(Acta Paediatr Jpn 1992; 34: 282

- 289)

Growth Hormone Secretory Status in Patients with Turner Syndrome Dao-Hua Zhang, M.D.*, Koichi Yano, M.D., Yoshiya Itoh, M.D., Ryou Mitamura, M.D., Naoki Suzuki, M.D. and Akimasa Okuno, M.D. Drpartnimr qf P d i a t r i u . Asahikmw Medical College, Asahikawa '

The growth hormone (GH) secretory capacities in patients with Turner syndrome aged 5.1-15.9 years and those with constitutional short stature (CSS) aged 5.2-14.2 years were evaluated by pharmacological and physiological means. The GH response to hypoglycemia in the patients with Turner syndrome was lower than that in the patients with CSS. However, the GH response to arginine was not significantly different between the two patient groups. For the physiological test, the integrated concentration of GH (ICGH), the number of episodic peaks and their mean height were evaluated using blood obtained from the patients every 20 minutes for a period of 24 hours. The ICGH and the mean height of the episodic peaks in the patients with Turner syndrome were significantly lower than those in the CSS patients during the night but not during the day. Negative correlation between the bone age and the night-time values of ICGH was observed in the patients with Turner syndrome. Such correlation was not observed in the CSS patients. The patients with CSS showed a significant day-night difference in the ICGH and the mean height of the episodic peaks, but the patients with Turner syndrome did not show any significant day-night difference in either the ICGH or the mean height of episodic peaks. In conclusion, the GH secretory capacity in patients with Turner syndrome is lower than that in CSS patients. Key Words

Turner syndrome, Constitutional short stature, Growth hormone, Episodic secrection, Circadian rhythm

Introduction

RUXi\ed: September 2 . 1991 K K \ I ~Xovernber : 14. 1991 4cceptcd: December 6. I99 I

Cortrspondence addi-esh: Akirnasa Okuno. M.D.. Department ol Pediatric$. Asahikawa Medical College. 4-5-3-1 I. \i\hikagura. .Asihikaua 078. Japan

* Recipient ol J a p a n e s e GoLernrnent ( M o n b u s h o u ) Scholai-\hip. Abbre\iarions - G H : growth hormone. ICGH: integrated concrnrration of G H , ATT: arginine test. ITT: insulin te\t. CSS: conztitutional short stature.

Short stature is one of the most constant symptoms of Turner syndrome [3, 14, 211. The mechanism of this growth failure is not clear. It has been reported by several authors that growth hormone (GH) response to insulin-induced hypoglycemia is diminished in Turner syndrome [2, 91, but normal GH response to provocative tests has also been reported [7, 20, 241. Ross et al [18] have reported that spontaneous secretion of GH is normal in patients with Turner syndrome

GH secretion in Turner syndrome (25) 283 below 9 years of age but is decreased in patients aged 9 to 20 years. Similar findings have been reported by Villdolid [24] and Ranke [15]. In this paper, GH responses to insulininduced hypoglycemia and arginine infusion, and spontaneous secretion of GH in patients with Turner syndrome were compared with those in patients with constitutional short stature.

Patients and Methods Fifteen patinets with Turner syndrome aged 5 to 15 years and 19 patients with constitutional short stature (CSS) aged 5 to 14 years were studied after obtaining informed consent from the parents and the patients aged 10 years or more. The patients with CSS included 8 males and 7 females at prepuberty, and 3 males and 1 female at early puberty. The diagnosis of Turner syndrome was based on an analysis of chromosomes on peripheral lymphocytes and the diagnosis of CSS was based on the criteria of Horner et a1 [6], which are as follows: height standard deviation score (SDS) for chronological age of less than -2.0, delayed bone age comparable to height age, normal birth weight and no evidence of malnutrition, psychosocial dwarfism, organic disease and GH deficiency. For ethical reasons no control study was performed on normal children. None of the patients had been treated at the time of this study. Pubertal development was assessed by Tanner’s criteria [22] and bone ages were determined by the TW2 method (20-bone score) [23]. The arginine test (ATT) and the insulin test (ITT) were performed after an overnight fast. Arginine (0.5g/ kg) was infused intravenously over 30 minutes for ATT and insulin (0.1 U/kg) was injected as a single i.v. injection for ITT. Blood samples were obtained before and also 15, 30, 60, 90, and 120 minutes after the drug had been administered. GH deficiency was excluded on the basis of the serum GH responses of more than 10ng/ml, either in ITT or in ATT, or in both. Spontaneous

Vol. 34 No. 3 June 1992

secretion of GH was studied by measuring GH concentrations in the blood obtained every 20 minutes for 24 hours [8, 121. On the day of this study the patients were encouraged to follow their normal routine from when they got up until 20.00h. At this time, they were asked to go to bed and the room lights were turned off. Sleep was monitored visually by nursing personnel and it was recorded that they fell asleep between 20.00 and 22.00 h. Serum samples were stored at -20°C until they were ready for use and the GH concetrations were measured by the double antibody method. Episodic peaks of GH were identified by means of the PULSAR program [l I] in which the default values were set as follows: ASSAY SD(Y)=(5.1X+ 12.5)/ 100 G(I):5.2, G(2):3.5, G(3):2.6, G(4):2.1, G(5): 1.6 Clock time of 8.00 to 20.00h was defined as day-time and 20.00 to 8.00h as night-time. Mean values of GH concentrations during those time periods were expressed as an integrated concentration of GH (ICGH). The mean of the identified peak-height was also calculated in each of the patients. Body weight index was expressed as percentage of the ideal body weight. Statistical comparisons were performed using the Student’s t-test.

Results Clinical characteristics of the study subjects are summarized in Table 1. Karyotypes of the patients with Turner syndrome were 45,X in 3, 46,XXp- in 1 and 46,X i(Xq) in 3 and mosaic in the rest of the patients. Their age was 11 . 1 2 . 5 (mean ~ fSD) and they showed no pubertal signs; their bone age was 9 . 5 k 2 . 4 ~ .There was a 1.6fIO.9~delay in their bone age. Their height SDS was -3.6fI0.4 (range -2.8 to -4.1) and body weight index was +32.7% (range -18 to +61%). The age of the patients with CSS was 8.9 3.2y, their bone age was 7.2 2.7 y with 1.7+ 1.2 y of delay and height SDS was -3.0+0.7 (range -2.0 to -4.5). Their pubertal development was at Tanner stage 1 in 8 males and 7 females, at stage B2 in 1 female, and stage G2 (testicular volumes of 4

+

+

+

284 (26) Zhang et al. Table 1. Clinical characteristics of the study subjects Case No.

Sex

C.A.

B.A.

Y

Y

Turner syndrome (n= 15) 1 F 5.1 3.0 2 F 6.8 5.9 10.1 10.6 3 F F 10.5 9.5 4 5 F 10.7 8.6 F 11.1 6 9.1 F 11.3 7 10.0 8 F 11.4 9.5 F 11.4 10.6 9 10 F 11.5 10.4 [I F 11.9 9.0 F 12.2 11.1 12 F 12.5 11.0 13 F 13.8 11.5 14 F 15.9 15 13.0 Mean SD

11.1 2.5

9.5 2.4

Constitutional short stature (n= F 5.2 5.1 16 F 5.2 3.5 17 18 F 5.5 4.0 19 F 5.6 4.5 F 6.0 6.0 20 5.0 21 F 6.8 F 11.4 10.0 22 F 12.3 11.0 23 24 M 5.3 3.0 25 M 5.4 4.5 M 9.0 7.1 26 M 9.3 9.0 27 M 9.6 9.8 28 M 10.3 8.0 29 M 11.0 8.2 30 M 12.5 9.2 31 M 11.2 8.5 32 M 14.0 10.2 33 11.0 34 M 14.2 Mean SD

8.9 3.2

7.2 2.7

Diff

Pubertal stage

-2.1 -0.9 0.5 -1.0 -2.1 -2.0 -1.3 -1.9 -0.8 -1.1

-2.9 - 1.1

-1.5 -2.3 -2.9

I I I I 1 I 1

1 I I I I I 1 1

-1.6 0.9 19) -0.1 -1.7

1 1

-1.5

I

-1.1 0.0 -1.8 -1.4

1

-1.3 -2.3 -0.9 -1.9 -0.3 0.2 -2.3 -2.8 -3.3 -2.7 -3.8 -3.2

2 I 1

- 1.7 1.2

I I 1

1 1

1 1 1

I 2 2 2

Height

Weight

% of weight -

cm

SDS

kg

89.0 117.8 113.3 116.2 118.2 118.9 120.8 116.6 122.0 124.2 128.0 129.6 134.4 134.2

-4.1 -3.2 -2.8 -3.8 -3.6 -3.6 -3.5 -3.5 -4.0 -3.3 -3.4 -3.5 -3.4 -3.8 -4.3

13.2 20.0 25.2 23.9 24.0 24.2 28.0 25.2 22.2 28.6 27.9 38.6 31.0 26.6 38.2

23.9 37.5 34.2 50.4 35.2 43.4 61.0 34.0 41.5 33.2 30.5 59.5 21.8 -18.0 2.3

118.9 11.9

-3.6 0.4

26.5 6.4

32.7 20.3

94.4 95.2 99.0 101.0 91.6 104.0 124.1 131.2 95.4 92.0 118.6 117.7 112.4 123.5 120.1 121.7 115.4 137.2 139.7

-2.8 -2.6 -2.2 -2.0 -4.5 -2.6 -3.0 -3.1 -2.9 -3.9 -2.2 -3.0 -3.3 -2.1 -3.4 -4.0 -3.9 -3.3 -3.1

13.4 14.4 15.9 14.8 12.4 17.0 25.2 26.7 15.4 12.4 21.6 19.3 16.6 23.4 24.8 26.4 25.2 31.3 27.8

6.1 11.4 -6.6 14.4 8.1 18.5 0.0 17.5 4.7 3.5 -5.3 -4.6 1.3 24.8 31.8 50.8 3.6 -15.9

112.3 15.5

-3.0 0.7

20.2 6.0

9.2 15.3

101.0

Karyotype

46,Xi(Xq) 45,X/46, XX 45.X 46,X i(Xq) 45,X 45,X 45,X/46,Xi(Xq)/47, Xi(Xq) i(Xq) 46,Xi(Xq) 45,X/46,X+mar 45,X/46,XX 45,X/46,XXp+ 45,X/46,Xi(Xq) 45,X/46,XXq+ 46,XXp45,X/46,Xi(Xq)

11.1

Acta Paediatr Jpn

G H secretion in Turner syndrome (27) 285 to 5 ml) in 3 males. Basic endocrine data including T4, T3, TSH and IGF-I were within the normal range

and there was no significant difference between the patients with Turner syndrome and CSS stature (Table 2). Serum LH and

Table 2. Basic endocrine data of the study subjects Case No.

Sex

Turner syndrome I F 2 F 3 F 4 F 5 F 6 F 7 F 8 F 9 F 10 F II F 12 F 13 F 14 F 15 F Mean SD

T4 &/dl 9.2 12.8 7.3 8.2 8.6 8.8 8.8 6.2 9.4 9.9 8.2 11.4 9.8 9.2 11.6 9.3 I .7

Constututional short stature 16 F 9. I 17 F 10.7 F 6.0 18 19 F 10.0 20 F 8.0 F 8.8 21 F 10.1 22 23 F 8.8 M 10.5 24 2s M 11.0 26 M 11.3 27 M 9.4 28 M 8.6 M 15.1 29 M 8.6 30 M 11.8 31 M 11.8 32 M 9.9 33 M 13.6 34 Mean SD

Vol. 34 No. 3 June 1992

10.2 2. I

T3

TSH pU/ml

LH mU/ml

FSH mU/ml

IGF-I U/ml

1 .5

13.7 2.8 4.7 35.7 29.0 80.6 73.2 23.5 71.5 5.1 195.0 64.0 106.5 215.0 33.5

19.9 2.4 17.9 91.9 81.5 201.5 131.1 36.5 130.0 16.7 161.0 168.5 136.9 235.0 50.7

0.29 0.61 I .06 0.94 0.48 1.13 0.64 1.04 1.15

1.1

1.8 1.5 6.8 2.1 4.8 3.0 1.7 1.5 1.7 5.9 1.6 1.5 1.5 I .9 1.7

I .6 0.5

2.6 1.8

63.6 65.5

98.8 74.0

0.82 0.38

1.5 I .2 0.9 1.6 I .2

6.5 3.3 8.2 5.9 9.7 5.2 10.5 13.0 9.5 6.3 15.3 4.3 4.4 6.3 7.2 10.3 7.6 13.5 12.0

4.7 5.0 5. I 6.0 3.0 2.2 6.5 5.8 I .8 2.5 3.4 2.9 2.4 2.3 2.4 4.9 4.2 5.7 6. I

0.66

I .4 I .2 1.8 1.8 1.6 I .6

2.2 I .5 4.3 1.7 2. I I .5 6.5 5.6 2.6 3.3 2.7 3.4 2.8 2.6 1.5 2.0 1.5 1.5 I .5

I .4 0.3

2.7 I .4

8.4 3.4

4.0 I .6

I .9 2.9 I .7 I .3 2.2 I .7 1.1

I .5 2.0

I .4 I .3 I .2

1.1 1.3 1.4 1.9 1.2 1.6 1.7

0.39 0.5 I 1.55

1.08 0.52 0.29 I .09 0.58 0.73 1.38

0.47 I .04 2.08

0.9 0.5

286 (28) Zhang et al. FSH levels were elevated in the patients with Turner syndrome and were far highter than those in the CSS patients. In 1TT blood glucose values decreased from 74.6 h 7.5 mg/dl to the minimum of 31.1 _+ 7.5 mg/dl in the Turner syndrome patients and from 73.0k9.9 mg/dl to 29.4+ 8.2 mgldl in CSS patients. There was no significant difference in the degree of the insulin-induced hypoglycemia between the two patient groups. Serum GH response to ITT in the Turner syndrome patients was lower than that in the CSS patients (p