Short-term recombinant human growth hormone therapy does not modify growth hormone, thyrotropin and prolactin responses to thyrotropin-releasing hormone in adult dialysis patients

Pedro Iglesias, Rafael Selgas1, Javier Méndez2, María José Fernández-Reyes3, María Auxiliadora Bajo4, Abelardo Aguilera4 and Juan José Díez5

Departments of Endocrinology and 3 Nephrology, Hospital General, Segovia, 1 Department of Nephrology, Hospital La Princesa, Madrid and Departments of 2 Biochemistry, 4 Nephrology and 5 Endocrinology, Hospital La Paz, Madrid, Spain



   Abstract
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Background. We recently have reported the first randomized, controlled study on the effects of short-term recombinant human growth hormone (rhGH|| therapy on the nutritional status of a group of malnourished adult dialysis patients. In order to evaluate whether rhGH administration exerts any influence on GH, thyrotropin (TSH|| and prolactin (PRL|| responses to TSH-releasing hormone (TRH||, we assessed these responses before and after rhGH therapy.

Methods. GH, PRL and TSH responses to TRH before and 1 month after rhGH therapy in a group of adult dialysis patients were evaluated. Seventeen dialysis patients (11 on continuous ambulatory peritoneal dialysis/six on haemodialysis|| were studied (rhGH group, n=8; control group, n=9||. In the rhGH group, 0.2 IU/kg/day rhGH was administered subcutaneously. Each patient was tested with TRH (400 µg bolus i.v.|| on two separate occasions, just before and immediately after the treatment period.

Results. rhGH treatment did not modify baseline serum GH concentrations (6.6±2.7 vs 4.1±1.1 µg/l||, paradoxical GH responses to TRH (six out of eight patients||, GH peak (11.9±4.6 vs 11.2±5.3 µg/l, NS|| or area under the secretory curve of GH (GH AUC; 19.1±4.5 vs 12.1±3.1 µg/h/l||. Both basal PRL (35.5±7.1 vs 36.7±8.6 µg/l|| and TSH (2.3±1.1 vs 2.8±1.7 mU/l|| concentrations, as well as their responses to TRH stimulation (PRL peak, 59.9±16.6 vs 59.5±11.8 µg/l; TSH peak, 6.2±2.6 vs 7.1±3.9 mU/l||, were also unaffected by rhGH therapy.

Conclusion. These results suggest that short-term rhGH therapy does not significantly influence the magnitude of the somatotropic, lactotropic or thyrotropic response to TRH in adult dialysis patients. However, this finding has to be interpreted with caution due to the two different patient groups included in this study.

Keywords: dialysis; growth hormone; prolactin; thyrotropin; thyrotropin-releasing hormone



   Introduction
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Recombinant human growth hormone (rhGH|| has been employed recently as an anabolic factor in different catabolic states [1]. Results of rhGH therapy in these patients, as well as the effects of rhGH therapy in growth-retarded children with chronic renal failure or end-stage renal disease (ESRD|| in dialysis [2], have provided a rationale for using rhGH to treat malnutrition in adult dialysis patients. To date, few studies have evaluated the anabolizing effects of rhGH in adult patients undergoing dialysis (3–5||.

Many neuroendocrine alterations have been described in ESRD patients. Among these are prominent abnormalities in the somatotropic, lactotropic and thyrotropic axes [6]. High basal serum GH concentrations, as well as atypical GH responses to both physiological and pharmacological stimuli, have been reported. Some patients show a paradoxical release of GH in response to TRH [7]. Hyperprolactinaemia is another hormonal disturbance associated with renal insufficiency and ESRD requiring haemodialysis (HD|| or continuous ambulatory peritoneal dialysis (CAPD|| [8–10]. The PRL response to the TRH stimulation test is generally blunted and prolonged [11,12]. Finally, ESRD patients usually present with important alterations in the hypothalamic–pituitary–thyroid axis. Serum free and total thyroxine (T4|| and triiodothyronine (T3|| concentrations have been found to be low in uraemic patients in relation to healthy subjects and, on many occasions, these hormones are in the range of hypothyroidism [6,13]. Serum TSH concentrations are normal in the majority of uraemic patients, although their response to TRH is usually decreased [6,7].

We recently have reported the first randomized, controlled study on the effects of short-term rhGH therapy on the nutritional status in a group of malnourished adult dialysis patients [5]. In order to evaluate whether rhGH administration exerts any influence on GH, TSH and PRL responses to TRH, we assessed these responses before and after rhGH therapy in a group of adult dialysis patients.



   Subjects and methods
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Subjects
Seventeen malnourished patients with chronic renal failure (nine women, eight men, mean age 60.9±3.2 years, range 30–78 years|| undergoing dialysis (eleven on CAPD/six on HD|| were studied. Patients were recruited to participate in a controlled randomized trial of the rhGH effects on nutritional parameters in adult dialysis patients (see reference [5] for details||. Patients were assigned randomly to the control group (n=9, six women/three men, mean age 58.4±5.6 years|| or the rhGH group (n=8, three women/five men, mean age 63.9±3.1 years||. The study was approved by the Local Ethical Committee and informed written consent was obtained from all patients before testing. The main clinical and analytical data of the patients are shown in Table 1Go. There were no statistically significant differences between both groups in terms of age, sex, body mass index, type of dialysis, time on dialysis, glucose, blood urea nitrogen, creatinine and albumin concentrations. We could not find any significant difference in hormonal concentrations [GH, PRL, TSH, insulin-like growth factor-1 (IGF-1|| and free T4] between patients on HD (n=6|| and those on CAPD (n=11|| at the beginning of the study. No patient had a history of diabetes. In the rhGH group, one patient was being treated with atenolol and one with clonidine to control hypertension. Another patient was receiving cisapride as an antiemetic agent. In the control group, one patient was receiving atenolol and one cisapride. During the study, there were no modifications in the dose of these drugs in any patient.


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Table 1. Basal clinical and analytical data of the studied patients

 

Study design
All patients were given a dietary treatment prescription to ingest 35 kcal/kg/day and 1 g of protein/kg ideal body weight/day for 4 weeks. In the rhGH group, rhGH (Saizen, Serono, Spain|| was administered at 0.2 IU/kg/day s.c. at 8:30 a.m. in CAPD patients, and in HD patients rhGH was administered immediately after a dialysis session. TRH tests were performed in each patient on two separate occasions, just before and immediately after the treatment period. Endocrine tests were begun at 8:00 a.m., after an overnight fast, with the subjects in the recumbent position. In HD patients, the studies were performed on the day preceding the dialysis session. An indwelling catheter was placed in a forearm vein and kept patient with a slow infusion of 0.9% NaCl solution. Thirty minutes later, the first blood sample was collected. Two basal blood samples were obtained with a 15 min interval, and TRH (TRH Prem, Zyma-Frumtost, Switzerland||, 400 µg i.v., in bolus form, was administered at time 0. Blood samples were collected at -15, 0, 15, 30, 60, 90 and 120 min. In all blood samples, serum GH and PRL concentrations were assessed. Serum TSH concentrations were determined at 0, 15, 30, 60 and 90 min. Blood haemoglobin and haematocrit values, and general biochemical serum parameters, free T4 (FT4|| and IGF-1 concentrations, were also determined at time 0.

Hormone assay
Blood samples were centrifuged immediately and the serum stored at -20°C until assayed. Human serum GH and TSH concentrations were determined by using an automated immunoenzymatic assay (Tosoh, AIA 1200, Tokyo, Japan||. Maximal intra-assay and inter-assay coefficients of variation of GH were 5.4 and 3.3%, respectively. The sensitivity of the GH assay was 0.1 µg/l. For TSH assay, the sensitivity was 0.06 mU/l, and maximal intra-assay and interassay coefficients of variation were 3.3 and 3.4%, respectively. The normal range for GH was <5 µg/l and for TSH, 0.4–5.0 mU/l. Serum PRL concentrations were measured by an automated immunoenzymatic assay (Tosoh, AIA 1200, Tokyo, Japan||. The sensitivity and maximal intra-assay and inter-assay coefficients of variation were, respectively, 1 µg/l, and 6 and 4.5%. Serum FT4 concentrations were determined by an immunoenzymatic assay (AIA-PACK FT4||. Maximal intra-assay and inter-assay coefficients of variation were 9.6 and 7.7%, respectively. The sensitivity of the FT4 assay was 1.28 pmol/l. The normal range was 11.71–28.05 pmol/l. Serum IGF-1 concentrations were measured by specific radioimmunoassay after acid–ethanol extraction (Nichols Institute Diagnostics, San Juan Capistrano, CA||. The intra- and inter-assay coefficients of variation were 2.9 and 11.4%, respectively. The sensitivity of the assay was 12.9 µg/l. The normal range was 83–450 µg/l for <40 years and 54–389 µg/l for <40 years. Blood haemoglobin concentrations and haematocrit values were measured in a Coulter counter, and serum biochemistry determinations were done using an automated multichannel analyser (Hitachi 737, Compana Ltd, Japan||.

Statistical methods
Results are expressed as the mean±SEM. Clinical and analytical data at different time points of the study for the same patients were compared by using repeated measures analysis of variance. For comparisons between groups, the Mann–Whitney test was employed. The areas under the secretory curve (AUC|| were calculated by a trapezoidal method. The differences were considered to be significant when P<0.05.



   Results
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 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Baseline hormone concentrations
At the beginning of the study, baseline serum GH concentrations were normal or slightly increased in both groups. No significant differences in basal serum GH concentrations between groups were found either before or after rhGH treatment. Serum IGF-1 concentrations increased significantly from 216.6±42.5 to 581.2±171.5 µg/l (P<0.01|| after rhGH administration, and a slight, but significant, rise in IGF-1 concentrations was also observed in the control group at the end of the treatment phase (231.4±43.6 vs 258.7±50.3 µg/l, P<0.05||. Basal serum concentrations of TSH and FT4 were in the normal range in both groups, and no modifications were observed after rhGH therapy. Serum PRL concentrations were high in both groups of patients at the beginning of the study and they did not vary throughout the study in either group of patients (Table 1Go, Figures 1–3GoGoGo||.



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Fig. 1. GH responses to the TRH stimulation test before and after the treatment period in the control group (A|| and the rhGH group (B||. Data are mean±SEM.

 


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Fig. 2. TSH responses to the TRH stimulation test before and after the treatment period in the control group (A|| and the rhGH group (B||. Data are mean±SEM.

 


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Fig. 3. PRL responses to the TRH stimulation test before and after the treatment period in the control group (A|| and the rhGH group (B||. Data are mean±SEM.

 

Growth hormone
A paradoxical GH response to TRH administration was considered to be present when the GH peak after TRH administration was >5 ng/ml. According to this criterion, six of the eight patients in the rhGH group and four of the nine patients in the control group showed this paradoxical response in the first TRH stimulation test. Considering the groups as a whole, the rhGH group showed a GH peak of 11.9±4.6 µg/l, whereas the GH peak in the control group was 5.7±1.7 µg/l, NS. However, these increments were not statistically greater than baseline values. The value of AUC of GH was significantly greater in the rhGH group with respect to the control group (19.1±4.5 vs 8.8±2.1 µg/h/l, P <0.05||.

The second TRH stimulation test produced a paradoxical GH response in six patients in the rhGH group and in three patients in the control group. In the rhGH group, the GH peak after TRH stimulation (11.2±5.3 µg/l|| was slightly higher than that at baseline (4.1±1.1µg/l, NS||. This response was also observed in the control group (4.2±1.6 vs 2.2±0.5 µg/l, NS||. No differences between GH peak values in both groups were observed. Treatment with rhGH did not modify either the GH AUC or the GH peak (Table 2Go, Figure 1Go||.


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Table 2. GH, TSH and PRL responses to TRH stimulation before and after rhGH therapy

 

Thyrotropin
In the first TRH stimulation test, serum TSH concentrations increased significantly in both groups of patients. The TSH peak in the rhGH group (6.2±2.6 mU/l, P<0.001 vs 0 min|| was obtained at 30 min, whereas in the control group, the TSH peak (6.0±1.3 mU/l, P<0.001 vs 0 min|| was achieved at 60 min. No differences in TSH peaks were found between both groups of patients. TSH AUC values were also similar in both groups (rhGH vs control, 9.1±3.7 vs 8.8±1.9 mU/h/l, NS||. In the second TRH stimulation test, TSH responses (TSH peaks and TSH AUC values|| to TRH were similar to those obtained in the first test in both groups of patients (Table 2Go, Figure 2Go||.

Prolactin
The first TRH test showed a significant increment in serum PRL concentrations from 35.5±7.1 to 59.9±16.6 µg/l (P<0.001; 90 min|| in the rhGH group, and from 34.7±8.4 to 68.3±17.2 µg/l (P<0.001; 30 min|| in the control group. PRL AUC values were similar in both groups of patients. We did not observe any significant change in PRL peak and PRL AUC after rhGH treatment, and no significant differences between both groups of patients were observed in the second TRH test (Table 2Go, Figure 3Go||.



   Discussion
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
The results of the present study indicate that short-term rhGH therapy in dialysis patients does not affect basal serum GH, PRL and TSH concentrations. Our data also show that GH, PRL and TSH responses to the TRH stimulation test are not modified by this therapeutic regimen in these patients. To our knowledge, this is the first study in which the effect of short-term rhGH therapy on these responses in adult dialysis patients has been evaluated.

It is well known that GH exerts several physiological actions at the hypothalamus–pituitary level. GH stimulates IGF-1 secretion, which itself inhibits GH gene expression and the release of GH in response to GH-releasing hormone (GHRH|| [14]. GH also increases hypothalamic somatostatin release, which inhibits GH as well as TSH secretion [15]. In our patients, baseline serum GH concentrations were unchanged by rhGH therapy despite a significant increase in IGF-1 serum concentrations. This observation might be due to several reasons. First, the half-life of rhGH (Saizen|| is ~5 h when it is administered s.c., and accumulation of rhGH has been excluded in both children with chronic renal failure [16] and adult dialysis patients [5,17]. Secondly, it is likely that both rhGH and the increment of serum IGF-1 contribute to the stimulation of the endogenous secretion of hypothalamic somatostatin, thereby decreasing the release of GH from the anterior pituitary.

A paradoxical GH response to TRH has been described in several pathological situations such as endocrine (acromegaly, primary hypothyroidism and diabetes mellitus||, neuropsychiatric (anorexia nervosa, depression and schizophrenia|| and metabolic (liver cirrhosis and chronic renal failure|| disturbances [18]. In chronic renal failure, this abnormal response is pronounced in those patients with a severe degree of renal function impairment [19] and is blocked by acute recombinant human erythropoietin administration [20]. The exact mechanism of this paradoxical GH response to TRH is unknown. It has been proposed that a decrease in hypothalamic release of somatostatin or an increase in GHRH secretion at the median eminence might be involved in GH release after TRH stimulation. In our patients, rhGH administration did not modify the paradoxical responses of GH to TRH. Therefore, it seems that short-term rhGH administration at pharmacological doses does not affect the mechanism for the release of GH after TRH stimulation.

Basal FT4 and free and total T3 concentrations have been found to be reduced in uraemic patients and to be sometimes even in the range of hypothyroidism [6,13]. Basal TSH concentrations are more often in the normal range although the TSH responses to TRH are generally blunted [6,7]. These endocrine disturbances, as well as the well known effects of GH on release of hypothalamic somatostatin which inhibits both GH and TSH secretion, might indicate the presence of latent hypothyroidism in these patients. However, to date, there is no evidence that rhGH therapy is accompanied by significant alterations in both basal thyroid hormones and thyrotropin concentrations in children with chronic renal failure [2,21]. Up to now, the effect of rhGH therapy on thyroid status in adult dialysis patients has been unknown. In our patients, basal TSH and FT4 were always in the normal range in both groups of patients. Treatment with rhGH did not affect the TSH response to TRH stimulation. These findings suggest that short-term rhGH therapy does not increase hypothalamic somatostatin release sufficiently to modify endogenous TSH pituitary secretion.

Another specific hormone disturbance in chronic renal failure is hyperprolactinaemia [8]. In fact, an increase in the frequency and amplitude of PRL secretory bursts has been reported in these patients. An elevation of serum PRL concentrations has been described in both HD [8] and CAPD [22] patients. Moreover, serum PRL concentration is similar before and after the dialysis session, and there is no significant influence of the type of dialysis or the time on dialysis [9,22]. PRL responses to TRH stimulation are generally decreased [6,12]. It has been hypothesized that the delayed decay of PRL concentrations after TRH probably reflects prolonged plasma half-life of TRH and/or PRL itself. In the present study, we observed high basal serum PRL concentrations in both groups of patients. Treatment with rhGH did not affect basal and stimulated PRL concentrations. This finding suggests that short-term rhGH treatment does not alter basal hyperprolactinaemia or blunted responses of PRL to TRH in dialysis patients.

The limited number of patients studied does not allow the detection of differences in the neuroendocrine patterns of CAPD and HD patients, although a previous study by our group [20] suggests that there is no differences in hormonal responses to TRH between HD and CAPD patients.

In summary, the present study shows that short-term treatment with rhGH in adult dialysis patients is not followed by changes in basal serum concentrations of GH, TSH and PRL, or modified responses of these hormones to the TRH stimulation test. These observations also suggest that rhGH therapy does not increase the hypothalamic somatostatinergic tone sufficiently to modify pituitary GH and TSH secretion. It should be taken into account that two groups of different patients were included in this study, i.e. those treated by HD and those by CAPD. Caloric rations and residual diuresis are, or may be, different in patients undergoing HD and CAPD. Therefore, the results obtained have to be interpreted with caution.



   Notes
 
Correspondence and offprint requests to: Dr Pedro Iglesias, Hospital General de Segovia, Ctra de Avila s/n, E-40002 Segovia, Spain. Back



   References
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 

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Received for publication: 25. 5.99
Revision received 8. 2.00.



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