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  • Author: Ulla Feldt-Rasmussen x
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Is increase in bone mineral content caused by increase in skeletal muscle mass/strength in adult patients with GH-treated GH deficiency? A systematic literature analysis

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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SEX AND AGE CORRELATED REFERENCE VALUES OF SERUM THYROGLOBULIN MEASURED BY A MODIFIED RADIOIMMUNOASSAY

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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SERUM THYROGLOBULIN IN PATIENTS WITH TOXIC AND NON-TOXIC GOITRES COMPARED TO SEX- AND AGE-MATCHED CONTROL SUBJECTS

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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Serum thyroglobulin during the menstrual cycle, during pregnancy, and post partum

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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EFFECT OF CLOMIFENE ON THYROID FUNCTION IN NORMAL MEN

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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Relationship between thyroid volume and serum thyroglobulin during long-term suppression with triiodothyronine in patients with diffuse non-toxic goitre

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.

Free access

Early endocrine alterations reflect prolonged stress and relate to 1-year functional outcome in patients with severe brain injury

Djordje Marina, Marianne Klose, Annette Nordenbo, Annette Liebach, and Ulla Feldt-Rasmussen

Objective

Severe brain injury may increase the risk of developing acute and chronic hypopituitarism. Pituitary hormone alterations developed in the early recovery phase after brain injury may have implications for long-term functional recovery. The objective of the present study was to assess the pattern and prevalence of pituitary hormone alterations 3 months after a severe brain injury with relation to functional outcome at a 1-year follow-up.

Design

Prospective study at a tertiary university referral centre.

Methods

A total of 163 patients admitted to neurorehabilitation after severe traumatic brain injury (TBI, n=111) or non-TBI (n=52) were included. The main outcome measures were endocrine alterations 3.3 months (median) after the brain injury and their relationship to the functioning and ability of the patients at a 1-year follow-up, as measured by the Functional Independence Measure and the Glasgow Outcome Scale-Extended.

Results

Three months after the injury, elevated stress hormones (i.e. 30 min stimulated cortisol, prolactin and/or IGF1) and/or suppressed gonadal or thyroid hormones were recorded in 68 and 32% of the patients respectively. At 1 year after the injury, lower functioning level (Functional Independence Measure) and lower capability of performing normal life activities (Glasgow Outcome Scale-Extended) were related to both the elevated stress hormones (P≤0.01) and the reduced gonadal and/or thyroid hormones (P≤0.01) measured at 3 months.

Conclusion

The present study suggests that brain injury-related endocrine alterations that mimic secondary hypogonadism and hypothyroidism and that occur with elevated stress hormones most probably reflect a prolonged stress response 2–5 months after severe brain injury, rather than pituitary insufficiency per se. These endocrine alterations thus seem to reflect a more severe disease state and relate to 1-year functional outcome.

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Autoreactive lymphocytes in thyroid disorders. Quantitation of anti-thyroglobulin antibody formation by a specific haemolytic plaque forming cell (PFC) assay

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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Environmental chemicals and thyroid function

Malene Boas, Ulla Feldt-Rasmussen, Niels E Skakkebæk, and Katharina M Main

There is growing evidence that environmental chemicals can disrupt endocrine systems. Most evidence originates from studies on reproductive organs. However, there is also suspicion that thyroid homeostasis may be disrupted. Several groups of chemicals have potential for thyroid disruption. There is substantial evidence that polychlorinated biphenyls, dioxins and furans cause hypothyroidism in exposed animals and that environmentally occurring doses affect human thyroid homeostasis. Similarly, flame retardants reduce peripheral thyroid hormone (TH) levels in rodents, but human studies are scarce. Studies also indicate thyroid-disruptive properties of phthalates, but the effect of certain phthalates seems to be stimulative on TH production, contrary to most other groups of chemicals. Thyroid disruption may be caused by a variety of mechanisms, as different chemicals interfere with the hypothalamic–pituitary–thyroid axis at different levels. Mechanisms of action may involve the sodium–iodide symporter, thyroid peroxidase enzyme, receptors for THs or TSH, transport proteins or cellular uptake mechanisms. The peripheral metabolism of the THs can be affected through effects on iodothyronine deiodinases or hepatic enzymes. Even small changes in thyroid homeostasis may adversely affect human health, and especially fetal neurological development may be vulnerable. It is therefore urgent to clarify whether the animal data showing effects of chemicals on thyroid function can be extended to humans.

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Thyroid size and function in healthy pregnant women with thyroid autoantibodies. Relation to development of postpartum thyroiditis

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.