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The Journal of Clinical Endocrinology & Metabolism Vol. 83, No. 1 135-139
Copyright © 1998 by The Endocrine Society

Original Studies

Programming of Growth Hormone Secretion and Bone Mineral Density in Elderly Men: A Hypothesis1

Caroline Fall, Peter Hindmarsh, Elaine Dennison, Samantha Kellingray, David Barker and Cyrus Cooper

Medical Research Council Environmental Epidemiology Unit, University of Southampton, Southampton General Hospital (C.F., E.D., S.K., D.B., C.C.), Southampton, United Kingdom SO16 6YD; and The Cobbold Laboratories, Middlesex Hospital (P.H.), London, United Kingdom W1N 8AA

Address all correspondence and requests for reprints to: Prof. Cyrus Cooper, Medical Research Council Environmental Epidemiology Unit, Southampton General Hospital, Southampton, United Kingdom SO16 6YD.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Epidemiological studies suggest that retarded growth in infancy is associated with low adult bone mass. The mechanism underlying this association is unknown, but the programming of GH secretion or sensitivity by environmental influences during early development may play a role. We examined this issue in a sample of 37 healthy men, aged 63–73 yr, whose weight gain in infancy had been recorded. Venous blood samples were obtained under standard conditions every 20 min over a 24-h period. Measurements were made of the GH secretory profile, insulin-like growth factor I (IGF-I), IGF-binding protein-1 and -3, and GH-binding protein. Bone mineral density was measured at the lumbar spine and femoral neck using dual energy x-ray absortiometry. There was a statistically significant association between peak GH concentration (r = 0.46; P < 0.01) and fasting IGF-I concentration (r = 0.46; P < 0.01) with femoral neck bone density. After allowing for the peak GH concentration, median GH was negatively (P < 0.05) associated with bone mineral density. Weight at 1 yr was not related to peak GH, but was strongly related to the median GH concentration (r = 0.42; P = 0.01). These observations are consistent with a dual effect of GH secretion on bone density. High peak GH values drive IGF-I production and maintain bone mineralization in adult life. However, integrated GH secretion, after adjusting for the effect of pulse amplitude, is negatively associated with bone density in adult life. This particular characteristic of the GH secretory profile correlates with growth during infancy and might be programmed by environmental factors during intrauterine or early postnatal life.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
REDUCED bone mass in the femoral neck is an important determinant of hip fracture in the elderly (1). Recent studies suggest that retarded growth in infancy is associated with low adult bone mass. In a follow-up study of 153 British women, low weight at 1 yr of age was an important predictor of reduced femoral neck bone mass at 21 yr of age (2). This observation was confirmed in a study of 413 men and women, aged 63–73 yr (3). The mechanism underlying this association is unknown, but abnormalities in GH secretion or sensitivity may play a role. GH, both directly and through promotion of insulin-like growth factor I (IGF-I) secretion, is the major regulator of growth in late infancy (4), and abnormalities of GH metabolism in adults are known to give rise to osteoporosis (5, 6, 7, 8, 9, 10, 11, 12, 13). We, therefore, speculated that the relation of infant weight to adult bone mass reflects programming of the GH-IGF-I axis. Programming is the term used for persisting changes in structure and function caused by undernutrition or other adverse influences acting during critical periods of early development. To explore this hypothesis, we assessed the pattern of GH secretion and bone mineral density (BMD) in a sample of healthy men, aged 63–73 yr, whose infant weight gain was recorded at the time.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
We studied 37 healthy men, aged 63–73 yr, who were born and are still resident in the county of Hertfordshire, UK. These men were selected to represent a wide range of birth weight and weight at 1 yr of age, and came from a larger group (n = 224) participating in a study of the relationship between growth in infancy and the subsequent risk of osteoporosis (3). The selection procedure for the larger sample has been described previously (3, 14, 15), and they are known to be representative of elderly men in Hertfordshire with regard to body build and cigarette smoking, variables that influence bone mass. Midwife and health visitor records of the birth of all 37 men had been preserved. These included birth weight, weight at the age of 1 yr, and the manner of feeding during the first year of life. All subjects gave written informed consent, and the study was approved by the local ethical committee.

The 37 men were admitted to hospital for overnight rest, and an indwelling iv cannula was inserted. At 0730 h, a blood sample was drawn for measurement of serum GH concentration, and samples were drawn every 20 min thereafter for 24 h. Standard meals were taken at 0800, 1230, and 1800 h, and a normal daily routine was encouraged within the confines of the hospital. At 0600 h, an additional blood sample was drawn for the measurement of IGF-I, IGF-binding protein-1 and -3 (IGFBP-1 and IGFBP-3), and GH-binding protein (GHBP).

GH was measured using a chemiluminescence technique (Nicholls Institute, San Juan Capistrano, CA) (16). The within-assay coefficients of variation (CVs) were 5.5%, 6.8%, and 10.5% at serum concentrations of 0.2, 4.0, and 7.2 ng/mL, respectively, and the between-assay CVs were 12.1%, 12.3%, and 9.0% at serum concentrations of 1.3, 2.4, and 7.0 ng/mL, respectively. The sensitivity of the assay was 0.02 ng/mL. Standards in the assay were calibrated against the International Reference Preparation (80/505).

Serum IGF-I was measured using an in-house polyclonal RIA with acid-alcohol extraction. The sensitivity of the assay was 0.07 U/mL. The within-assay CVs were 11.3%, 6.5%, and 4.7% at serum concentrations of 0.23, 1.23, and 3.53 U/mL, respectively; the between-assay CVs were 10.5%, 12.1%, and 5.1% at concentrations of 0.38, 0.99, and 3.54 U/mL, respectively.

IGFBP-3 was measured using a RIA kit (Diagnostic Systems Laboratories, Abingdon, UK). The sensitivity of the assay was 0.9 ng/mL. The within-assay CVs were 8.1% and 5.4% at serum concentrations of 2200 and 7800 ng/mL, respectively; the between-assay CVs were 9.8% and 4.8% at serum concentrations of 2200 and 8500 ng/mL, respectively.

IGFBP-1 was measured using reagents supplied by Dr. Sten Drop (Rotterdam, The Netherlands). The sensitivity of the assay was 1.5 µg/L. The between-assay CVs were 10.6% and 7.0% at serum concentrations of 106 and 253 µg/L, respectively, and the within-assay CVs were 10.3% and 9.1% at serum concentrations of 9 and 353 µg/L, respectively. GHBP concentrations were measured using a ligand-mediated immunofunctional assay (17). Serum estradiol and testosterone were measured by RIA (Diagnostic Products Corp.), as previously described (18).

BMD was measured in each subject by dual x-ray absorptiometry at the femoral neck and lumbar spine using a Hologic QDR 1000 instrument. Bone area and BMD were obtained directly from the scans. As BMD represents an areal density, we calculated the bone mineral apparent density (BMAD) using the method of Carter et al. (19). All three variables (area, BMD, and BMAD) were used in our analyses. Measurement precision, expressed as the CV, was 1.8% for femoral neck BMD and 1.1% for lumbar spine BMD.

Lateral thoracolumbar spine radiographs were obtained using a standard protocol. Radiographs were taken with the patient in the left lateral position, and the breathing technique was used to blur overlying rib and lung detail by motion. The thoracic film was centered at T7, and the lumbar film was centered at L2. Osteoarthritic change in the thoracolumbar spine was assessed using the Kellgren/Lawrence system (20). This uses a standard radiographic atlas to characterize the extent of disc narrowing, uncovertebral and apophyseal joint osteophyte, sclerosis, and cyst formation on a five-point scale (grade 0 = normal to grade 4 = severe).

GH profiles were analyzed to derive the following values. The trough value was designated as that below which 5% of all values lay during the 24-h period. The peak value was designated as that below which 95% of values fell during the 24 h. The median value was used as an estimate of total GH secretion over the 24 h. We explored the relationship between hormonal indexes, adult bone mass, and early weight using linear regression. Partial correlation coefficients after adjustment for body mass index were tested for statistical significance. Potential confounding variables were examined using multiple regression. Variables with a skewed distribution were normalized by an appropriate transformation where necessary.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Figure 1Go shows the 24-h GH profile from one of the men, with peak, median, and trough values indicated. The mean femoral neck BMD of the 37 men was 0.82 g/cm2 (SD = 0.13 g/cm2), and the mean lumbar spine BMD was 1.05 g/cm2 (SD = 0.18 g/cm2). Body mass index was significantly (P < 0.01) related to BMD, and we, therefore, examined the association between GH and BMD after adjusting for this variable. Table 1Go and Fig. 2Go show that femoral neck BMD was strongly associated with the peak GH concentration (P < 0.01). Lumbar spine BMD was also associated with peak GH, but this relationship was not statistically significant. In contrast to peak GH, median values were unrelated to BMD at either site. In a simultaneous regression including only these two GH parameters, the positive influence of peak GH on femoral neck BMD remained (ß = 0.024; P = 0.003), whereas median GH had a negative effect (ß = -0.23; P = 0.022). The relationships of peak and median GH with lumbar spine BMD acted in similar directions and were also statistically significant (peak GH ß = 0.023; P = 0.038; median GH ß = -0.32; P = 0.027).



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  		Figure 1. Pattern of GH secretion in one of the men studied. Samples were obtained every 20 min over a 24-h period. The peak value is that below which 95% of observations fall, the median is that below which 50% fall, and the trough is that below which 5% fall.

 

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  		Table 1. Indexes of GH/IGF-I secretory profile and bone density in Hertfordshire men

 


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  		Figure 2. Relation between characteristics of GH secretion and bone density among 37 men, aged 63–73 yr. a, Femoral neck BMD; b, lumbar spine BMD.

 
All three characteristics of the GH secretory profile showed a tendency to decline with age (peak GH: r = -0.25; P = 0.14; median GH: r = -0.33; P = 0.05; trough GH: r = -0.17; P = 0.30). The positive relationship between BMD at both sites and peak GH as well as the negative one between BMD and median GH were slightly strengthened and remained statistically significant (P < 0.02) after age adjustment.

BMD at both the femoral neck (P = 0.004) and lumbar spine (P = 0.03) was positively associated with the serum IGF-I concentration (Table 1Go). Peak GH concentrations were correlated with IGF-I concentrations (r = 0.46; P = 0.004), whereas median GH concentrations were not. BMD was related to serum IGFBP-3 concentrations (femoral neck: r = 0.31; spine: r = 0.22), but not with IGFBP-1 and GHBP concentrations.

As the bone mineral density values derived using dual energy x-ray absortiometry are areal, rather than volumetric, we derived the apparent BMAD for each subject using the algorithm of Carter et al. (19). Table 1Go also shows the relation between GH secretory profile and BMAD (as an approximation to true bone density) and bone area (the best index of bone size). The data clearly demonstrate that peak GH and IGF-I are positively associated with femoral neck BMAD (peak GH: r = 0.43; P < 0.01; IGF-I: r = 0.48; P < 0.01), rather than with femoral neck bone area (peak GH: r = 0.12; P = 0.50; IGF-I: r = -0.05; P = 0.76). As in the case of the relationships with BMD, those for lumbar spine BMAD were in the same direction as those for femoral neck BMAD, but were generally less marked.

Twenty-two (61%) of the men had radiographic evidence of moderate/severe osteoarthritis affecting the lumbar spine (Kellgren/Lawrence grades 3/4). When the associations for lumbar spine BMD shown in Table 1Go were adjusted for age and radiographic osteoarthritis score, in a multiple regression model, they were little changed. Likewise, the inclusion of age and osteoarthritis score did not markedly alter the positive association between lumbar spine BMD and peak GH (ß = 0.02; P = 0.07) or the negative one between BMD at this site and median GH (ß = -0.36; P = 0.008).

We examined the relation between birth weight, weight at 1 yr, and GH secretory profile. Weight at 1 yr was not related to peak GH, but was strongly related to median GH concentration (P for trend = 0.01; Table 2Go and Fig. 3Go). Neither peak nor median GH concentrations were related to birth weight.


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  		Table 2. Weight at 1 yr and GH secretory profile in 37 Hertfordshire men

 


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  		Figure 3. Relation between median GH secretion and weight at 1 yr among 37 men, aged 63–73 yr.

 
Consistent with the opposing associations of peak and median GH on femoral neck BMD, a bivariate analysis again revealed a positive association of femoral neck BMD with peak GH (ß = 0.018; P = 0.02), but a nonsignificant negative association with weight at 1 yr. Associations of GH concentration with lumbar spine BMD were similar, but did not reach statistical significance. The trough GH concentration was not associated with BMD at either site or weight in infancy. The associations of peak GH with femoral neck BMD and of median GH with weight at 1 yr remained significant after adjusting for age, serum estradiol, testosterone, method of infant feeding (breast, bottle, or both), and paternal social class.


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
We have examined the associations between BMD in the femoral neck and lumbar spine, weight gain in infancy, and the secretory profile of GH in a sample of elderly men. Our data show that peak GH and fasting IGF-I concentrations are positively associated with bone density. After allowing for the peak GH concentration, however, median GH is negatively associated with BMD. For any given level of peak GH, the higher the background GH concentration, outside the episodic pulses, the lower the BMD. These observations persisted after adjusting for age and body mass index; they suggest a dual effect of GH secretion on BMD, which is more pronounced at the hip than the spine.

The men in our study were born in Hertfordshire between 1920–1930 and still lived in the county. Their mean height, weight, and body mass index were similar to those of the larger group of men from which they were selected. Their BMD values fell within the normal range provided by the dual energy x-ray absortiometry scan manufacturer. Their GH profiles were similar to those reported previously for men of a similar age (21). The manner of characterizing the pattern of GH secretion is not widely agreed upon, and our derivation of peak, median, and trough values follows a simple mathematical procedure. The measurements were made during a carefully controlled in-patient admission. Random variability in GH values would tend to obscure, rather than accentuate, relationships between GH and BMD or weight at 1 yr. The relationships between GH secretion and BMD were stronger for the hip than the spine. The accuracy of lumbar spine measurements in elderly men is likely to have been compromised at least in part by the high frequency of degenerative joint disease, aortic calcification, and vertebral deformities. However, we obtained thoracolumbar radiographs of the subjects and showed that the relationships between GH and spine BMD were consistent with those for hip BMD and little affected by adjustment for the severity of degenerative joint disease (the most frequent of these artifacts).

The bone mass of an individual at any stage in later life depends upon the peak level attained during skeletal growth and the subsequent rate of bone loss. A critical time for GH and IGF-I action on bone acquisition is during the adolescent growth spurt, and a potential explanation for our finding of a relationship between GH secretion and BMD in elderly men is that it reflects a residual effect of GH from adolescence. However, this seems unlikely for two reasons. First, the relationships we found of peak GH and IGF-I to bone mineral were strongest for BMAD and were not apparent for bone area, suggesting an effect of GH/IGF-I on volumetric density rather than simply bone size. Second, we were also able to adjust for the confounding effects of two indexes of childhood environment: method of infant feeding and paternal social class. The associations of peak GH with BMD and of median GH with weight at 1 yr remained statistically significant in these analyses.

The GH/IGF-I axis is known to have important actions on bone metabolism, although its role in determining BMD and the risk of osteoporosis is unclear (22, 23). GH stimulates linear growth in childhood and bone remodeling throughout life. It stimulates chondrocytes in the growth plate to secrete IGF-I, which, in turn, signals the chondrocytes to differentiate, leading to cartilage formation and linear growth. In addition, GH probably has growth effects independently from IGF-I. GH also has complex effects on bone remodeling that are thought to be mediated by osteoblast IGF-I production. GH deficiency is associated with a deficit in adult BMD (7, 8, 9, 24, 25, 26). Some, but not all, studies (5, 6, 27, 28) suggest that administration of GH corrects this. Case-control studies show lower circulating IGF-I levels in patients with osteoporosis than in normal controls (22). The administration of GH to elderly men and women has, however, produced inconsistent, but generally negative, results (29, 30, 31).

The pulsatile nature of GH secretion is controlled by the episodic secretion of two hypothalamic hormones with opposing effects: GH-releasing hormone and somatostatin or GH release-inhibiting hormone (32). The biological function of this pulsatile pattern is unknown. The amplitude of GH peaks correlates with IGF-I concentration and height during childhood (33, 34, 35, 36), suggesting that the GH signal for growth is in the episodic pulses of the hormone. Our study provides evidence that the pulses of GH also have a positive influence on BMD. The biological significance of the baseline level of GH is not clear, partly because assay technology has only recently allowed measurement of GH at very low concentrations. Our study suggests that high levels of GH outside the pulses have an effect on BMD opposite that of the pulses themselves. This could be because high background GH concentrations diminish the anabolic impact of the pulses, or because they directly reduce BMD in the elderly by increasing activation frequency and thereby the rate of bone remodeling. This abnormal pattern of GH secretion (high integrated GH secretion with normal pulse amplitude) is observed in patients with acromegaly (37). Although acromegalic patients are generally reported to have normal or high bone density values (38, 39), the disorder is also associated with increased bone size. We were unable to find any studies that attempted to disentangle the influences of acromegaly on bone size and volumetric bone density. Furthermore, a proportion of acromegalic patients is known to have low bone density (40).

We also found that high weight at 1 yr was associated with a high median GH concentration in later life, independently of current body mass index. This raises the possibility that the pattern of GH secretion is programmed in early life. There is evidence from experiments in animals that GH secretion in adult life can be altered by transient events in early postnatal life. In rats, there is a sexually dimorphic pattern of GH secretion. Adult males show a high amplitude pattern of secretion, whereas females secrete low amplitude pulses on a high background baseline. The pattern of secretion can be altered to resemble that of the opposite sex by the transient neonatal manipulation of sex steroids (41). Temporary dietary protein restriction in rats after weaning causes persisting reductions in peak GH concentrations (42). Little is known about GH in relation to early events in humans, although babies who experienced intrauterine growth retardation have high GH and low IGF-I concentrations at birth (43, 44, 45, 46). Furthermore, abnormal GH profiles, including low amplitude peaks and high baseline secretion, have been demonstrated in childhood in intrauterine growth retardation babies with postnatal growth failure (47, 48). As low weight at 1 yr may reflect prenatal events (4, 49) or nutrition and health in infancy itself, it is impossible from our data to comment on the likely timing of programming effects on GH.

In conclusion, this study suggests an association between certain aspects of the GH secretory profile and bone density in elderly men. Our data also suggest that the total amount of GH secreted over a 24-h period is programmed, rather than the pattern of secretion. Further studies of the programming of GH in early life in humans are now required.


   Acknowledgments
 
We thank the men who participated in the study and the nurses and radiology staff who administered the bone density measurements. Computing support was provided by Vanessa Cox and Paul Winter, and the manuscript was prepared by Gill Strange and Denise Gould. We are grateful to Jane Pringle, University College London, for measuring GH and IGF-I, and to Ragnar Bjornasson, University of Goteborg, for measuring GHBP. Elaine Dennison was in receipt of a Wellcome Trust Research Training Fellowship


   Footnotes
 
1 This work was supported by project grants from the Wessex Medical School Trust and the Medical Research Council of Great Britain. Back

Received May 19, 1997.

Revised September 9, 1997.

Accepted September 24, 1997.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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