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Oliver Klefter and Ulla Feldt-Rasmussen

Objective

Adult patients with GH deficiency (GHD) are characterized by a reduced muscle mass, but also reduced bone mineral density (BMD) and content (BMC), which have been ascribed to GHD per se.

The aim of this study was to investigate if changes in BMD/BMC in adult GHD patients could be due to a muscle modulating effect, and if treatment with GH would primarily increase muscle mass and strength with a secondary increase in BMD/BMC, thus supporting the present physiological concept that mass and strength of bones are mainly determined by dynamic loads from the skeletal muscles.

Method

We performed a systematic literature analysis, including 51 clinical trials published between 1996 and 2008, which had studied the development in muscle mass, muscle strength, BMD, and/or BMC in GH-treated adult GHD patients.

Results

GH therapy had an anabolic effect on skeletal muscle. The largest increase in muscle mass occurred during the first 12 months of therapy.

Most trials measuring BMD/BMC reported significant increases from baseline values. The significant increases in BMD/BMC occurred after 12–18 months of treatment, i.e. usually later than the increases in muscle parameters. Only seven trials studied both muscle and bone variables concomitantly. No trials studied the relationship between the changes in muscle and bone measurements.

Conclusion

Although in vitro studies have shown that GH has a direct effect on bone remodeling, present physiological concepts and the results of clinical trials from 1996 to 2008 suggest that the anabolic changes in muscle mass and strength may also contribute to changes in BMD/BMC in GH-treated adult GHD patients.

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Ulla Feldt-Rasmussen, Karine Bech and John Date

ABSTRACT

To study serum thyroglobulin (Tg) levels in patients with thyroid disorders compared to sex- and age-matched control subjects and to correlate the Tg levels to the thyroid function, 71 patients were investigated before treatment was started.

Serum Tg, measured by a double antibody radioimmunoassay, was elevated in all groups with thyroid disorders, as compared to their controls, but the values showed large overlaps between groups. The highest median values were seen in the two groups of patients with toxic goitres (toxic adenoma and Graves' disease). The Tg values in patients with non-toxic goitres (diffuse and nodular) and in controls showed a log normal distribution, whereas the distribution of values from patients with toxic goitres was different. No correlation was found between serum Tg and serum thyroxine, serum triiodothyronine and serum TSH, respectively.

It is concluded that determination of serum Tg is of little diagnostic value in thyroid diseases.

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Ulla Feldt-Rasmussen, Per Hyltoft Petersen and John Date

ABSTRACT

The aim of the present investigation was to describe variations in serum thyroglobulin in relation to sex and age in a group of normal persons. The method used was a modified double antibody radioimmunoassay characterized by pre-incubation at 37°C of standard or sample with antiserum, resulting in a reduced total incubation time. Both sensitivity and precision were comparable to other published methods.

Of the 152 blood-donors initially investigated, 7 were excluded due to the presence of antithyroglobulin antibodies as evidenced by a radioassay. Both sexes were equally represented with an even distribution of ages from 20-65 years.

Increased serum thyroglobulin with increasing age was demonstrated, the correlation being significant in women (Kendall's τ, P < 0.001). Detectable concentrations of serum thyroglobulin (above 1.7 μg/l) were found in 94 %. Based on the logarithmic transformation, the upper reference limits were determined for men ≦ 40 years: 36 μg/l, > 40 years: 44 μg/l (difference between groups not significant, P > 0.05), and for women ≦ 40 years: 30 μg/l, > 40 years: 60 μg/l (significant difference, P < 0.005).

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Jøgen Petersen, Ulla Feldt-Rasmussen, Flemming Larsen and Kai Siersbæk-Nielsen

Abstract. Blood mononuclear cells (MNC) from 21 patients with autoimmune thyroiditis were assayed for secretion of immunoglobulins in vitro by a reverse haemolytic plaque forming cell (PFC) assay. An anti-gen-specific assay was employed to quantify anti-thyroglobulin antibody (TgAb) secreting cells. The sensitivities of the two PFC assays were similar. The antigen specificity of the Tg-PFC assay was demonstrated by the ability of free Tg to inhibit PFC formation.

The number of spontaneous TgAb-secreting cells was low (median 3 IgG-Tg-PFC/106, range 0–35/106); TgAb activity was found in 3% (range 0–11%) of total IgG-PFC. The number of spontaneous IgG-TgAb-secreting cells correlated positively to TgAb titres in serum. MNC from most patients secreted IgG-TgAb upon polyclonal stimulation in vitro for six days with pokeweed mitogen (52 IgG-Tg-PFC/106, range 0–478/106); TgAb activity was found among 2% (range 0–8%) of total IgG-PFC. Again, pokeweed mitogen-induced TgAb secretion correlated positively to TgAb titres in serum. Finally, MNC from most patients secreted TgAb after culture with Tg. The Tg-induced response was about 1/3 of the pokeweed mitogen-induced TgAb response. Tg did not increase the production of total IgG indicating that Tg is not a polyclonal stimulus. Few TgAb-secreting MNC were discovered in euthyroid sex and age-matched control patients.

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Ulla Feldt-Rasmussen, Laszlo Hegedüs, Jens M. Hansen and Hans Perrild

Abstract. Twenty-five patients with non-toxic diffuse goitre were studied during and after 12 months of treatment with 60 μg triiodothyronine daily in order to see whether a correlation could be found between the reductions of thyroid volume, using ultrasonic scanning, and serum thyroglobulin. Thyroid function tests and thyroid volume determination were performed before treatment and after 3, 6 and 12 months of therapy in 19 patients (group 1). In patients of group 2 (n = 19) the same tests were performed at the end of 12 months treatment and 6 and 12 months after withdrawal. Before treatment all patients had a significantly increased thyroid volume compared to controls matched according to sex, age and body weight (P < 0.001). Serum thyroglobulin was elevated compared to controls (P < 0.02), with a significantly positive correlation to the thyroid volume (Spearmann's Rho = 0.52, P < 0.02). Both serum thyroglobulin and thyroid volume decreased during treatment in the majority of the patients, concomitantly in approximately half of them. After withdrawal of treatment (group 2) serum thyroglobulin showed a median increase of 54% after 6 months and remained unchanged thereafter, whereas the thyroid volume was unchanged after 6 months. These findings might support the concept that the regulation of thyroid growth and of protein synthesis and degradation might be determined by different factors.

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Nini G. Rasmussen, Peter J. Hornnes, Laszlo Hegedüs and Ulla Feldt-Rasmussen

Abstract.

Serum thyroglobulin, TSH, thyroid hormones and thyroid volume were investigated during the menstrual cycle in 10 healthy females (day 2, 9, 16, 23 and day 2 of next cycle), during pregnancy (week 18, 24, 30 and 36) and post partum (1, 2, 3, 6 and 12 months) in 20 healthy females. During the menstrual cycle median serum thyroglobulin increased from 27 (day 2) to 32 μg/l (day 23, p < 0.01 ). Serum TSH and thyroid volume demonstrated a similar increase with a positive correlation between serum thyroglobulin and thyroid volume (r = 0.65, p < 0.02). Median serum thyroglobulin was significantly increased during the whole pregnancy (week 36, 73 μg/l) compared with post partum (1 month post partum, 22 μg/l, p < 0.01), as was thyroid volume. Serum TSH was unaltered and free thyroid hormone indices decreased during pregnancy compared with post partum. No relation between changes in serum thyroglobulin and thyroid volume, TSH or thyroid hormones could be demonstrated. Serum thyroglobulin alterations thus were related to alterations in TSH and thyroid volume during the menstrual cycle. However, the increase in serum thyroglobulin and thyroid volume during pregnancy were unrelated to changes in serum TSH, indicating other mechanisms of regulation than TSH. When interpreting serum thyroglobulin levels in women, the co-existence of pregnancy and time of menstrual cycle should be taken into account in order to avoid misinterpretation of results.

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Nini G. Rasmussen, Peter J. Hornnes, Mimi Høier-Madsen, Ulla Feldt-Rasmussen and Laszlo Hegedüs

Abstract.

In a study of postpartum thyroiditis, thyroid function and ultrasonically determined thyroid size were evaluated in 36 thyroid autoantibody positive healthy women during pregnancy and the first postpartum year. Twelve women (33%) developed postpartum thyroiditis with permanent thyroid dysfunction in three. However, only one woman had symptoms and needed treatment. The most common type of thyroid dysfunction was a transient hyperthyroid phase as seen in 7 women. A significant increase by 20-30% in mean thyroid volume during pregnancy was demonstrated independent of development of postpartum thyroiditis. We conclude that initial thyroid volume or changes during pregnancy and post partum are not useful indicators of the development of postpartum thyroiditis. The fact that the condition is oligosymptomatic suggests that screening procedures are necessary if one wants to diagnose the earliest phases of postpartum thyroiditis.

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Ulla Feldt-Rasmussen, Axel P. Lange, John Date and Mogens Kern Hansen

ABSTRACT

To study the effect on thyroid function 100 mg of clomifene citrate was given once a day to two groups of healthy male volunteers for 5 and 12 consecutive days, respectively.

In both groups serum concentrations of TSH, thyroxine, triiodothyronine, T3 resin uptake test and thyroid hormone binding proteins were measured before, during and after oral administration of clomifene. The effect of clomifene treatment was evaluated in Group 1 by means of serum FSH and LH measurements. Further in Group 2 the serum TSH response to iv TRH (200 μg) was also investigated.

The mean per cent elevations in serum concentrations of FSH and LH were 145 and 200, respectively. In Group 1 a small but statistically significant decrease within reference limits in triiodothyronine (P < 0.01) and free thyroxine index (P < 0.02) was found on day 4 of clomifene. On day 5 a slight increase in TSH was observed (P < 0.05). In Group 2 the response of TSH to TRH showed a non-significant increase after 5 days and a significant increase (P < 0.01) after 12 days of clomifene. Eight days after discontinuation of the drug the response was restored to normal. No changes in the thyroid hormone binding proteins in serum could be demonstrated. Though the observed changes were slight, they indicate that clomifene exerts an influence directly on the thyroid function.

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Line Pickering, Poul Jennum, Steen Gammeltoft, Lars Poulsgaard, Ulla Feldt-Rasmussen and Marianne Klose

Objective

To assess the influence of craniopharyngioma or consequent surgery on melatonin secretion, and the association with fatigue, sleepiness, sleep pattern and sleep quality.

Design

Cross-sectional study.

Methods

A total of 15 craniopharyngioma patients were individually matched to healthy controls. In this study, 24-h salivary melatonin and cortisol were measured. Sleep–wake patterns were characterised by actigraphy and sleep diaries recorded for 2 weeks. Sleepiness, fatigue, sleep quality and general health were assessed by Multidimensional Fatigue Inventory, Pittsburgh Sleep Quality Index, Epworth Sleepiness Scale and Short-Form 36.

Results

Patients had increased mental fatigue, daytime dysfunction, sleep latency and lower general health (all, P≤0.05), and they tended to have increased daytime sleepiness, general fatigue and impaired sleep quality compared with controls. The degree of hypothalamic injury was associated with an increased BMI and lower mental health (P=0.01). High BMI was associated with increased daytime sleepiness, daytime dysfunction, mental fatigue and lower mental health (all, P≤0.01). Low midnight melatonin was associated with reduced sleep time and efficiency (P≤0.03) and a tendency for increased sleepiness, impaired sleep quality and physical health. Midnight melatonin remained independently related to sleep time after adjustment for cortisol. Three different patterns of melatonin profiles were observed; normal (n=6), absent midnight peak (n=6) and phase-shifted peak (n=2). Only patients with absent midnight peak had impaired sleep quality, increased daytime sleepiness and general and mental fatigue.

Conclusion

Craniopharyngioma patients present with changes in circadian pattern and daytime symptoms, which may be due to the influence of the craniopharyngioma or its treatment on the hypothalamic circadian and sleep regulatory nuclei.

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Hans Perrild, Anette Grüters-Kieslich, Ulla Feldt-Rasmussen, David Grant, Enio Martino, Lars Kayser and Francois Delange

Perrild H, Grüters-Kieslich A, Feldt-Rasmussen U, Grant D, Martino E, Kayser L, Delange F. Diagnosis and treatment of thyrotoxicosis in childhood. A European questionnaire study. Eur J Endocrinol 1994;131:467–73. ISSN 0804–4643

A covering letter and a questionnaire covering the diagnosis and treatment of thyrotoxicosis in childhood was circulated between October 1992 and February 1993 amongst 672 European members of the European Thyroid Association (ETA) and members of the European Society for Pediatric Endocrinology (ESPE). Almost 50% replied to the letter and 99 individuals or groups from 22 countries completed the questionnaire. A consensus was reached on the use of total thyroxine (T4) and/or free T4 and thyrotropin as routine diagnostic tools. Two-thirds included total triiodothyronine (T3) and/or free T3 and 32% used a thyrotropin-releasing hormone test. Surprisingly, thyroglobulin autoantibodies were used as a routine test by 78%; 63% included thyrotropin receptor antibodies and 60% microsomal antibodies, whereas only 50% measured thyroperoxidase antibodies. For thyroid imaging, 40% performed a thyroid scintigram and 56% measured the size of the thyroid gland by ultrasound. Antithyroid drugs (ATD) were the basic initial treatment of choice given by 99% of the respondents for children with uncomplicated Graves' disease. Carbimazole, methimazole and thiamazole were the most frequently used drugs, with a median initial dose of 0.8 mg · kg1 · day1. Two-thirds added betablockers and a few used sedatives. The ATD dose was adjusted for each patient by 39%, whereas 56% combined ATD with T4 for long-term treatment; 84% gave treatment for a fixed period (44% for 1–2 years). Surgery was considered the treatment of choice in children with an adenoma (83%), with a nodular (53%) or large goiter (16%) and recurrence after ATD (14%). Radioiodine was the treatment of choice by 18% of the respondents for patients with recurrence after surgery and recurrence after ATD (7%).

Hans Perrild, Department of Medicine B, Bispebjerg University Hospital, 2400 Copenhagen, Denmark