Growth hormone in the regulation of hyperlipidemia

Growth Hormone in the Regulation

of Hyperlipidemia

P. R. Blackett, P. K. Weech, W. J. McConathy, and J. D. Fesmire Plasma concentrations of triglyceride, cholesterol, and apolipoproteins A-l and 6 in young growth hormone deficient subjects were measured at intervals during the five weeks after initial hormone-replacement therapy. The mean concentrations of cholesterol, apolipoproteins A-l and B decreased significantly during that period: the decreases were progressive and in similar proportion to each other. Also, the amount by which apolipoprotein A-l concentration decreased was correlated with its plasma concentration before treatment. The data suggests that growth hormone may play a role in the regulation of these three major plasma lipoprotein components and tend to suppress the development of hypercholesterolemia which has been observed in some adult growth hormone deficient subjects.

I

T HAS BEEN unclear whether or not human growth hormone (hGH) has any effect on the maintenance of normal plasma cholesterol and triglyceride concentrations. High lipid concentrations conforming to a phenotype of hypercholesterolemia were found in hGH deficient adults’ whereas lower concentrations (but relatively high for their age and sex) were found in hGH deficient children.* Family studies3 suggested that hyperlipidemia was associated with hGH deficiency only in kindreds characterized by familial combined hyperlipidemia in members of normal stature, although the hyperlipidemia was most pronounced in the hGH deficient members. This would suggest that the extreme hyperlipidemia of some adults arose from a less marked hyperlipidemia in childhood as a result of continued hGH deficiency. No significant decrement in lipid values has been observed in previous studies in which the effect of growth hormone treatment has been studied’.**-’ except for Friedman et al.4 who used much higher daily doses of growth hormone (25 IU per day) for a week to lower cholesterol suggesting hGH has a role in maintaining normal plasma cholesterol concentrations. Therefore, to elucidate whether or not conventional therapeutic doses of hGH can regulate the plasma concentrations of lipoprotein components and if a deficiency of hGH could be responsible in part for hyperlipidemia, we studied the plasma concentrations of apolipoproteins A-I and B as well as cholesterol and triglyceride during the first 5 wk of hGH replacement. MATERIALS AND METHODS HGH deficiency was demonstrated by two provocative tests’ given to the ten subjects. They had all demonstrated serum levels of hGH below 7 ng/ml following standard provocation tests before being eligible for hGH therapy. Following complete pituitary evaluation, all other detected hormonal deficits had been treated for more than a month before hGH therapy was commenced. All subjects had been previously treated with hGH but had been off therapy for more than 2 mo before the study. L-thyroxine levels (determined by radioimmunoassay) were all within the normal range. The diagnosis, age, sex, Tanner stage of puberty6 and height were recorded. Their heights were measured with a stadiometer (Holtain, Ltd., U.K.) over a 4 mo period to determine their initial rates of linear growth after hGH replacement.

Metabolism,

Vol. 31, No. 2 (February), 1982

Blood samples were drawn from each subject after an overnight fast, before treatment, and 1 hr. 1 wk and 5 wk after beginning a course of intramuscular injections of 2 units hGH, 3 times each week. HGH was obtained from the National Pituitary Agency. Serum triglyceride and cholesterol concentrations were measured by the procedures of the Lipid Research Clinics;’ serum apolipoproteins A-l and B were assayed by electroimmunoassays.8,9

RESULTS

The characteristics of the ten hGH deficient subjects are given in Table 1. Nine were male, their ages were from ten to twenty years and they were all short in stature and delayed in pu.bertal development secondary to nonprogressive hypopituitarism or isolated growth hormone deficiency. After treatment with hGH, the linear growth in each subject was recorded for four months; their rates of growth were from 1.67 to 7.50 mm per mo. Before treatment, five subjects had serum cholesterol concentrations greater than those of the 95th percentile of children of the same age and sex in the Lipid Research Clinics Prevalence Study.” Linear regression analysis of L-thyroxine levels with cholesterol and triglyceride levels before hGH treatment indicated no significant (p > 0.20) correlation. After 5 wk of treatment with hGH, only two subjects still had cholesterol concentrations above these values and in one of the two, a decrease of concentration equal to 64 mg/dl had occurred. Only two subjects had initial serum triglyceride concentrations greater than the

From the Laboratory of Lipid and Lipoprotein Studies, Oklahoma Medical Research Foundarion. The Department of Pediarrics, University of Oklahoma Health, Sciences Center, and Oklahoma Children’s Memorial Hospital, Oklahoma Cit,y, Oklahoma. Received for publication February 25, 1981. This work was supported by National Institutes of Health Grant HL 23181-03. The Human Growth Foundation, The National Pituitary Agency and resources of the Oklahoma Medical Research Foundation and Oklahoma Children’s Memorial Hospital. Address reprint requests to Piers R. Blackett. M.D., Department of Pediatrics, University of Oklahoma Health Sciences Center, P.O. Box 26901. Oklahoma City, Oklahoma 73190. 0 I982 by Crune & Stratton. Inc. 0026-0495/82/3102/0002$01.00/0

117

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8LACKEl-r

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Table 1. Clinical Characteristics of the hGH Deficient Subjects Hormone Patient

Diagnosis*

Tanner

Replacementst

Sex

Stage

1.

IGD

nil

M

2.

IGD

nil

M

3

3.

IGD

nil

F

2

4.

IGD

nil

M

5.

IGD

nil

M

6.

IGD

nil

7.

HP

8.

HP

9. 10.

Deviation

*Diagnoses

were:

tHormone

Growth Rate$

cm

cm/yr

11.5

28.4

112.5

7.5

17.5

43.2

154

8.2

25.1

117

9.0

35.8

153.5

4.0

2

15.0

42.2

142.5

3.5

M

1

11.8

28.3

119.6

8.8

CT

M

1

10.9

37.8

119

CT

M

20

39.1

HP

CT

M

1

14.0

45.1

139

2.0

HP

CTD

M

1

12.5

26.2

126.3

5.9

1.4

13.9

128.1

5.9

0.7

3.2

18.5

1.4

HP = Hypopituitarism;

during

Height

kg

9.9

Replacements:

SDetermined

Weight

15.7

Mean Standard

Age YrS

IGD

C = cortisol;

initial

= Isolated

growth

T = L-thyroxine;

hormone

D = DDAVP,

deficiency.

desamino-d-arginine

vasopressin.

ol, triglyceride, apolipoprotein A-I and B concentrations expressed as a fraction of the initial control value for each subject. Progressive decreases in concentration were found, on average, for each parameter except triglyceride concentration, which increased significantly. The mean fractional values were significantly less than the control value of 1.000 (p -c 0.02) for apolipoprotein A-I (0.866 i 0.112) and cholesterol (0.857 * 0.135) concentrations after 5 wk of treatment and for apolipoprotein B (0.924 + 0.079) concentrations after 1 hr. However, the mean values of each of these three parameters decreased progressively from 1.000 with increasing time after treatment, and after 5 wk they reached similar values for the fraction of their initial control value. To determine if there was significance in the trend for the mean values to decrease progressively with increasing time of treatment, the method of least

Table 2. Changes in Plasma Triglyceride, Cholesterol, Apolipoproteins A-l and B Concentrations

Triglyceride w/d1

Before

and

After

at 1 hr. 1 wk. and 5 wk

Treatment

A-l

Cholesterol

ApoB

Fraction’

w/d1

Fraction

mgldl

Fraction

1.000

195

1.000

154

1.000

mg/dl

Fracflon

treatment

Mean

77

SD

37

After

4.4

4 mo.

95th percentile of children of the same age and sex (10); only one had such an elevated concentration of triglyceride after five weeks of treatment. The mean serum concentrations of apolipoproteins A-I and B in the subjects were similar to the mean concentrations of these apolipoproteins in normolipidemic adults with similar or greater serum cholesterol and triglyceride concentrations.” After commencement of treatment, the values for the concentrations of cholesterol and apolipoproteins A-I and B showed a decrease (Table 2) which was significant (p < 0.01, p < 0.006, p < 0.06) after 5 wk. To analyze these changes, each of the values before treatment were considered as control values for the effect of treatment on that subject, and the subsequent values during treatment were expressed as a fraction of the control value. Table 2 gives the mean values at each time point during treatment for serum cholester-

Before

6.1

97.7

108

1.000

33

19

42

treatment

1 hr Mean

80

1.073

189

0.996

53

0.999

99ll

0.924$

SD

44

0.122

40

0.052

25

0.150

28

0.079

88

1.191

191

0.970

43

0.961

93

0.922

45

0.321

49

0.144

21

0.174

25

0.198

5 wk Mean

76

0.092

162t

0.857$

325

0.866$

9Jcc

0.882

SD

44

0.463

37

0.135

11

0.122

37

0.196

1 wk

Mean

SD

*Mean

of fraction

tsignificant $Value

of control

decrease

of fraction

value

in cholesterol

significantly

decrease

in the ApoA-I

BSignificant

decrease

in the ApoB

decrease

in the ApoB

standard

value

different

SSignificant

**Significant

with

after

from

value value

after

after

value

after

deviation 5 weeks

below.

from

1 .OO by a t test, 5 wk from 1 hr from

the value

the value

the value

5 wk from

before

treatment

in a paired

t test

&tailed).

(p < 0.01).

p < 0.02. before

before

the value

treatment

treatment

before

treatment

in a paired in a paired

t test

t test

in a t tailed

(2-tailed),

(2-tailed),

test

(p < 0.006). (p < 0.03).

(p < 0.05).

119

GROWTH HORMONE AND LIPOPROTEINS

squares linear regression was used to estimate the rate of decrease, as a fraction of the initial value, for each parameter in each subject. A t test was used to determine the probability that the mean rate of change for all subjects was less than zero. The means of the least squares estimates of the initial values before treatment were 0.996,0.960 and 0.998 for apolipoproteins A-I and B and cholesterol, respectively. These values represent the intercepts of the control value at the start of treatment. The mean rates of decrease were 4.33 x 10e3, 5.52 x 10e3 and 4.03 x IO-‘of the control value per day of treatment for apolipoproteins A-I and B and cholesterol, respectively. These rates of decrease were significantly less than zero with probabilities of 0.005, 0.08 and 0.005, being due to chance. Therefore, on average there was a significant decrease in the values of the three parameters, as a fraction of their control value, that was linear with time and of the same order of magnitude for each of the three. The actual decrease of serum apolipoprotein A-I concentration in mg/dl after 5 wk of treatment was significantly and positively correlated (r = 0.843, p < 0.01) with the apolipoprotein A-I concentration before treatment. By least squares linear regression analysis the initial A-I concentration at which no decrease would have occurred after 5 weeks treatment was 129 mg/dl, a value only slightly less than the mean value for normolipidemic adults.”

DISCUSSION

The results of this study demonstrate that hGH treatment of young hGH deficient subjects can be effective in changing the plasma concentrations of three major lipoprotein components-apolipoproteins A-I, B and cholesterol-by a comparable decrease in each of them during the initial 5 wk of hormone replacement. Before treatment half of the subjects had plasma cholesterol concentrations exceeding those of the 95th percentile of subjects of the same age and sex in the Lipid Research Clinic’s study.” This hypercholesterolemia could be reduced by 14% on average during five weeks of treatment, indicating that a continued deficiency of hGH could prolong and exacerbate hypercholesterolemia into adult years. Friedman et a1.4 found that the daily administration of hGH (25 IU) to normocholesterolemic and hypercholesterolemic adults, who had no reported hGH deficiency, caused a decrease in their plasma cholesterol concentrations in one week. Thus, it seems that plasma cholesterol concentration can be decreased by hGH administration to persons that do or do not have an earlier deficiency of hGH supporting the contention that hGH has a role in lipoprotein metabolism. These

results do not confirm the absence of an effect of hGH on lipids described by Winter et al.,3 but the children in their study had a significantly lower mean plasma cholesterol concentration before hGH treatment (165 mg/dl) than those in the present study (195 mg/dl). In the former study the mean plasma cholesterol concentration before treatment was similar to that in our study after five weeks of treatment (162 mg/dl) indicating resistance to a further lowering. This is the first report of the plasma concentrations of apolipoproteins A-I and B in hGH deficient children. Their values were similar to those of adults with similar plasma cholesterol and triglyceride concentrations” and both apolipoproteins decreased in concentrations after 5 wk of hGH replacement. Although the decrease in apo-B after 5 wk was significant only at the p < 0.05 level utilizing a one-tailed t test, this data suggests that hGH can partly regulate the metabolism of both apolipoproteins A-I and B, the major protein components of high density and low density lipoproteins, respectively. There is well-documented evidence that cells can derive cholesterol from plasma low density lipoproteins in vitro, and that this process regulates cholesterol synthesis in the cells.” Regulation of cholesterol synthesis in many rat tissues is affected by plasma low density or high density lipoproteins in viva.” The number of receptors for low density lipoprotein uptake, a necessary step in the regulation of cholesterol synthesis in vitro,‘* is greater in rapidly dividing than in nondividing cells in vitro.14 If cells rely more heavily on plasma lipoproteins for the lipids required by their accelerated growth under the influence of hGH, then the cellular uptake of lipoproteins would be stimulated, resulting in an increased fractional rate of catabolism from the plasma and a subsequent decrease in their plasma concentrations. The lipid-lowering effect could also be mediated by other hormones such as insulin,‘5.‘6 glucagonl’.” or somatomedin” which are induced by growth hormone and in the case of insulin” and glucagon” are known to lower plasma lipid levels. Thus, combined or independent effects of enhanced cellular uptake of high and low density lipoproteins,” glucagon-mediated inhibition of hepatic triglyceride production,*’ and insulin induced degradation of very low density lipoprotein” could plausibly explain the decreases in plasma apolipoproteins A-I and B, and cholesterol concentrations. ACKNOWLEDGMENT We wish to thank Dr. John W. Drake for referring two of his patients and Dr. Petar Alaupovic, Ph.D. for providing the facilities for electroimmunoassay

and for helpful advice.

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