Unique alterations of thyroid function parameters after i.v. administration of alkylating drugs (cyclophosphamide and ifosfamide).

Alkylating drugs (cyclophosphamide and ifosfamide) have been in clinical use for the treatment of malignant diseases in the past. They are most useful anticancer agents and cyclophosphamide is also widely used for its immunosuppressive properties. However the effect of alkylating drugs on thyroid hormone parameters have not been evaluated so far. Three groups of patients were prospectively evaluated: Group I: 15 patients with Wegener's granulomatosis and 4 patients with severe scleritis received a single dose cyclophosphamide (15 mg/kg bw/day) and 250 mg prednisone i.v. Group II: 9 patients with malignant lymphomas were treated according to the IMVP 16-protocol. Patients received daily ifosfamide 1000 mg/m2 from day 0 to 4 and vepesid from day 0 to 2. Patients did not receive corticosteroids additionally. Group III: 6 patients with a relapse of malignant lymphomas received ifosfamide 1.500 mg/m2/day from day 0 to 4 i.v. and dexamethasone 40 mg/m2 as well as ara-c and etoposid. All patients received mesna to prevent hemorrhagic cystitis and odansetran or metoclopramide as antiemetic drugs. Alkylating drugs were given as a one hour infusion. Thyroid hormone parameters were determined before and on day 1, 2, 3, 4 after drug administration. We observed a significant increase in T4 and fT4 concentrations and a concomitant fall in TSH in either group one day after the administration of alkylating drugs. The effect was most pronounced in group III: T4 increased from 113 +/- 8 nmol/L to 175 +/- 8 (normal: 58-154) and fT4 from 14.0 +/- 0.8 to 24.8 +/- 2.5 pmol/L (normal 10-25). TSH dropped from 1.27 +/- 0.16 to 0.33 +/- 0.07 mU/L (normal 0.3-4). All changes were significant: p < 0.001. Two of the six patients displayed biochemical hyperthyroidism. Also reverse T3 increased significantly. Two days after drug administration a gradual normalization occurred. However, T3, Tg, TBG, Transthyretin and albumin levels did not change throughout the study period. One patient with coexisting hypothyroidism, who received his last thyroxine substitution therapy one day before the administration of cyclophosphamide (as in group I), also demonstrated an increase in T4, fT4 and rT3 and a fall in TSH concentrations. I.v. administrations of cyclophosphamide and ifosfamide induce a transient increase in T4 and fT4 concentrations and a concomitant fall of TSH in the presence of normal Tg, T3 and thyroid binding protein concentrations. These data suggest, that the changes are not due to a release of thyroid hormones from the thyroid itself, but is likewise related to a release of thyroxine from cellular pools such as the liver.

Influence of various modes of androgen substitution on serum lipids and lipoproteins in hypogonadal men.

We investigated whether the androgen type or application mode or testosterone (T) serum levels influence serum lipids and lipoprotein levels differentially in 55 hypogonadal men randomly assigned to the following treatment groups: mesterolone 100 mg orally daily ([MES] n = 12), testosterone undecanoate 160 mg orally daily ([TU] n = 13), testosterone enanthate 250 mg intramuscularly every 21 days ([TE] n = 15), or a single subcutaneous implantation of crystalline T 1,200 mg ([TPEL] n = 15). The dosages were based on standard treatment regimens. Previous androgen substitution was suspended for at least 3 months. Only metabolically healthy men with serum T less than 3.6 nmol/L and total cholesterol (TC) and triglyceride (TG) less than 200 mg/dL were included. After a screening period of 2 weeks, the study medication was taken from days 0 to 189, with follow-up visits on days 246 and 300. Before substitution, all men were clearly hypogonadal, with mean serum T less than 3 nmol/L in all groups. Androgen substitution led to no significant increase of serum T in the MES group, subnormal T in the TU group (5.7 +/- 0.3 nmol/L), normal T in the TE group (13.5 +/- 0.7 nmol/L), and high-normal T in the TPEL group (23.2 +/- 1.1 nmol/L). 5 alpha-Dihydrotestosterone significantly increased in all treatment groups compared with baseline. Compared with presubstitution levels, a significant increase of TC was observed in all treatment groups (TU, 14.4% +/- 3.0%; MES, 18.8% +/- 2.5%; TE, 20.4% +/- 3.0%; TPEL, 20.2% +/- 2.6%). Low-density lipoprotein cholesterol (LDL-C) also increased significantly by 34.3% +/- 5.5% (TU), 46.4% +/- 4.1% (MES), 65.2% +/- 5.7% (TE), and 47.5% +/- 4.3% (TPEL). High-density lipoprotein cholesterol (HDL-C) showed a significant decrease by -30.9% +/- 2.8% (TU), -34.9% +/- 2.5% (MES), -35.7% +/- 2.6% (TE), and -32.5% +/- 3.5% (TPEL). Serum TG significantly increased by 37.3% +/- 11.3% (TU), 46.4% +/- 10.3% (MES), 29.4% +/- 6.5% (TE), and 22.9% +/- 6.7% (TPEL). TU caused a smaller increase of TC than TE and TPEL, whereas the parenteral treatment modes showed a lower increase of TG. There was no correlation between serum T and lipid concentrations. Despite the return of serum T to pretreatment levels, serum lipid and lipoprotein levels did not return to baseline during follow-up evaluation. In summary, androgen substitution in hypogonadal men increases TC, LDL-C, and TG and decreases HDL-C independently of the androgen type and application made and the serum androgen levels achieved. Due to the extended washout period for previous androgen medication and the exclusion of men with preexisting hyperlipidemia, this investigation demonstrates more clearly than previous studies the impact of androgen effects on serum lipids and lipoproteins. It is concluded that preexisting low serum androgens induce a "male-type" serum lipid profile, and increasing serum androgens further within the male normal range does not exert any additional effects. The threshold appears to be above the normal female androgen serum levels and far below the lower limit of normal serum T levels in adult men. These findings may have considerable implications for the use of androgens as a male contraceptive and for androgen therapy in elderly men.

Thyroid antibodies in children of mothers with auto-immune thyroid disease.

UNLABELLED: In a cross-sectional study, 29 children aged between 1 month and 15.3 years (average age 6.8 years) born to mothers with Graves disease or Hashimoto thyroiditis were examined clinically, biochemically, and by sonography of the thyroid gland. At the time of examination all children were clinically euthyroid. Tests of thyroid peroxidase antibody, thyroglobulin antibody, TSH receptor antibody and free thyroxine (fT4) gave normal results. In 3 children subclinical hypothyroidism with elevated TSH and normal fT4 concentrations were found; one of these children had a minor decrease of total thyroxine. Three children with otherwise normal test results had marginally elevated triiodothyronine concentrations. Increased antibody titres were present in 8 out of 29 children. TSH function-blocking antibodies were elevated in 8 cases. In addition, cytotoxic antibodies were found in one of the children. The distribution pattern of antibodies was different in each child and unrelated to the type of maternal thyroid disease. CONCLUSION: Children of mothers with auto-immune thyroid disease often have thyroid antibodies without signs of thyroid disease. Whether antibody-positive children have an increased risk of developing thyroid disorders later in life must be examined in a longitudinal study.

Effect of small doses of iodine on thyroid function in patients with Hashimoto's thyroiditis residing in an area of mild iodine deficiency.

OBJECTIVE: Several studies have suggested that iodine may influence thyroid hormone status, and perhaps antibody production, in patients with autoimmune thyroid disease. To date, studies have been carried out using large amounts of iodine. Therefore, we evaluated the effect of small doses of iodine on thyroid function and thyroid antibody levels in euthyroid patients with Hashimoto's thyroiditis who were living in an area of mild dietary iodine deficiency. METHODS: Forty patients who tested positive for anti-thyroid (TPO) antibodies or with a moderate to severe hypoechogenic pattern on ultrasound received 250 microg potassium iodide daily for 4 months (range 2-13 months). An additional 43 patients positive for TPO antibodies or with hypoechogenicity on ultrasound served as a control group. All patients were TBII negative. RESULTS: Seven patients in the iodine-treated group developed subclinical hypothyroidism and one patient became hypothyroid. Three of the seven who were subclinically hypothyroid became euthyroid again when iodine treatment was stopped. One patient developed hyperthyroidism with a concomitant increase in TBII titre to 17 U/l, but after iodine withdrawal this patient became euthyroid again. Only one patient in the control group developed subclinical hypothyroidism during the same time period. All nine patients who developed thyroid dysfunction had reduced echogenicity on ultrasound. Four of the eight patients who developed subclinical hypothyroidism had TSH concentrations greater than 3 mU/l. In 32 patients in the iodine-treated group and 42 in the control group, no significant changes in thyroid function, antibody titres or thyroid volume were observed. CONCLUSIONS: Small amounts of supplementary iodine (250 microg) cause slight but significant changes in thyroid hormone function in predisposed individuals.

Efficacy and safety of iodine in the postpartum period in an area of mild iodine deficiency.

BACKGROUND: Iodine deficiency (even moderate) plays a major role in pregnancy associated goiter development, which is only party reversible after pregnancy. The prevalence of post partum thyroiditis is reported to be slightly lower in areas of iodine deficiency. Thus iodine supplementation may be effective in decreasing pregnancy associated increase in thyroid volume, but enhances the risk of increasing the prevalence of thyroid dysfunction in the post partum period. Therefore, we evaluated the effect of iodine supplementation (with two different doses: 50 microg and 250 microg) on the prevalence of post partum thyroiditis and the decrease in thyroid volume up to 8 months post partum in an area of mild iodine deficiency. PATIENTS AND METHODS: Thyroid volume of 56 women was evaluated 5 days and 3 months after delivery (study I). In an intervention study (Study II) 70 women were randomized to receive 50 or 250 microg of potassium iodide for a period of 8 months post partum beginning five days after delivery. Thyroid volume, the echogenecity of the thyroid gland, thyroid hormone parameters (T4, T3, fT4, TSH) and thyroid antibodies (TPO and Tg-Ab) were measured 5 days, 3 and 8 months after delivery. RESULTS: A total number of 11 women developed postpartum thyroid dysfunction: 4 women developed manifest thyroid dysfunction (3 hyperthyroidism and 1 hypothyroidism) 3 months post partum. The remaining seven had subclinical hypo- or hyperthyroidism. All changes were clinically mild and transient as evidenced by normalization of thyroid hormone parameters on reexamination at 8 months. Among the eleven, 6 women in the 50 microg iodine group and 5 women of the 250 microg iodine group developed thyroid dysfunction, suggesting that the iodine dose did not affect post partum thyroiditis. The administration of only 50 microg iodine was associated with a significant fall of thyroid size already 3 months after delivery (25.4 +/- 1.5 ml (mean +/- sem) to 18.2 +/- 1.25 p <0.001). The application of 250 microg iodine was equally effective. 8 months post partum a slight but further decrease could be demonstrated. On the other hand, in study I no significant reduction in thyroid volume was observed in women receiving no supplementary iodine (thyroid volume at delivery 29 +/- 2.2 ml; at 3 months 27.5 +/- 3.0 ml. CONCLUSION: The administration of supplementary iodine (up to 250 microg) to an unselected population, residing in an area of mild iodine deficiency, in the post partum period is save as indicated by a prevalence of 5.7% manifest thyroid dysfunction. These changes are clinically mild and transient. Even the amount of 50 microg of iodine supplementation seems to by very efficient in reducing pregnancy associated increments in thyroid volume.

Sequential changes of biochemical bone parameters after kidney transplantation.

BACKGROUND: Persistent hyperparathyroidism after renal transplantation (Rtx) has been reported in several studies. However these studies evaluated biochemical bone parameters either only during a short time period (up to 6 months) or for a longer time period, but with long intervals in between. Therefore, we prospectively evaluated biochemical bone parameters of kidney-transplant recipients at short intervals for 2 years after surgery. METHODS: Biochemical bone parameters were prospectively investigated in 129 patients 2, 3, 5, 8, 12, 18 and 24 months after Rtx. All patients received prednisone and cyclosporin A as immunosuppressive therapy, and 75 patients also received azathioprine. None of the patients was treated with calcium, phosphorus, or vitamin D preparations. RESULTS: Serum creatinine levels decreased from 166.8 +/- 5.4 mumol/l to 140.0 +/- 4.9 two years after Rtx; (data are expressed as mean +/- s.e.m.). Serum phosphorus levels increased slightly from 0.9 +/- 0.022 mmol/l to 0.98 +/- 0.025 (12 m), but remained within the lower normal range. We observed a rise in total and albumin adjusted calcium concentrations 3 months after Rtx. 52% of all patients had serum calcium levels above 2.62 mmol/l (upper normal limit in our laboratory) 3 months after renal transplantation with a gradual decrease thereafter. There was no correlation of calcium and PTH levels. We observed a significant rise in biochemical bone parameters from 2 to 5 months after renal transplantation (P < 0.001): alkaline phosphatase (AP) increased from 164.3 +/- 9.4 to 236 +/- 12.7 U/l (normal 50-180), bone specific alkaline phosphatase (BAP) rose from 17.7 +/- 1.36 to 23.2 +/- 1.7 ng/ml (normal:4-20) and osteocalcin (OC) increased from 20.2 +/- 1.5 to 26.7 +/- 1.9 ng/ml (normal 4-12). AP and BAP levels values normalized 12 months after renal transplantation, whereas OC was still above normal throughout the study period. Patients were subdivided into two groups: those with good and those with impaired graft functions. Patients with good graft function had stable serum creatinine levels (< or = 132 mumol/l or < or = 1.5 mg/dl) well below the mean serum creatinine concentration during the study period. The significant changes in AP, BAP, and OC occurred irrespective of renal function. However, patients with impaired graft function (n = 65) had significantly higher PTH-levels (70 pg/ml higher) than patients with good graft function (n = 64), P < 0.01. PTH was positively correlated with serum creatinine (r = 0.81, P < 0.001). Moreover, patients with low 25 (OH) vitamin D levels (n = 63) had significantly higher PTH concentrations (between 40 and 80 pg/ml, P < 0.01) throughout the study period compared to patients (n = 66) with a sufficient 25(OH)D supply irrespective of graft function. There was a negative correlation of 25 (OH)D levels and PTH; (r = -0.49, P < 0.001). 1,25(OH)2D3 (evaluated in 24 patients) levels increased from 46.5 +/- 6.6 to 76.9 +/- 7.6 pg/ml (normal:35-90) at 12 months. CONCLUSION: Hypercalcaemia is a common phenomenon in the early period after kidney transplantation and occurs in the presence of low normal phosphorus levels. It is most probably related to improved PTH action and 1-hydroxylation of vitamin D. The rise in biochemical bone parameters between 3 and 5 months occurs irrespective of graft function and normalization is only achieved 1 year after transplantation. PTH is constantly elevated for up to 2 years after kidney transplantation and is most probably related (a) to impaired graft function and (b) to suboptimal 25 OH vitamin D supply.

Is there a methimazole dose effect on remission rate in Graves' disease? Results from a long-term prospective study. The European Multicentre Trial Group of the Treatment of Hyperthyroidism with Antithyroid Drugs.

OBJECTIVE: The optimal antithyroid drug regimen for Graves' disease remains a matter of controversy. The European Multicentre Trial Group has investigated the effects of methimazole drug dose on the long-term outcome of Graves' disease. DESIGN: Extended follow-up of patients from a prospective multicentre trial, designed to study methimazole dose effects on the outcome of Graves' disease. We have reported previously that the relapse rates did not differ after a medication-free observation period of 12 months; the relapse rates were 37% and 38%, respectively. In this paper, we describe the outcome in these patients after a mean observation period of 4.3 +/- 1.3 years and have looked for potential predictors of this outcome. PATIENTS: Three hundred and thirteen patients with Graves' disease were randomized to treatment with a constant dose of 10 or 40 mg of methimazole for 1 year, with levothyroxine supplementation as required. MEASUREMENTS: At the time of inclusion into the trial: thyroid size, T4, T3, TSH-binding inhibiting immunoglobulins, urinary iodide excretion, thyroid uptake, Crook's therapeutic index of hyperthyroidism (a measure of clinical disease severity). At the time of follow-up examination: TSH, T4, T3, thyroid size, thyroid ultrasound, THS-binding inhibiting immunoglobulins. RESULTS: The overall relapse rate was 58%. There was no difference in relapse rates between patients treated with either 10 or 40 mg of methimazole (58.3 vs. 57.8%). Five patients had become spontaneously hypothyroid, without obvious relationship to antithyroid drug dose. Patients who relapsed and patients who remained in remission did not differ with respect to: age, goitre size, ophthalmopathy, median iodine excretion, serum T4 or serum T3, Crook's therapeutic index and thyroid uptake at the time of study entry. Thus, none of these variables was potentially suitable for predicting outcome. This finding was confirmed by Cox's proportional hazard regression. Thyroid volume, measured by ultrasound, did not differ between patients in remission and patients with relapse. There was no difference in the course of endocrine eye signs, in the requirement for steroid and radiotherapy for eye signs, or in thyroid echostructure between patients in the 10 and in the 40 mg group, nor was serum TSH different in patients who had remained in remission (0.8 +/- 0.6 mU/l in the 10 mg group, 1.0 +/- 0.8 mU/l in the 40 mg group). CONCLUSIONS: The dose of methimazole in Graves' disease therapy can safely be kept to the minimal required dose. This will provide the same chance of remission as higher doses, and provide the best balance of risk and benefit.

Testosterone substitution normalizes elevated serum leptin levels in hypogonadal men.

The ob gene product leptin (OB) is a feedback signal from the adipocyte to the hypothalamus and is involved in regulation of food intake and energy expenditure in rodents. A major determinant of serum OB levels is fat mass. Several studies suggest that men have lower OB levels than women even after adjustment for percent body fat. We, therefore, investigated the influence of testosterone (T) substitution in hypogonadal men on serum OB levels. Hypogonadal men with T levels of 3.6 nmol/L or less and off substitution therapy for at least 3 months were assigned to two treatment groups: testosterone enanthate (TE; 250 mg, i.m., every 21 days; n = 10) or a single s.c. implantation of 1200 mg crystalline T (TPEL; n = 12). Blood samples for determination of T, 5 alpha-dihydrotestosterone (DHT), sex hormone-binding globulin, and 17 beta-estradiol were obtained before therapy and then every 21 days until day 189 and at follow-up visits on days 246 and 300. Serum OB levels were assessed on days 0, 42, 84, 126, 168, and 300. OB levels were referred to a normal range for men based on the analysis of OB levels in 393 adult men. Substitution with T led to a large rise in T and DHT in both groups compared to baseline values (average T, days 21-189: TE, 14.33 +/- 2.63 nmol/L; TPEL, 24.98 +/- 1.64; average DHT, days 21-189: TE, 4.20 +/- 0.57 nmol/L; TPEL, 5.11 +/- 0.56; P < or = 0.05). Concomitantly, 17 beta-estradiol increased in both groups, and sex hormone-binding globulin levels were significantly decreased. At baseline, serum OB levels in hypogonadal men were 3-fold elevated compared to those in normal men (12.39 +/- 2.93 micrograms/L vs. 4.28 +/- 0.52; P < 0.01) and not different between groups (TE, 13.7 +/- 5.6; TPEL, 11.3 +/- 2.9 micrograms/L). This elevation was retained after adjustment for body mass index in the normal control group [TE, 1.45 +/- 0.51 SD score (P < 0.0001); TPEL, 0.98 +/- 0.35 SD score (P < 0.0008)]. During T substitution serum OB was completely normalized (trough levels: TE, 4.6 +/- 1.0 micrograms/L; TPEL 4.3 +/- 0.9 micrograms/L). In multiple regression analysis, the androgen (T plus DHT)/estrogen ratio was the only significant determinant of OB levels (r = -0.32; P < 0.01). At baseline, OB levels did not correlate with body mass index, but during substitution, the correlation was considerably improved. We conclude that hypogonadal men exhibit elevated OB levels that are normalized by substitution with T. The only determinant of OB levels was the androgen/estrogen ratio, indicating a major influence of sex steroids on OB production. The interaction of T and OB might be part of a hypothalamic-pituitary-gonadal-adipose tissue axis that is involved in body weight maintenance and reproductive function.

Effects of various modes of androgen substitution therapy on erythropoiesis.

In order to investigate differential effects of androgens on erythropoiesis, 55 men with clincally and biochemical confirmed hypogonadism were randomly assigned to 4 groups receiving different forms of androgen substitution: Mesterolone (MES) 100 mg/d, testosterone undecanoate (TU) 160 mg/d, testosterone enanthate (TE) 250 mg i.m./21 days or 1200 mg crystalline testosterone (TPEL) subcutaneously implanted at study begin. Previous testosterone medication had been suspended at least 3 months prior to study begin. Testosterone (T), dihydrotestosterone (DHT), hemoglobin (HB) and hematocrit (HC) were assessed before, during and after substitution of androgens. MES did not increase serum T and TU raised average T levels during substitution to 5.7 +/- 0.3 nmol/l, thereby doubling baseline concentrations. TE resulted in a 6fold increase of baseline T yielding 13.5 +/- 0.7 nmol/l and TPEL increased serum T 8.5fold to 23.2 +/- 1.1 nmol/l. Average DHT levels during substitution were 4.3 +/- 0.2 (MES), 3.3 +/- 0.2 (TU), 4.0 +/- 0.4 (TE) and 5.5 +/- 0.4 (TPEL) nmol/l. The groups receiving TPEL, TU or TE showed a significant rise of HB and HC compared to baseline, whereas in the MES group these parameters did not change significantly. MES increased HB by 5.6 +/- 1.8 g/l, TU by 12.7 +/- 2.8 g/l, TE by 21.1 +/- 2.6 g/l and TPEL by 21.7 +/- 4.0 g/l. HC was raised by 1.8 +/- 0. 4% in the MES group, 3.9 +/- 1.1% in the TU group and 6.4 +/- 0.9% and 6.5 +/- 1.6% in the TE and TPEL groups, respectively. Except for 1 subject in the TPEL group, the HB and HC stayed within the normal limits. We conclude that, T, but not DHT, stimulates erythropoiesis in a dose dependent manner. T levels within the low normal range for men are required for maximal stimulation of erythropoiesis.

Triiodothyronine (T3) reflects renal graft function after renal transplantation.

OBJECTIVE: Abnormalities in thyroid function are observed in patients with end stage renal disease. However, there are no data available evaluating sequential changes of thyroid function after renal transplantation. Therefore, we have studied thyroid hormone function in the immediate post-operative period after renal transplantation in order to determine the relationship between improving renal function and changes in thyroid hormone economy. DESIGN AND PATIENTS: Thyroid function was evaluated in 22 patients before and on days 1, 3, 7 and 15 after renal transplantation. All patients received prednisone and cyclosporin as immunosuppressive therapy. Twelve patients with normal renal function undergoing comparable surgical procedures served as a control group. MEASUREMENTS: Serum creatinine and thyroid hormone parameters (total T4, total T3, free T4, free T3, thyroxin binding globulin (TBG), reverse T3, T3 sulphate and TSH) were measured. RESULTS: According to post-operative kidney function after renal transplantation, patients could be subdivided into three groups: five patients had primary graft function (group I); seven patients had delayed graft function because of acute renal failure (group II); 10 patients had delayed graft function requiring high doses of prednisone and some also of OKT3 because of acute rejection (group III). There was a significant fall in T3 and T4 concentrations with a concomitant rise in reverse T3 in all patients up to 3 days after renal transplantation. However, only patients in group I reached pre-operative values on day 15 after renal transplantation (serum creatinine 167 +/- 52 microM), whereas patients in group II (creatinine 609 +/- 118 microM) and group III (creatinine 839 +/- 71 microM) continued to have T3 concentrations well in the hypothyroid range (group I, 1.68 +/- 0.28 nM) vs 0.87 +/- 0.09 nM in group II and 0.76 +/- 0.10 nM in group III; P < 0.01). Serum T4 concentrations were also low in group III (47.7 nM vs 100.2 nM in group I; P < 0.05) 15 days after renal transplantation. These changes were accompanied by a concomitant fall in T3/TBG ratio and in free T3. Elevated reverse T3 returned to normal values in all groups on the 15th day after renal transplantation. TSH fell significantly on the first post-operative day, but did not return to pre-operative values in renal transplantation patients. In the control group, TSH did not change during the study period. T3 sulphate, known to be elevated in chronic renal failure, remained above normal in all patients irrespective of graft function during this study period. CONCLUSIONS: T3 concentrations reflect renal graft function after renal transplantation. T3 is below normal in patients with delayed graft function (acute renal failure or acute rejection). The post-operative period (up to 3 days after renal transplantation) is associated with a low T3 syndrome. TSH does not return to pre-operative values even in patients with primary graft function. This might be due to the administration of prednisone. T3-sulphate is elevated before and after renal transplantation irrespective of graft function.

Significant changes in thyroid hormone parameters after a four week recreation period at the North Sea without alterations of iodine intake.

UNLABELLED: Many studies have been carried out evaluating thyroid hormone parameters in patients suffering from various illnessess. However data on thyroid function after a recreation period are missing. Therefore we evaluated thyroid hormone parameters in 178 patients (mostly suffering from chronic obstructive lung disease) undergoing a four week recreation period in a health spa on the island Borkum at the North Sea. We observed a subtle, but significant increase in basal TSH concentrations from 1.20 mU/l (median) to 1.50 mU/l; (p<0. 001) and a fall in T4 values from 97.5 +/- 17.7 nmol/l (mean +/- SD) to 90.3 +/- 17.0 (p<0.001) and T3 from 2.21 +/- 0.33 nmol/l to 2.09 +/- 0.33 (p<0.001). However no increase in iodine intake occurred during the four weeks: median iodine excretion 61 microg iodine/g creatinine at the beginning vs 65 microg iodine/g creatinine at the end. IN CONCLUSION: a recreation period at the North Sea is associated with subtle but significant changes in thyroid hormone parameters. However no increase in iodine intake occurs during the four week observation period.

Influence of coronary artery bypass surgery on thyroid hormone parameters.

UNLABELLED: The postoperative period after cardiac surgery with cardiopulmonary bypass (CPB) is associated with a low T3 syndrome, i.e. low T3 and fT3 concentrations in the presence of normal T4 and TSH concentrations. So far, results from studies evaluating thyroid function during and after CPB are rather conflicting. We therefore evaluated prospectively thyroid function in 28 patients before, during and up to 3 days after coronary artery bypass surgery. We could demonstrate the most significant changes in thyroid hormone concentrations on day 1 after CPB (low T3 and fT3 concentrations, elevated rT3 concentrations in the presence of a significant fall of TSH). T3 fell from 1.93 to 0.6 nmol/1 and fT3 from 5.5 to 1.42 pmol/1. Those patients with low cardiac output syndrome after surgery had significantly lower T3 concentrations than patients without this complication. Moreover, those patients, who already had significant lower T3 values prior to CPB, also demonstrated low T3 concentrations on day 1 after CPB. Cortisol usually has a suppressive effect on TSH secretion. However, the effect of cortisol on TSH in patients undergoing CPB seems to be not that important: those patients with high endogenous cortisol concentrations on day 1 after CPB had similar TSH values to those patients with only slightly elevated cortisol concentrations. Also, the application of high doses of catecholamines seems to have only minor effects on TSH secretion, because those patients requiring high doses of dopamine over a prolonged time period had essentially the same TSH values after CPB. Patients who had been exposed preoperatively to high doses of iodine did not demonstrate significantly different thyroid hormone concentrations. IN CONCLUSION: We could demonstrate that CPB induces a low T3 syndrome up to 3 days after surgery. Those patients with low T3 concentrations prior to surgery demonstrate postoperatively a more severe degree of nonthyroidal illness (NTI). Catecholamines and cortisol seem to have only minor effects on the TSH secretion after CPB. The influence of a previous iodine contamination is negligible.

[Thyroid hormone resistance: variable clinical manifestations in five patients]. / Schilddrüsen-Hormon-Resistenz: unterschiedlicher klinischer Ausprägungsgrad bei fünf Patienten.

AIM: The syndrome of thyroid hormone resistance (RTH) is characterised by elevated circulating thyroid hormones, unsuppressed TSH levels and peripheral refractoriness to hormone action. Patients with RTH may be clinically hyperthyroid if the pituitary gland is more insensitive than other tissues to thyroid hormones. More often, patients have peripheral tissue resistance as well and are euthyroid. RTH is related to point mutations in the T3-binding domain of the beta-receptor gene. We report the variable clinical and biochemical features of five patients with RTH. METHODS: Five patients with RTH were clinically and biochemically evaluated: thyroid tests were done at baseline, after TRH stimulation and after T3-suppression test. Thyroid ultrasound was performed as well. Individual exons of the thyroid hormone receptor beta gene were amplified from leucocyte DNA in these patients using the polymerase chain reaction (PCR). RESULTS: Sequence analysis identified a single point mutation at a certain nucleotide position. This corresponds to aminoacids substitutions at one position in the predicted aminoacid sequence. RTH was familial in three individuals and sporadic in two. Three of the patients underwent thyroid surgery or radioiodine treatment because of recurrent goiter and/or "refractory hyperthyroidism". Moreover, one of our patients with RTH developed also hyperthyroidism due to Graves disease and underwent thyroid surgery for the third time. Her brother, besides RTH, demonstrated strongly positive TPO-antibodies and a hypoechogenic pattern on ultrasound. So the diagnosis of Hashimoto's thyroiditis was made. CONCLUSIONS: RTH has to be considered in all patients with inappropriate TSH secretion. The clinical manifestation of patients with RTH is heterogenous. Thyroid antibody measurements should be performed regularly in order to detect the development of coexisting autoimmune thyroid disease.

Pharmacokinetics and pharmacodynamics of subcutaneous testosterone implants in hypogonadal men.

OBJECTIVE: There are advantages and disadvantages with all of the presently available types of testosterone replacement for hypogonadal men. We performed this investigation to establish detailed data about the pharmacokinetics, pharmacodynamics, feasibility and side-effects of subcutaneously implanted testosterone (T) pellets. DESIGN AND MEASUREMENT: In a single-dose, open-label, non-randomized study, 6 T-pellets, each containing 200 mg of fused crystalline T, were implanted in the subdermal fat tissue of the lower abdominal wall of 14 hypogonadal men. Blood samples for determination of T, LH, FSH, 5 alpha-dihydrotestosterone (DHT), sex hormone binding globulin (SHBG) and oestradiol (E2) were obtained at 0, 0.5, 1, 2, 4, 8, 12, 24, 36, 48 hours and on day 21 after implantation and then every 3 weeks until day 189, and on days 246 and 300 during follow-up. In another 36 hypogonadal men the feasibility and side-effects of T-pellets were evaluated. PATIENTS: Fourteen patients participated in the detailed pharmacokinetic study and another 36 patients in the assessment of feasibility and side-effects. All patients (age range 18-61 years) suffered from primary or secondary hypogonadism (T < 3.6 nmol/l). RESULTS: The pharmacokinetic study in 14 hypogonadal men revealed an initial short-lived burst release of T with a peak concentration of 49.0 +/- 3.7 nmol/l at 0.5 +/- 0.13 days which was followed by a stable plateau lasting until day 63 (day 2, 35.2 +/- 2.3; day 63, 34.8 +/- 2.6 nmol/l). Thereafter serum T gradually declined and was close to baseline concentrations on day 300. Apparent terminal elimination half-life (t1/2) was 70.8 +/- 10.7 days and apparent mean residence time 87.0 +/- 4.5 days. On average, serum T was below 10 nmol/l after 180 days. Absorption of T followed a zero-order release kinetic with an absorption half-time of 74.7 days (95% confidence interval: 71.1-78.5) and was almost complete by day 189 (95.9 +/- 0.84%). Serum DHT and E2 were significantly elevated from day 21 to day 105 and correlated significantly with T (DHT, r = 0.65, P < 0.0001, E2, r = 0.67, P < 0.0001). SHBG was significantly decreased from day 21 to day 168. In 6 men with primary hypogonadism T suppressed LH and FSH to the eugonadal range from day 21 to 126 and 42 to 105, respectively, with nadirs occurring at day 84 (LH) and day 63 (FSH). LH and FSH were highly inversely correlated with T (r = -0.47 and -0.57). The only side-effect observed during 112 implantations in the total group of 50 men were 6 local infections (5.4%) leading to extrusion of 5 pellets in 3 men. When given the choice, all patients except one preferred T-pellets to their previous T medication for permanent substitution therapy. CONCLUSION: T-pellets are the androgen formulation with the longest biological action and strongest pharmacodynamic efficacy in terms of gonadotrophin suppression. The pharmacokinetic features are advantageous compared to other T preparations and the patient acceptance is high.

Differential presentation of cortical and trabecular peripheral bone mineral density in acromegaly.

Growth hormone (GH) has been suggested as a therapeutic tool for the treatment of osteopenia. To assess the differential influence of growth hormone on cortical and trabecular bone, bone mineral densities (BMD) of the ultradistal radius were determined in 18 men and 19 women with clinically and biochemically confirmed acromegaly using peripheral computed tomography and a specialized scanner (Stratec XCT 900). The results were expressed in equivalents to hydroxyl-apatite (mg/ccm) and compared with the BMD of healthy controls (17 men, 34 women). Cortical bone mineral density was significantly higher in acromegalic women (295.2 +/- 18.4, X +/- SEM) and men (339.4 +/- 21.2) compared to healthy women (243.0 +/- 12.8) and men (272.2 +/- 15.9). In contrast, trabecular BMD did not differ between acromegalic patients (men: 161.0 +/- 16.1; women: 116.5 +/- 10.5) and controls (men: 158.0 +/- 12.2; women: 134.1 +/- 6.3). Acromegalic women showed a significant correlation between insulin-like growth factor (IGF-I) expression and cortical BMD, whereas in acromegalic men GH levels correlated significantly with cortical BMD. Greatly increased serum osteocalcin levels in both, acromegalic men (15.5 +/- 3.3 ng/ml) and women (12.9 +/- 1.8) compared to controls (men: 6.7 +/- 1.7; women: 7.7 +/- 1.0) indicates the activation of osteoblastic bone formation. This study revealed an increase in cortical BMD at the forearm; in acromegalic patients; though trabecular BMD did not differ from controls. The differential mineralization of cortical and trabecular bone in acromegaly may be indicative of the detrimental effect accompanying pituitary insufficiency can have on trabecular bone, despite substitution therapy, but could also be due to different reactivity of cortical and trabecular bone to GH and/or IGF I. The observable increase of bone mineral density in acromegaly suggests a potential use for GH in treating osteoporosis.

Response to methimazole in Graves' disease. The European Multicenter Study Group.

OBJECTIVE: A variety of regimens continue to be used in the treatment of Graves' disease with antithyroid drugs. We have investigated the factors which determine the initial response to methimazole (time until euthyroidism is achieved) in Graves' disease. PATIENTS: Five hundred and nine patients with Graves' disease in different European countries with normal and subnormal iodine supply. Patients were randomized to treatment with either 10 or 40 mg of methimazole per day for one year, with levothyroxine supplementation as required to maintain euthyroidism. Investigations were carried out before treatment and at 3 and 6 weeks and 3, 6, 9 and 12 months. MEASUREMENTS: Response was assessed by serial measurements of serum thyroid hormones. TSH receptor antibodies, thyroid autoantibodies and urinary iodide excretion were measured centrally. Twenty-minute thyroid uptake was measured by standard techniques. Data were collected and analysed centrally. Standard techniques as well as a stepwise logistic regression model were used to examine the relations between methimazole dose, age, goitre size, presence of endocrine eye signs, thyroid hormone levels, urinary iodide excretion, thyroid uptake, index of disease severity (Crooks), presence of TSH receptor antibodies and duration of the hyperthyroid phase. RESULTS: Within 3 weeks, 40.2% of patients responded to 10 mg of methimazole and 77.5% responded within 6 weeks. The corresponding figures for 40 mg of methimazole were 64.6 and 92.6%. Significant associations were found between duration of hyperthyroidism and the following variables: goitre size, urinary iodide excretion, methimazole dose, presence of TSH receptor antibodies (TBIAb), index of disease severity (Crooks) and pretreatment thyroid hormone levels. Response to methimazole was delayed in patients with large goitres, iodine excretion of > or = 100 micrograms/g creatinine, high pretreatment thyroid hormone levels, elevated levels of TBIAb and treatment with only 10 mg of methimazole. In the 10-mg group, 46% of patients were euthyroid within 3 weeks when urinary iodide was < 50 microgram/g of creatinine, and only 27% when iodide was above 100 micrograms/g. By stepwise logistic regression, the main factors for the response to methimazole were daily dose, pretreatment T3 levels, and goitre size. CONCLUSION: Methimazole dose, pretreatment serum T3 levels, and goitre size are the main determinants of the therapeutic response to methimazole in Graves' disease, at least in areas comprising low, subnormal and normal iodine supply.

Effectiveness of prophylactic therapy on goiter recurrence in an area with low iodine intake--a sonographic follow-up study.

There is no agreement as to whether or not drug treatment after surgery for nodular goiter is effective in preventing recurrence of goiter. Data about recurrences in areas of marginally low iodine intake (like Germany) vary widely. Therefore, we performed a retrospective study in 104 patients who had been treated surgically because of benign uninodular or multinodular goiter. The mean follow-up period was 6.4 years (minimal 1 year) with at least three examinations. Thyroid ultrasound with volumetric analysis was recorded in each patient. Thirty-two patients did not receive any prophylaxis, 50 patients were treated with L-thyroxine, 17 patients with a combination of L-thyroxine and iodine and 5 patients with iodine alone. Recurrence of goiter was documented in 28.0% of the untreated patients and in 8.9% of the patients on prophylaxis (P < 0.05). The mean increase of thyroid volume was 7.3 ml versus 3.1 ml in patients without versus with prophylactic drug treatment (not significant). No significant correlation was found between the increase of thyroid volume and age of the patients, follow-up time, or initial thyroid volume, respectively. These data clearly demonstrate the effectiveness of prophylactic drug therapy to prevent recurrence of goiter after thyroid surgery in an iodine-deficient area.