the dose of 131I according to the serum TSH level, in addition to adjustment for goitre size and 24-h 131I uptake.

Nuclear 3,5,3'-triiodothyronine receptor binding in mononuclear blood cells from patients with malignant blood diseases and small cell carcinoma of the lung.

We have previously demonstrated enhanced daily turnover of thyroid hormones in patients with hypermetabolic symptoms due to malignant haematologic disorders or small cell carcinoma of the lung. We hypothesized that some of these symptoms might be due to enhanced peripheral effects of T3. We therefore studied the nuclear T3 receptor binding in circulating mononuclear blood cells in 5 patients with malignant haematologic disorders, 5 with untreated small cell carcinoma of the lung, and 11 healthy controls. Maximal binding capacity of T3 (MBC) was increased 2.5 times in the diseased patients, (median (range)) 110 fmol/mg DNA (75-519) in the haematologic group (p < 0.01), 106 fmol/mg DNA (47-490) (p < 0.10) in small cell carcinoma patients, as compared to 43 fmol/mg DNA (26-94) in controls. The affinity constant Ka of bound T3 was reduced to one-third in the diseased patients. No differences were found between serum thyroid hormone or TSH levels. It is hypothesized, that previously demonstrated enhanced turnover of thyroid hormones in these states of disease might in part be due to increased peripheral consumption of thyroid hormones, including enhanced receptor binding of T3.

Free thyroxine and 3,3',5'-triiodothyronine levels in cerebrospinal fluid in patients with endogenous depression.

Total and free concentrations of T4 and rT3 in serum and cerebrospinal fluid were estimated by ultrafiltration in 12 patients with unipolar endogenous depression before and after electroconvulsive treatment. Recovery from depression resulted in a decrease in CSF concentrations of free T4 (median) (26.2 to 21.4 pmol/l, p less than 0.02) and free rT3 (14.1 to 12.3 pmol/l, p less than 0.05). Concentrations of free T4 in the cerebrospinal fluid were lower than those in serum (p less than 0.02), the ratio being 0.6. In contrast, levels of free rT3 in the cerebrospinal fluid were considerably higher than those found in serum (p less than 0.01), the ratio being 25. These ratios did not change following recovery from depression. In 9 patients with nonthyroidal somatic illness, concentrations of free T4 and rT3 in the cerebrospinal fluid were similar to those found in patients with endogenous depression, whereas 4 hypothyroid patients and one hyperthyroid patient had considerably lower and higher, respectively, concentrations of both free T4 and rT3. In conclusion, levels of free T4 and free rT3 in the cerebrospinal fluid are increased during depression compared with levels after recovery, probably reflecting an increased supply of T4 from serum and an increased production of rT3 from T4 in the brain. The data also suggest that the transport of iodothyronines between serum and the cerebrospinal fluid is restricted.

Effects of octreotide on lipoproteins and endothelial function of type 1 (insulin-dependent) diabetic patients.

Hypersecretion of growth hormone (GH) is a characteristic feature of Type 1 diabetic patients. In healthy subjects growth hormone is able to induce an increase in endothelial cell proteins such as fibrinogen and von Willebrand factor. Plasma concentrations of such proteins, which are markers of cardiovascular risk, are elevated in diabetic patients with microalbuminuria, suggesting endothelial cell dysfunction. In a randomized prospective study we therefore evaluated the possible effects of 1 year's treatment with a somatostatin analogue, octreotide, on lipoproteins and on endothelial function in Type 1 diabetes mellitus. Seven patients were allocated to treatment with a continuous subcutaneous infusion of 400 micrograms octreotide per day. Seven patients served as a control group. During treatment a decrease in plasma LDL-cholesterol (2.62 (2.17-3.11) (median (range] vs 2.00 (1.89-2.96) mmol l-1, p less than 0.05) and serum apolipoprotein A-I (1.47 (1.25-1.60) vs 1.23 (1.13-1.90) g l-1, p less than 0.05) was observed in the treated group. Furthermore a probable reduction during treatment in plasma concentrations of von Willebrand factor (1.72 (0.84-3.04) vs 1.24 (0.94-1.82) U ml-1, p = 0.08) and fibrinogen (11.3 (7.3-25.3) vs 8.1 (7.5-11.8) mumol l-1, p = 0.06) was found, and after withdrawal of treatment an increase towards the initial levels was seen. The platelet count declined (326 (301-612) vs 217 (206-400) x 10(9) l-1, p less than 0.01) during octreotide treatment and remained depressed 2 months after withdrawal.

Effect of one year continuous subcutaneous infusion of a somatostatin analogue, octreotide, on early retinopathy, metabolic control and thyroid function in Type I (insulin-dependent) diabetes mellitus.

Growth hormone is assumed to be involved in the development of diabetic retinopathy. In a randomized study we evaluated the possible effects of one year treatment with a somatostatin (SRIH) analogue, octreotide, on early retinopathy and on metabolism in Type I (insulin-dependent) diabetes mellitus. Eleven patients were allocated to treatment with a continuous sc infusion of 400 micrograms octreotide per day and 9 served as controls. Only 7 patients from each group completed the study. Three octreotide-treated patients left the study owing to severe diarrhea. The subjects were evaluated at entry, after 2, 6 and 12 months treatment, and 2 months after withdrawal. Octreotide induced a decrease in GH secretion, expressed as the area under the 24 h serum GH profiles (p less than 0.05), and of the serum levels of IGF-I (p less than 0.05). The entire decline in GH levels occurred during the daytime, whereas the nocturnal levels were unaffected. Retinopathy, as assessed by determination of the blood retina barrier permeability, by colour fundus photography, and flurescein angiography was unchanged in both groups. Apart from a decline in insulin requirements, octreotide had no major effect on glycemic control, but induced a mild transient pituitary hypothyroidism, not clinically relevant. We conclude that treatment with octreotide for one year has modest effects on GH, IGF-I, and glucose metabolism, but has no significant effect on early retinopathy in Type I (insulin-dependent) diabetes.

Hypothalamic-pituitary and thyroid function in chronic alcoholics with neurological complications.

Endocrinological tests were performed in 14 chronic alcoholic men with signs of intellectual impairment and/or peripheral neuropathy. All had been abstinent from alcohol for at least 1 month. Basal serum growth hormone (GH) was consistently increased in only one patient whereas the GH responses to insulin hypoglycemia stimulation was normal in all patients. Thyroid function values (T4, T3, rT3, TSH) were normal in all patients whereas baseline serum prolactin values were significantly increased in alcoholics as compared with a control group. In a combined TRH- and GnRH-stimulation tests, GH-responses were also normal whereas TSH and prolactin responses were blunted or absent in about half of the patients, the responses correlating significantly (p less than 0.01). It is concluded that disturbances in the hypothalamic-pituitary axis may occur in chronic alcoholics with nervous impairment independently of the physical deterioration, which often is associated with chronic alcoholism.

Increased production of thyroxine and inappropriately elevated serum thyrotropin in levels in endogenous depression.

The increased serum thyroxine (T4) levels in endogenous depression (ED) might be due to an increased production or a reduced degradation of T4. We therefore performed turnover studies of radiolabeled T4 and 3,5,3'-triiodothyronine (T3) in 6 patients with ED and 8 age-matched healthy controls. In ED, the median daily production of T4 was 130 nmol/day/70 kg, (range 100-186 nmol/day/70 kg) and elevated compared to control values which were 99 nmol/day/70 kg (range 85-142 nmol/day/70 kg) (p less than 0.05), whereas that of T3 was similar in the two groups. Serum thyrotropin (TSH) levels (0.90 mU/liter, 0.18-2.15 mU/liter) were elevated in ED compared to a group of 7 L-T4-treated hypothyroid subjects with similar production and serum levels of T4 and T3 (0.11 mU/liter, 0.07-1.10 mU/liter) (p less than 0.02). The data show that increased serum T4 levels in ED are secondary to an increased thyroidal production of T4, which is at least partly due to inappropriately high serum TSH levels.

The pituitary-thyroid axis in patients with pituitary disorders.

The pituitary-thyroid axis of 12 patients, exposed to transsphenoidal pituitary microsurgery because of nonfunctioning adenomas (6), prolactinomas (3) and craniopharyngioma (1), or to major pituitary injury (1 apoplexy, 1 accidental injury), was controlled more than 6 months following the incidents. The patients did not receive thyroid replacement therapy and were evaluated by measurement of the serum concentration of thyroxine (T4), 3,5,3'-triiodothyronine (T3), 3,3',5'-triiodothyronine (rT3), T3-resin uptake test and thyrotropin (TSH, IRMA method) before and after 200 micrograms thyrotropin releasing hormone (TRH) iv. The examination also included measurement of prolactin (PRL) and cortisol (C) in serum. Apart from 1 patient with pituitary apoplexy all had normal basal TSH levels and 9 showed a significant TSH response to TRH. Compared to 40 normal control subjects the 12 patients had significantly decreased levels of T4, T3 and rT3 (expressed in free indices), while the TSH levels showed no change. Five of the patients, studied before and following surgery, had all decreased and subnormal FT4I (free T4 index) after surgery, but unchanged FT3I and TSH. The levels of FT4I were positively correlated to both those of FT3I and FrT3I, but not to TSH. The TSH and thyroid hormone values showed no relationship to the levels of PRL or C of the patients exposed to surgery. It is concluded that the risk of hypothyroidism in patients exposed to pituitary microsurgery is not appearing from the TSH response to TRH, but from the thyroid hormone levels.

Concentrations of thyroxine, 3,5,3'-triiodothyronine, 3,3',5'-triiodothyronine, 3,3'-diiodothyronine, and 3',5'-diiodothyronine in human red blood cells.

A simple and rapid method for the estimation of cellular concentration of thyroxine (T4), 3,5,3'-triiodothyronine (T3), 3,3',5'-triiodothyronine (rT3), 3,3'-diiodothyronine (3,3'-T2), and 3',5'-diiodothyronine (3',5'-T2) as well as their distribution between cytosol and membranes in human red blood cells (RBC) is presented. Concentrations of iodothyronines in RBC (RBC-T) were calculated by multiplying the total serum concentrations by the ratio of radioactivity in equal volumes of packed RBCs and serum, pre-incubated with 125I-labelled iodothyronines of high specific activity. Plasma and RBC were separated by centrifugation in capillary glass tubes. The separation of membranes and cystosol was performed by hypotone lysis and centrifugation. The median RBC-T of T4, T3, rT3, 3,3'-T2, and 3',5'-T2 from 17 euthyroid subjects were 360 pmol/l, 156 pmol/l, 2.77 pmol/l, 6.81 pmol/l, and 2.17 pmol/l, respectively. The cytosol/cytosol + membrane ration were 66%, 40%, 84%, 77%, and 97%, respectively. The differences in RBC-T were not similar to the differences in free serum concentrations. The ratio of RBC-T to free serum concentration differed considerably between T4 (16.6), T3 (24.4), and 3,3'-T2 (15.5) as compared to rT3 (5.8) and 3',5'-T2 (2.6). Data on three patients with thyroid diseases suggested that RBC-T values were increased in hyperthyroidism and decreased in hypothyroidism, whereas the cytosol/cytosol + membrane-ratio was unaltered.

The hidden, nonexchangeable pool of 3,5,3'-triiodothyronine and 3,3',5'-triiodothyronine in man: does it exist?

The validity of estimation of the production rates of T3 and rT3 in man based on noncompartmental analysis of blood-derived data has been questioned owing to incomplete exchangeability of T3 and rT3 between plasma and extrathyroidal tissues in which a local production of these iodothyronines takes place. The possible existence of a nonexchangeable or hidden pool of T3 and rT3 would result in an underestimation of the daily production. By contrast, the production rate of T4 can be estimated reliably using noncompartmental analysis. We have studied 16 women with pretreatment severe hypothyroidism on constant levothyroxine therapy. Simultaneous measurements of T4, T3 and rT3 production rates were performed using bolus injection of radiolabelled iodothyronines. The tracers were isolated from plasma using gel separation/antibody extraction, and production rates were calculated by noncompartmental analysis. Mean (+/- SD) production rate of T4, T3 and rT3 were: 119 +/- 43, 40.0 +/- 22.0 and 54.9 +/- 20.0 nmol.day-1.(70 kg)-1, respectively. Thus 79.5 +/- 7.0% of T4 was deiodinated into T3 and rT3. This leaves 20.5% to other metabolic pathways of T4 and to a possible underestimation of T3 and rT3 production rate. Based on conservative estimates from the literature, the other metabolic pathways of T4 amount: oxidative deamination 1.1%; ether link cleavage 0%; urinary excretion 2.5%; and fecal excretion 14%. Thus, the various metabolic pathways seem to explain 97% of daily produced and degradated T4 in man. Therefore the understimation of T3 and rT3 production rates in man using noncompartmental analysis seems of little if any importance, and existence of a hidden pool of these iodothyronines may be questioned.

Thyroid hormone metabolism in hypermetabolic patients with haematological disorders.

Turnover tracer studies of T4 and T3 using the single injection, noncompartmental approach were performed in 6 hypermetabolic patients with haematological disorders (HHD) (basal metabolic rate (BMR): median 141%, range 122-166%), in 10 controls with stable, nonthyroidal illness (NTIC), and in 14 healthy controls (HC). The main finding was an increase of approximately 30% of the production rate (PR) of both T4 and T3 in patients with HHD. Median PR of T4 was 134 nmol/day x 70 kg in HHD, compared to 78 nmol/day x 70 kg in NTIC (P less than 0.05) and 98 nmol/day X 70 kg in HC (p less than 0.1), whereas median PR of T3 was 40.3 nmol/day x 70 kg in HHD, compared to 25.6 nmol/day x 70 kg in NTIC (P less than 0.01) and 31.1 nmol/day x 70 kg in HC (P less than 0.1). An increase of similar magnitude was found for the apparent distribution volume and the pool size of both T4 and T3. In contrast, the mean transit times of the hormones were similar in the 3 groups. Patients with HHD had normal levels of basal serum TSH as well as of the TSH response to TRH. Only PR of T3 correlated to the BMR (R = 1.00, P less than 0.02). The data are compatible with an increased consumption of thyroid hormones by malignant haematologic cells, and the increase of BMR seems to be dependent on the production of T3.

Metabolic clearance and production of diiodotyrosine in healthy man.

Metabolic clearance rate (MCR) and daily production rate (PR) of diiodotyrosine (DIT) were estimated using a constant infusion technique of trace amounts of [125-I]-DIT followed by chromatographical isolation of tracer. Median DIT MCR was in eight healthy subjects estimated to 162 l/day x 70 kg (range 135-242), whereas PR was 52 nmol/day x 70 kg (range 25-126). The median serum DIT concentration was 0.27 nmol/l (range 0.16-0.62). In five L-thyroxine substituted subjects without endogenous thyroxine (T4) production, serum DIT concentrations were below 0.02 nmol/l, suggesting that more than 94% of daily produced DIT is secreted by the thyroid gland.

The pituitary-thyroid axis in acromegaly.

The pituitary-thyroid axis of 12 acromegalic patients was evaluated by measurement of the serum concentrations (total and free) of thyroxine (T4), triiodothyronine (T3) and reverse T3 (rT3) and thyrotropin (TSH), growth hormone (GH) and prolactin (PRL) before and after iv stimulation with thyrotropin releasing hormone (TRH). Using an ultrasensitive method of TSH measurement (IRMA) basal serum TSH levels of the patients (0.76, 0.07-1.90 mIU/l) were found slightly, but significantly (P less than 0.01), lower than in 40 healthy controls (1.40, 0.41-2.50 mIU/l). The total T4 levels (TT4) were also reduced (84, 69-106 nmol/l vs 100, 72-156 nmol/l, P less than 0.01) and significantly correlated (P less than 0.02, R = 0.69) to the TSH response to TRH, suggesting a slight central hypothyroidism. The acromegalics had, however, normal serum levels of TT3 (1.79, 1.23-2.52 nmol/l vs 1.74, 0.78-2.84 nmol/l, P greater than 0.10), but significantly decreased levels of TrT3 (0.173, 0.077-0.430 nmol/l vs 0.368, 0.154-0.584 nmol/l, P less than 0.01) compared to the controls. The serum concentration of the free iodothyronines (FT4, FT3, FrT3) showed similar differences between acromegalics and normal controls. All the acromegalics showed a rise of serum TSH, GH and PRL after TRH. Positive correlation (P less than 0.05, R = 0.59) was found between the TSH and GH responses, but not between these two parameters and the PRL response to TRH. These findings may be explained by the existence of a central suppression of the TSH and GH secretion in acromegalic subjects, possibly exerted by somatostatin. Euthyroidism might be maintained by an increased extrathyroidal conversion of T4 to T3.

Thyroid hormone turnover in patients with small cell carcinoma of the lung.

Patients with small cell carcinoma of the lung often present with symptoms suggestive of hyperthyroidism i.e. weight loss without anorexia. Consequently [125I]T4 and [131I]T3 turnover was studied using simultaneously iv bolus injection and noncompartmental analysis in 6 patients with untreated small cell carcinoma of the lung and 14 normal subjects of comparable ages. Both T4 and T3 production rates were enhanced, T4 production being in median 135 nmol.day-1.70 kg-1 (range 111-200) in patients with small cell carcinoma of the lung vs 98 nmol.day-1.70 kg-1 (range 69-134) in controls (P less than 0.01), and T3 production being 46 nmol.day-1.70 kg-1 (range 33-65) vs 31 nmol.day-1.70 kg-1 (range 24-45) (P less than 0.01). The mean transit time was shortened for both T4 and T3, T4 mean transit time being 5.9 days (3.9-8.0 days) vs 8.3 days (6.1-11.2 days) in controls (P less than 0.01), and T3 mean transit time being 0.74 days (0.36-0.98 days) vs 1.03 days (0.81-1.45 days) in controls (P less than 0.01). Serum total and free T4 and T3 levels were unchanged. Basal serum TSH levels and the TSH response to iv TRH were also normal. Thyroid-stimulating immunoglobulins were only present in the serum in 1 of 6 patients. Thus, thyroid hormone production seemed under pituitary regulation. The peripheral effect of thyroid hormones was evaluated measuring serum sex hormone binding globulin levels, which were increased to in median 270% (77-310%) (P less than 0.01) of that in controls, suggesting some degree of hyperthyroidism in liver tissue.(ABSTRACT TRUNCATED AT 250 WORDS)

Assessment of the clinically significant TSH response to TRH in patients with nodular goitre.

Twenty-five patients with nodular goitre who had thyroid hormone levels within normal ranges and an absent thyrotropin (TSH) response to TSH releasing hormone (TRH) as measured by a conventional radioimmunoassay with a lower detection limit of 0.6 mU/l were studied. Based on these data, and the clinical evaluation patients were divided into a hyperthyroid group (n = 12) and a euthyroid group (n = 13). The samples from the TRH test were reanalyzed by an immunoradiometric TSH assay with a detection limit of 0.05 mU/l. Basal serum TSH showed a considerable overlap between the two groups, but values above 0.10 mU/l were always associated with euthyroidism. Using this level of discrimination 76% of the patients were correctly classified. A TSH response to TRH of 0.10 mU/l provided a better discrimination allowing a correct diagnosis in 92% of the patients. It is concluded that serum TSH as measured by a sensitive assay is suitable as a first line test in patients with nodular goitre. However, patients with basal serum TSH levels below 0.10 mU/l need further investigation with a TRH-test. A TSH response to TRH above 0.10 mU/l seems to secure euthyroidism, whereas lower responses almost always are associated with hyperthyroidism.