Influence of erythropoietin on paradoxical responses of growth hormone to thyrotropin-releasing hormone in uremic patients

Kidney International, VoL 46 (1994), pp. 1387—1391

Influence of erythropoietin on paradoxical responses of growth

hormone to thyrotropin-releasing hormone in uremic patients Ju J. D1EZ, PEDRO L. IGLESIAS, JULIA SASTRE, ANTONIO GOMEZ-PAN, RAFAEL SELGAS, JORGE MARTINEZ-ARA, JosÉ L. MIGUEL, and JAVIER MENDEZ Departments of Endocrinology, Nephrology and Biochemistiy, Hospital La Paz, Madrid, Spain

Influence of erythropoietin on paradoxical responses of growth hor-

mone to thyrotropin-releasing hormone in uremic patients. Several alterations in growth hormone (GH) secretion have been reported in patients with chronic renal failure. The aim of the present report has been to assess the effect of acutely administered recombinant human erythro-

poietin (rHuEPO) infusion on GH responses to thyrotropin-releasing

Growth hormone (GH) secretion appears to be altered by rhEPO administration in patients with chronic renal failure. A potentiation of GH responses to OH-releasing hormone (OHRH) has been obtained in a group of hemodialyzed patients after acute administration of an intravenous rHuEPO infusion [6], supporting

hormone (TRH) in uremic patients. Twelve male patients (mean age 46.2 years, range 24 to 69) were studied. Seven of them were on continuous

the hypothesis of a direct effect of rHuEPO on OH secretion.

ambulatory peritoneal dialysis (CAPD), two on chronic hemodialysis (HD) and two in pre-dialysis (PreD). None had been treated before with rHuEPO. Each patient was tested with TR}I (400 sg i.v. in bolus), and with TRH plus rHuEPO (40 U/kg in constant infusion for 30 mm) on different days. TRH administration provoked a paradoxical response of

to GHRH after chronic treatment with rHuEPO in uremic

sg/liter) in nine (5 CAPD, 2 HD, 2 PreD) out of 12

anemia with rHuEPO did not modify the exaggerated OH responses to OHRH in a group of five hemodialysis patients,

GH (peak >

5

patients. In this group of patients with anomalous OH responses, rHuEPO infusion produced an abolishment of the paradoxical responses (GH peak <5 rg/liter) in eight patients and a marked decrease in a further one. On

the contrary, in patients with no paradoxical GH response, stimulation

with TRH plus rHuEPO did not induce any change in GH release compared with that observed after TRH alone. rHuEPO had no effect on TRH-induced thyrotropin release. These results suggest that the paradoxical OH response to TRH in patients with chronic renal failure is blocked by rHuEPO administration. This rHuEPO action might be mediated by an increased release of somatostatin or an inhibited GH-releasing hormone secretion.

However, conificting results have been reported on OH responses

patients. Thus, some investigators found that rHuEPO treatment

potentiated GH secretion after GHRH stimulation [7], while more recently RamIrez et a! [8] have shown that correction of the

although it corrected the baseline elevation of GH plasma levels. On the other hand, it is well known that a paradoxical increase in

OH levels after TRH administration is a frequent finding in uremic patients [9]. This anomalous OH response was eliminated

by chronic rHuEPO therapy in a group of five hemodialyzed anemic patients studied by RamIrez et al [5], although the mechanism of this action could not be established. Therefore, the

aim of the present work has been to assess whether acutely administered rHuEPO exerts any influence in paradoxical OH

Correction of the anemia with recombinant human erythropoi- increases obtained after TRH injection in a group of patients with etin (rHuEPO) in patients with end-stage renal disease has been chronic renal failure, to give further insight into the pituitary associated with improvement of several abnormalities in hypo- effects of rHuEPO.

thalamo-hypophyseal functions. Long-term therapy with this agent in uremic patients undergoing maintenance hemodialysis

Methods has been followed by improvement in sexual function in men and Patients women [1, 2], increase in plasma levels of testosterone in male patients [3], normalization of prolactin levels [4], normalization of Twelve male patients with chronic renal insufficiency were the response of thyrotropin (TSH) to thyrotropin-releasing hor- studied. Six healthy volunteers with normal renal function (mean mone (TRH) [5], and restoration of follicle-stimulating hormone plasma creatinine 92.8 4.4 p.mol/liter, blood hemoglobin conresponses to exogenous gonadotropin-releasing hormone [5]. A centration 8.73 0.26 mmol/liter) matched for age and body mass better oxygen supply due to the improvement of anemia and a index were studied as controls. The study was approved by the

direct trophic action of rHuEPO at hypothalamic or pituitary levels have been speculated to be the causative factors of these endocrine modifications.

Local Ethical Committee and informed consent was obtained from all study participants before testing. There were two patients on conservative management (predialysis) with creatinine clearances of 13 and 15 ml/min, two patients on hemodialysis (HD) and eight patients on continuous ambulatory peritoneal dialysis (CAPD). Table 1 shows clinical and analytical features of the nine patients found to be responders to TRH. All patients were clinically stable, and did not receive

Received for publication March 23, 1994 and in revised form June 20, 1994 Accepted for publication June 20, 1994

rHuEPO or any medication known to affect OH secretion. All

© 1994 by the International Society of Nephrology

patients received aluminum hydroxide and water-soluble vitamins.

1387

DIez et al: Influence of EPO on OH responses

1388

Table 1. Clinical and analytical data of uremic patients with paradoxical response of OH to TRH

Patient 1 2 3 4 5 6 7 8 9

GH peak OH peak after Mode after TRH EPO + TRH Baseline OH Albumin of BMI Creatinine Months of Hemoglobin Age pg/liter g/liter pg/liter kg/rn2 p..'nol/liter mrnol/liter years Diagnosis therapy dialysis — 4 1 7 5.1 44 20.0 698 31 Pre CON 49 44

Mean SEM

33 31 24 69 42 63 42.89 5.09

CON

Un IN

PKD NH PKD DN DN

Pre HD HD CAPD CAPD CAPD CAPD CAPD

273 20.8 24.7

15

46 42.00 13.23

Controls (N = 6) 37.17 Mean SEM

—

48 84 7 5 89

27.2 21.5 16.0 27.2 20.0 22.7 1.34 24.9 1.04

5.33

522 1105 1096 972 787 796 955 645 841.8 67.7

92.8" 4.4

7.6

5.7 5.6 7.8 6.9

6i

10 21 10 12

7 4 4

7 9

4

46 43 44 44 48

2

31

2 9

26

1

7

5

3 1 1

6.4

42

65 6.41 0.30

32 41.56 1.99

2.78 0.89

8.73" 0.26

46.5 0.89

1.00

1.2

0.10

0.2

12.11

2.26

3 3

2 4 3.89 0.45 3.0 1.76

Abbreviations are: OH, growth hormone; TRH, thyrotropin-releasing hormone; BMI, body mass index; CON, chronic glomerulonephritis; Un, unknown; IN, interstitial nephropathy; PKD, polycystic kidney disease; HN, hypertensive nephrosclerosis; DN, diabetic nephropathy; Pre, pre-dialysis; I-ID, hemodialysis; CAPD, continuous ambulatory peritoneal dialysis.

ap < 0.005, "P < 0.001, controls vs. patients

Three patients (no. 8 and 9 in Table 1, and 1 non-responder) were and hematocrit values and serum concentrations of albumin, insulin-treated diabetics. They were in regular metabolic control, creatinine, free thyroxine and triiodothyronine were also deteras judged by their concentrations of hemoglobin Ale, which mined at time 0 in one of the experiments.

ranged from 7.5 to 8.3%. Five patients (no. 3, 6 and 8, and 2 non-responders) were hypertensive and were treated with calcium channel blockers or angiotensin converting enzyme inhibitors with adequate control of blood pressure. All patients were on a stable diet containing about 147 kJ/kg/day and about 1 to 1.4 g/kg high biological value protein per day. Body mass index (BMI) ranged between 16.0 and 30 kg/rn2 (mean 24.0 1.21) in patients and

between 20 and 27.3 kg/rn2 (mean 24.87

1.04) in controls

(differences not significant). Serum albumin concentration ranged

between 31 and 48 g/liter (mean 40.3

Hormone assay

Blood samples were centrifuged immediately and the plasma stored at —20°C until assayed. Human plasma OH and TSH concentration were determined by using an automated immunoenzymatie assay (Tosoh, AlA 1200). Maximal intra-assay and interassay coefficients of variation of OH assay were 5.4% and

3.3%, respectively. The sensitivity of the OH assay was 0.1 pg/liter. For TSH assay, the sensitivity was 0.06 gU/mI and

1.6) in patients and

maximal intra-assay and interassay coefficients of variation were 3.3% and 3.4%, respectively. Thyroxine and triiodothyronine were We could not find any statistically significant difference in the measured by commercially available radioimmunoassay kits (Ambetween 44 and 50 g/liter (mean 46.5

0.89, P C 0.05) in controls.

values of BMI and serum albumin between patients divided

ersham, Arlington Heights, Illinois USA). Blood hemoglobin

according to their modality of therapy (conservative, HD, CAPD) or the presence or absence of diabetes mellitus or hypertension.

concentrations and hematocrit values were measured in a Coulter

Study design

secretory curve (AUC) were calculated between 0 and 120

Counter, and the serum chemistry determinations were made Likewise, there were no significant differences in the values of using an automated multichannel analyzer (Technicon). transferrin and prealbumin in the diverse groups of patients (HD Statistical methods vs. CAPD, diabetics vs. non-diabetics; data not shown). Results are expressed as mean SEM. The areas under the Endocrine tests were begun at 08:30, after an overnight fast, with the subjects recumbent. In patients on HD the studies were performed on the day preceding a dialysis session. An indwelling catheter was placed in a forearm vein and kept patent with a slow infusion of 0.9% NaCI. Thirty minutes later the first blood sample

minutes by a trapezoidal method. For statistical evaluation of the

OH and TSH responses after TRH alone and after TRH plus rhEPO administration, the obtained values were analyzed by using the Wilcoxon's signed rank test. For comparisons between

patients and control subjects the Mann-Whitney test was emwas collected. Each subject received TRH (TRH Prem, Zyma- ployed. The differences were considered to be significant when P Frumtost, Switzerland), 400 tg i.v. in bolus at time 0. Blood <0.05. samples were collected at —30, 0, 15, 30, 60, 90 and 120 minutes. In another experiment, seven days apart, subjects were tested with

TRH plus rHuEPO (Erantin, Boehringer Mannheim, OmbH, Germany), 40 lU/kg body weight, infused at a constant rate for 30

Results Growth hormone

A paradoxical response of OH in the TRH test was considered minutes, starting 15 minutes before TRH administration. The tests with TRH alone and TRH plus rHuEPO were performed in to be present when the OH peak after TRH administration was randomized order, In all blood samples plasma OH and TSH higher than 5 xg/liter. According to this criterion, 9 (75%) out of concentrations were assessed, Blood hemoglobin concentration the 12 studied patients showed this anomalous response (Table 1).

1389

Diez et a!: Influence of EPO on GH responses

Table 2. Baseline and stimulated hormonal concentrations in GHresponder uremic patients and control subjects

12

Patients

(N=9)

10 Baseline GH pg/liter GH peak after TRH

L 8

pg/liter

GH peak after EPO + TRH pg/liter

0 E

0

0.89 2.26

1.0 1.2

0.10

3.89

0.45

3.0

1.76

I

Baseline TSH U/ml

2

2.52

0.45

2.80

0.51

1.47 10.0

0.29 2.08

8.67

1.76

9.67

isU/ml

TSH AUC after TRH

pUhr/ml

I

0 —30

I

0

—

30

60

£

t

90

120

Time, minutes Fig. 1. Plasma growth hormone responses to TRH (400 pg. i.v., airow)

(open circles) and to TRH plus rhEPO (40 U/kg body wt iv. infusion for 30 mm, rectangle) (closed circles) in the 9 uremic patients with paradoxical growth hormone responses to TRH. Abscissa scale: time (mm). Ordinate

scale: plasma growth hormone concentrations (sg/liter). Each point represents the mean

SEM.

< QØ5,

< 0.01.

TSH AUC after EPO + TRH hr/mi Free thyroxine pmol/liter Triiodothyronine nmol/liter

2.08 0.08

0.71

10.17 2.12

TSH peak after TRH sU/ml TSH peak after EPO + TRH

020b

4.43

pg• hr/liter

4

(N=6)

2.78 12.11

16.08 4.44

GH AUC after TRH pg hr/liter GH AUC after EPO + TRH

6

Controls

1.98

17.68 3.39

14.64 2.85

17.34 3.19

12.71

1.62

19.7

1.54

17.8

1.80

1.37

0.10

1.39

0.16

Data are mean SEM. P < 0.05, b P < 0.005 controls vs. patients

Baseline GH concentration were not significantly different between normal subjects and uremic patients with or without paradoxical responses to TRH. There were no relationships

In this group of patients rHuEPO infusion produced an abolish- between the presence of paradoxical OH responses and the age of ment of the paradoxical response (that is, peak < 5 .tg/liter) in the patients, the hemoglobin concentration, hematocrit value, eight patients and a marked decrease in a further one (patient no. time of dialysis, BMI or the presence of diabetes or hypertension.

2). Mean (±sEM) values of GH peak, which were reached at No particular features of patients with paradoxical response different times in individual patients, in responsive patients (N = 2.26 pg/liter after TRH stimulation and 3.89 9) were 12.11 0.45 pg/liter after TRH plus rHuEPO infusion, being this difference statistically significant (P < 0.01). Figure 1 represents the mean values of GH levels throughout the time period of the tests performed in the group of nine patients with

paradoxical response. When TRH was injected during rHuEPO infusion GH release was significantly less than after the administra-

tion of TRH alone, reaching these differences the limit of statistical significance between 30 and 120 minutes. The area under the curve of GH secretion in this group of patients was 16.08 4.44

hr/liter after TRH challenge and 4.43 0.71 .tg hr/liter (P < 0.01) after TRH plus rHuEPO infusion (Table 2). On the contrary, in patients who showed no paradoxical re-

sponse to TRH, the administration of TRH during rHuEPO

compared with patients without such a response were identifiable. Thyrotropin

All patients showed plasma concentrations of thyroxine and triiodothyronine that were not different from those found in normal subjects (Table 2). Baseline TSH concentration in healthy volunteers were 1.47 0.29 U/ml. These levels reached a peak of 10.0 2.08 U/ml 30 minutes after TRH stimulation. When this stimulus was injected during rHuEPO infusion there were no significant modification in the time (30 mm) or the magnitude 1.76 kUIml) of the TSH peak (Table 2). The group of (8.67 nine uremic patients with paradoxical responses of GH showed baseline TSH levels (2.80 0.51 xU/ml) slightly higher but not significantly different than those found in normal subjects. The TSH peak was elicited in these patients at 30 minutes of TRH administration and reached a value of 10.17 2.12 .tU/ml when TRH was administered alone and 9.67 1.98 jxU/ml when TRH was injected in the rHuEPO infusion (P> 0.05). No significant differences were observed between TSH responses to TRH (esti-

infusion did not induced any significant change in GH release in comparison with that observed after TRH alone. In these patients the mean values of GH peak and AUC were 1.33 0.33 p.g/liter and 2.08 0.08 pg hr/liter, respectively, after TRH stimulation and 2.30 0.88 pg/liter and 2.63 0.58 pg hr/liter, respectively, mated by peak and AUC) in the presence or in absence of rHuEPO in uremic patients. Neither was there any difference after TRH plus rHuEPO. In healthy volunteers TRH did not produced any paradoxical between TSH responses obtained in patients and controls or

response of GH in any subject. When tested with TRH plus between TSH responses in patients divided according to the rHuEPO one subject showed a OH peak of 10 pg/liter at 120 presence or absence of paradoxical GH response (data not minutes, with the remaining OH levels being 1 pg/liter. In the shown). remaining five subjects GH concentrations were always at levels equal or less than 2 xg/liter throughout the tests.

No subjective side effects were reported during the tests either in control subjects or in patients with chronic renal failure.

1390

Diez et a!: Influence of EPO on OH responses

Discussion

lated that rhEPO might act as a JOE I-like substance at the hypothalamic level and, accordingly, reduce OH responses to

Data reported here confirm that TRH can induce a OH release TRH through an increase of somatostatin release or a reduction in some patients affected by chronic renal insufficiency, in accor- of the release of OHRH as it has been demonstrated for JOE I dance with previous reports [9—12]. Results of the present paper [27]. This mechanism of action might also account for the also show that the paradoxical OH response to TRH in patients reduction in OH responses to some hypothalamic stimuli reported with end-stage renal disease is significantly reduced by acute by our group in uremic patients undergoing CAPD [23] and by rhEPO administration. This effect of rhEPO was independent of others in hemodialyzed patients treated with rhEPO [28]. Separate pathways in the neuroregulation of OH and TSH the age of the patients, the degree of anemia, the mode of therapy, the duration of dialysis or the presence of diabetes or hyperten- secretion in uremic patients have been proposed [10]. In fact, we sion. Therefore, a clear relationship between OH responsiveness could not find any effect of acutely administered rhEPO on TSH to TRH and the patient characteristics could not be established. response to TRH. This is in agreement with results reported by These results are in agreement with those obtained by RamIrez other authors [29, 30], who found no change in TSH responses to and coworkers [5], who reported that chronic therapy with rhEPO TRH after partial correction of the anemia by means of several was accompanied by a disappearance of the paradoxical OH weeks of rhEPO therapy in hemodialyzed patients. Nonetheless, RamIrez et al [5] encountered that TSH responses to TRH were reaction to TRH in hemodialyzed patients.

In normal humans, TRH does not modify OH release. However, the so-called 'paradoxical' increase in OH in response to TRH has been documented in certain pathological situations. In renal failure, TRH-induced OH release was first observed by Oonzález-Barcena et al [9] as an unexpected finding in seven of eight uremic patients given TRH to study TSH secretion. Several authors have confirmed this uremia-associated hormonal derangement [5, 11], and have shown that these anomalous OH reactions are more pronounced in patients with more severe degrees of renal funcional impairment [12] and are not sup-

markedly potentiated after rhEPO therapy. It is likely that the disparate populations of patients we have examined could explain some discrepancies between our results and previously published studies.

In summary, results here reported show that anomalous OH reactions to TRH are reduced by acutely administered rhEPO in uremic patients. We are aware of the limited scope of our results,

but we think that these data, together with those previously

reported by others [5—8, 28], suggest that rhEPO therapy may improve some of the uremia-associated derangements in OH pressed by triiodothyronine administration [10], thus suggesting a secretion. The mechanisms by which rhEPO affects somatotropic separate mechanism for the release of OH and TSH. Paradoxical cell function in patients with chronic renal failure remain to be OH responses to TRH are also well known findings in patients elucidated. It is no doubt that a better oxigenation of the with acromegaly [13], hypothyroidism [14], anorexia nervosa [15], hypothalamo-hypophyseal areas may give rise to an improvement diabetes mellitus [16] and liver cirrhosis [17]. Therefore, it seem in OH secretion; however, the data in our study also suggest that that TRH is a non-specific OH stimulator in several pathological a direct modulatory action of rhEPO may not be ruled out. In vitro conditions. The mechanism of this abnormal response remains studies about rhEPO effects on hypothalamic and pituitary funcunclear. In rats it has been shown that TRH can elicit OH tions have been suggested [31], but are lacking at present time. secretion from normal or tumoral somatotropic cells, thus sugAcknowledgments gesting a direct pituitary stimulatory action [18—20]. It has been also proposed that a decrease in hypothalamic release of somaThis work was supported by grant 92/0559 from the Fondo de Investitostatin [21] or an increase in GHRH secretion [22] at the median gaciones Sanitarias de Ia Seguridad Social, Spain. The authors are eminence might be involved in OH release after TRH stimulation. indebted to Ms. Isabel Molina for her technical assistance.

How can rhEPO interfere with these hormonal regulatory Reprint requests to Juan J. D(ez, M.D., Travesma Tellez 8, 4$, 28007 systems to block the paradoxical responses is a question that remains unsolved with the present results. RamIrez et al [5] Madrid, Spain. suggested that correction of the anemia, accompanied by a relative nutritional improvement, might normalize OH secretion and, hence, eliminate the paradoxical response. However, this explanation cannot account for the findings encountered in acute

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