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Endocrinology Vol. 144, No. 6 2553-2558
Copyright © 2003 by The Endocrine Society

Dexamethasone Differentially Inhibits Thyroxine- or Growth Hormone-Induced Body and Organ Growth of Snell Dwarf Mice

Raoul P. A. Rooman, Gilliam Kuijpers, Ria Gresnigt, Ruud Bloemen, Johanna G. Koster and Sylvia C. van Buul-Offers

Department of Pediatric Endocrinology, University Medical Center, 3508 AB Utrecht, The Netherlands

Address all correspondence and requests for reprints to: Raoul Rooman, M.D., Department of Pediatrics, Antwerp University Hospital, Wilrijkstraat 10, B-2650 Edegem, Belgium. E-mail: raoul.rooman{at}uza.be.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Supraphysiological doses of glucocorticoids cause growth retardation in both animals and humans. Many studies have addressed the interaction of glucocorticoids with the GH/IGF system, but little is known about the effect of glucocorticoids on T4-stimulated growth. The Snell dwarf mouse is deficient in GH, thyroid-stimulating hormone, and prolactin and therefore allows the study of the effect of glucocorticoids on the growth induced by GH and T4 without their mutual interaction. Four weeks of treatment with T4 (1 µg/d) or human GH (50 mU/d) equally increased nose-tail length (3.1 ± 0.1 cm and 3.0 ± 0.2 cm, respectively). Dexamethasone (DXM) had much less impact on T4-stimulated growth than on GH-induced growth (T4 + DXM: 2.4 ± 0.1 cm vs. GH+ DXM: 1.4 ± 0.1 cm). Similar data were obtained for body weight gain. T4 and GH had a different effect on the weight of various organs: GH caused a higher increase in liver and lumbar vertebrae weight, and T4 was a better stimulator for kidney (P < 0.05), thymus, and spleen growth. Remarkably, T4-stimulated growth of the organs was less affected by DXM than GH-induced organ growth. GH even potentiated the growth inhibition by DXM in the thymus and tibia. In conclusion, T4-stimulated growth in Snell dwarf mice is less affected by DXM than growth stimulated by GH


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
GLUCOCORTICOIDS CAUSE GROWTH retardation when used in supraphysiological amounts in children with chronic illness (1, 2). There is a lot of controversy on the mechanism by which glucocorticoids stunt growth. Most investigators have focused on the interaction of glucocorticoids with the GH/IGF/growth plate axis (3, 4, 5), but very little is known about the interference of glucocorticoids with T4-stimulated growth. An important problem is the extensive cross-talk that exists between T4 and GH (6). In intact mice, the administration of GH will alter thyroid hormone metabolism. Conversely, treatment with thyroid hormone would increase GH synthesis (7).

To avoid this mutual interaction, we used the Snell dwarf mouse model (8). Snell dwarf mice have a mutation in the PIT-1 gene, rendering them deficient in GH, TSH, and prolactin. The mice can be stimulated to grow by either GH or T4 (9), but GH cannot alter T4 production, and T4 fails to increase serum IGF-I concentrations (10).

In this study we compared the effect of dexamethasone on GH and T4-stimulated growth of Snell dwarf mice.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Materials
BSA and T4 were obtained from Sigma (St. Louis, MO). Recombinant human GH (hGH) was kindly provided by Pharmacia-Upjohn (Woerden, The Netherlands).

T4 was dissolved in 0.1 M NaOH. The pH was adjusted to pH 7.4 with HCl, and the solution was diluted in PBS, pH 7.4, containing 0.2% BSA.

The hGH and dexamethasone (DXM) were also dissolved in PBS with 0.2% BSA.

Animals
Snell dwarf mice were bred and kept under standardized conditions in accordance with the NIH guidelines for the care and use of laboratory animals as described earlier (11, 12). The experimental protocol was approved by the Committee for Animal Experiments of the University Medical Center Utrecht.

Experimental design
Because of the limited amount of dwarf mice (dw/dw) in each litter, the study was subdivided into four separate experiments. In each experiment mice 6–8 wk old were divided into groups of four or five animals ensuring equal means and SDs for body length and weight in each group at the start of the experiment. Care was also taken to obtain an equal number of male and female animals in each group.

Because there was no significant difference in body length and body weight at the start of each experiment and at the end of the experiment in the controls, the data from all the animals were pooled for further analysis. Because each individual experiment contained a control and a hormone-stimulated group, the number of mice is different in the various treatment groups.

The animals were injected once a day, 5 d/wk, sc in the neck with vehicle (PBS, pH 7.4, n = 15); DXM 10 µg (n = 9); T4 1 µg (n = 9); hGH 50 mU (n = 10); DXM 10 µg + T4 1 µg (n = 4); or DXM 10 µg + hGH 50 mU (n = 5) for a total time of 4 wk.

The animals were measured and weighed every week. Nose-tail length was determined under ether anesthesia by the method of Hughes and Tanner (13). After 4 wk, the mice were killed by cervical dislocation under ether anesthesia 2 h after the last injection. Organs were immediately removed, frozen in liquid nitrogen, and weighed to the nearest milligram. The tibiae were carefully dissected out and cleared from adjacent muscle. The length of the tibia was determined on frozen bones using a caliper calibrated to 0.05 mm. The lumbar vertebrae were immersed overnight in 100% ethanol:ether (1:1), dried, and weighed to minimize the contribution of muscle tissue (14).

Statistical analysis
The differences among the groups were analyzed by a two-tailed t test.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Effects on body length and body weight (Fig. 1Go)
The increment in length during the 4-wk treatment period is shown in Fig. 1Go, A and B. Control animals grew only 0.9 ± 0.2 cm (mean ± SE of the mean) in 4 wk, as expected for Snell dwarf mice (11). DXM inhibited growth almost completely (0.3 ± 0.1 cm, P <= 0.05 vs. PBS group). T4 (1 µg/d) and hGH (50 mU/d) were found to significantly increase nose-tail length by 3.1 ± 0.1 cm and 3.0 ± 0.2 cm, respectively, after 4 wk of treatment (not statistically different between T4 and GH). Mice simultaneously treated with GH and DXM grew better than mice who received DXM alone (DXM + GH: 1.4 ± 0.1 cm vs. DXM: 0.3 ± 0.1 cm, P <= 0.05), but their nose-tail length remained significantly shorter than in mice treated with GH alone. T4 was more potent to reverse DXM-induced growth arrest than GH (T4 + DXM: 2.4 ± 0.1 cm vs. DXM: 0.3 ± 0.1 cm, P <= 0.05) (T4 + DXM: 2.4 ± 0.1 cm vs. DXM + GH: 1.4 ± 0.1 cm, P <= 0.05). Very similar data were obtained for body weight gain (Fig. 1Go, C and D).



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  		Figure 1. Increase in body length (A and B) and body weight (C and D) during 4 wk of treatment with PBS ({diamondsuit}), DXM 10 µg/d ({square}), 1 µg T4({blacktriangleup}), DXM + T4 ({bullet}), hGH 50 mU/d ({triangleup}), or DXM + hGH ({circ}). Results are means and SEs. Symbols indicate a P <= 0.05 by t test after 4 wk of treatment, compared with PBS controls (*), DXM alone ($), or DXM + T4 vs. T4 or DXM + GH vs. GH alone (§). Note: Not all significant differences are shown, but only the relevant differences are indicated.

 
At the end of treatment, weight for length was significantly lower in the DXM-treated animals, and T4, but not GH, significantly increased weight for length when given simultaneously with DXM (Fig. 2Go).



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  		Figure 2. Weight by length, tibia length, and selected bone and organ weights after 4 wk of treatment. Results are means and SEs. Symbols indicate a P <= 0.05 by t test after 4 wk of treatment, compared with PBS controls (*), DXM alone ($), or DXM + T4 vs. T4 or DXM + GH vs. GH alone (§), GH vs. T4 (£), DXM + T4 vs. DXM + GH (#). Note: Not all significant differences are shown, but only the relevant differences are indicated.

 
Effects on the tibia and lumbar vertebrae (Fig. 2Go)
The differences in total body length in the different treatment groups were also reflected in the length of the tibia. DXM had no effect on the length or weight of the tibia but both GH and T4 increased tibia length and weight significantly, compared with PBS controls. T4 also significantly increased tibia length in animals cotreated with DXM. Surprisingly, when GH and DXM were combined, the tibiae became even shorter than with DXM alone. Similar results were obtained for the weight of the tibia.

The dry weight of the lumbar vertebrae was reduced by DXM and significantly increased by GH and T4. Cotreatment with DXM significantly reduced the effect of GH but had less impact on the T4-stimulated weight gain. However, both hormones significantly increased lumbar vertebrae dry weight, compared with mice treated with DXM alone.

Effects on various organs (Fig. 2Go)
Although T4 and hGH almost identically stimulated total body length and weight, their effect on the various organs was different.

DXM alone did not change liver weight, but both GH and T4 significantly increased liver weight; however, this growth stimulation was completely abolished by DXM.

Kidney weight was greatly increased by T4 and GH, but 1 µg T4 was a better growth stimulator than 50 mU GH. DXM alone had no effect on kidney weight, but it reduced T4-stimulated growth by 40% and GH-induced growth by 50%.

The weight of the spleen was reduced to 56% by DXM and strongly increased by T4 and GH. T4 was still able to increase the weight of the spleen in the presence of DXM. In contrast, GH-induced growth of the spleen was completely wiped out by DXM.

DXM reduced the weight of the thymus to less than 20%, but T4 and GH increased thymus weight. In mice cotreated with DXM and T4, the weight of the thymus doubled, compared with DXM alone, but was still significantly smaller than in control mice. The thymus was no longer visible in mice treated with the combination of GH and DXM.


   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
The Snell dwarf mouse has a mutation in the POU-domain transcription factor PIT-1 that interrupts the normal development of the anterior pituitary gland resulting in loss of synthesis of GH, TSH, and prolactin and sluggish growth (15). It is therefore an excellent model to study the growth-promoting effects of GH or T4 excluding their mutual interaction. The model also allows analysis of the effect of DXM on GH- or T4-induced growth separately.

DXM alone restrained the already slow growth in body length by 65% and body weight by 40% in these animals. In our previous work in normal mice, a comparable dose of DXM decreased body length by only 26% and body weight by 16% (14). The presence of endogenous GH and/or T4 may partially protect normal mice from the growth restraining effects of DXM.

Human GH (50 mU/d) and T4 (1 µg/d) caused a similar increase in body length and body weight, but T4 was the better growth stimulator in the presence of DXM. DXM reduced T4-stimulated body length by 35%, but the effect of GH was reduced by 75%. There are, to the best of our knowledge, no data in the literature on the interaction of GH and glucocorticoids in Snell dwarf mice. With the exception of the report by Altman et al. (16) in normal mice, most data on the interaction between GH and DXM were obtained in rats. Because rats, in contrast to mice (and men), lose weight when treated with glucocorticoids, one must be careful when comparing both animal models. Nevertheless, in most mouse and rat studies, the negative effects of DXM on body weight and body length were partially counteracted by concomitant GH administration (17, 18, 19, 20, 21) except when long-acting depot glucocorticoids were used in rats (22, 23). Data on the interaction between T4 and DXM on body growth are lacking altogether.

GH and T4 had different effects on the skeleton: T4 had more effect on the tibia, but GH was the better stimulator of lumbar vertebra weight. Surprisingly, GH potentiated the growth-inhibitory effect of DXM on tibia length and weight. Because this phenomenon was not found in normal mice (16) or rats (20), it may be speculated that T4, which is very low in the Snell dwarf mouse (9), is essential for GH to counteract the growth-inhibiting effect of DXM on the tibia. Indeed, our data show that T4 is a stimulator of tibia growth, even in the presence of DXM.

The deleterious interaction between DXM and GH was not seen in the lumbar vertebrae: GH significantly stimulated lumbar vertebrae dry weight, even in the presence of DXM. In a previous study on the effect of DXM in normal and IGF-II transgenic animals (14, 24), we also found a difference between the tibia and lumbar vertebrae: IGF-II overexpression protected the tibia but not the lumbar vertebrae.

Both GH and T4 stimulated liver growth, but this effect was completely wiped out by the coinjection of DXM. The strong growth induced by T4 in the kidney was reported before in Snell mice (9, 25) and hypophysectomized neonatal rats (26). In contrast to the liver, GH- and T4-stimulated kidney growth partially remained in the presence of DXM.

Both GH and T4 strongly stimulated the growth of the thymus and the spleen as described before (9). T4 partially counteracted the involution of the thymus and spleen by DXM. GH was uneffective in the spleen and even amplified the severe growth inhibition of DXM in the thymus to a point that the thymus was no longer visible. This phenomenon is not seen in normal rats; the weight of the thymus in rats cotreated with GH and prednisone was higher than in rats treated with prednisone alone but not different from that of vehicle-treated control animals. In contrast to the present report, GH also stimulated spleen growth in these glucocorticoid-treated rats (20, 21). The difference in species and absence of T4 in our Snell mice may explain these discrepancies.

The mechanism of T4-stimulated growth remains unclear. In intact animals, T4 modulates the GH-IGF-I axis. T4 was shown to increase GH secretion by the pituitary (6, 7). In GH-sufficient rats, Cynomolgus monkeys, and humans, serum IGF-I decreased during hypothyroidism and increased significantly after T4 supplementation (27, 28, 29, 30, 31). Hypothyroidism also attenuated the IGF-I response to exogenous GH administration (32).

However, in the Snell dwarf mouse model, the growth-promoting effect of T4 cannot be explained by its modulation of GH and/or IGF-I secretion because it lacks somatotrophic cells and T4 treatment does not increase serum IGF-I (10). The separate pathways used by both growth stimulators may explain why the combined treatment of thyroid hormone and GH is more effective than each hormone separately (9, 33, 34), GH is unable to fully induce cartilage growth and differentiation (33, 34), and some organs are more responsive to GH and others respond better to T4. Very similar observations were made in hypophysectomized neonatal rats (26, 35).

The powerful growth-stimulating effect of T4 in our model must therefore be explained by a different mechanism. Other growth factors, such as epidermal growth factor and nerve growth factor, rise after T4 treatment and may mediate some of the growth effects of T4 (36, 37). The potent growth effect of T4 on the kidney, for example, is probably mediated by locally produced epidermal growth factor (38).

Thyroid hormone may also act directly at the target cells. Thyroid hormone receptors are present in growth plate chondrocytes (39, 40), and in vitro cell culture experiments indicate that T4 can directly modulate growth and differentiation of growth plate chondrocytes (39, 41, 42). It also regulates the feedback loop via Indian hedgehog and PTH-related protein within the growth plate (40).

The interaction between glucocorticoids and T4 has not been studied before. In our model, DXM had, in general, less impact on T4-stimulated growth than on the growth-promoting effect of GH. Both glucocorticoids and thyroid hormones use nuclear receptors to mediate their effects, and extensive cross-talk has been reported between the thyroid hormone receptors and other nuclear receptors. A competitive interaction between T4 and glucocorticoids can therefore occur, e.g. by promiscuous binding to hormone response elements, by the formation of heterodimer receptors or competition for cofactors (43).

GH was found to partially counteract the detrimental effects of glucocorticoids in humans (44, 45, 46, 47, 48, 49, 50, 51). Our data in mice suggest that T4 may be more effective in this regard. Optimization of the thyroid hormone status should therefore be explored to help restore growth in glucocorticoid-treated children.


   Footnotes
 
This work was supported by a grant from the Belgian Study Group for Pediatric Endocrinology (to R.P.A.R.).

R.P.A.R. and G.K. contributed equally to this manuscript.

Current affiliation for R.P.A.R.: Department of Pediatrics, Antwerp University Hospital, Edegem, Belgium.

Abbreviations: DXM, Dexamethasone; hGH, human GH.

Received January 13, 2003.

Accepted for publication March 4, 2003.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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