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The Journal of Clinical Endocrinology & Metabolism Vol. 83, No. 5 1502-1506
Copyright © 1998 by The Endocrine Society

From the Clinical Research Centers

The Relationship between Growth Hormone Kinetics and Sarcopenia in Postmenopausal Women: The Role of Fat Mass and Leptin1

Ronenn Roubenoff, Laura C. Rall, Johannes D. Veldhuis, Joseph J. Kehayias, Clifford Rosen, Margery Nicolson, Nancy Lundgren and Seymour Reichlin

Nutrition Exercise Physiology and Sarcopenia Laboratory, Jean Mayer U.S. Department of Agriculture Human Nutrition Research Center on Aging at Tufts University (R.R., L.C.R., J.J.K., N.L.), and Tupper Research Institute, Department of Medicine, Tufts University School of Medicine and New England Medical Center (R.R., S.R.), Boston, Massachusetts 02111; School of Health Promotion and Human Development, University of Wisconsin (L.C.R.), Stevens Point, Wisconsin 54481; the Division of Endocrinology and Metabolism, University of Virginia Medical School (J.D.V.), Charlottesville, Virginia 22908; Maine Center for Osteoporosis Research and Education, St. Joseph Hospital (C.R.), Bangor, Maine 04402; Amgen, Inc. (M.N.), Thousand Oaks, California 91320; and the Department of Medicine, University of Arizona College of Medicine (S.R.), Tucson, Arizona 85724

Address all correspondence and requests for reprints to: Ronenn Roubenoff, M.D., M.H.S., Jean Mayer U.S. Department of Agriculture Human Nutrition Research Center, Tufts University, 711 Washington Street, Boston, Massachusetts 02111. E-mail: roubenoff{at}hnrc.tufts.edu


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Sarcopenia, the decline in body cell mass (BCM) and especially in muscle mass with age, is an important age-related cause of frailty and loss of independence in the elderly. Because the decline in BCM with age parallels a decline in GH secretion from young adulthood to old age, loss of GH secretion has been considered an important contributory cause of sarcopenia in the elderly. To test this hypothesis in a group of healthy postmenopausal women (n = 15; mean ± SD age, 66.9 ± 7.8 yr), 24-h GH concentrations and secretory kinetics were correlated with BCM (measured by whole body counting of 40K) and percent body fat (measured by dual energy x-ray absorptiometry or neutron inelastic scattering). Serum leptin levels were determined as a measure of adipocyte mass. Contrary to prediction, GH secretion was lower in women with higher BCM (r = -0.50; P < 0.05), whereas their mean fat mass was higher (r = 0.51, P < 0.05). These data indicate that sarcopenia in postmenopausal women is not associated with reduced GH secretion and is inversely correlated with fat mass. Serum leptin levels were inversely associated with GH secretion (r = -0.67; P < 0.006). Although a causal relationship has not been demonstrated, these data suggest that leptin could modulate GH secretion through its action on the aging hypothalamic-pituitary axis, or that GH regulates leptin secretion.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
GH PRODUCTION by the anterior pituitary gland declines with age (1). GH levels are highest during puberty and then decline exponentially, so that by the time healthy adults are in their seventies, GH secretion is less than half of that seen in healthy 20 yr olds (2, 3). In response to the declining secretion of GH, the plasma insulin-like growth factor I (IGF-I) concentration declines; in the Framingham Heart Study, the mean IGF-I level in elderly women was 139 ± 56.7 mg/dL and fell with age even between age 70–92 yr (4).

In parallel with the decline in GH and IGF-I, body composition also changes with age. Body cell mass (BCM) declines and fat mass increases between the second and seventh decades (5, 6). The loss of BCM with age, which has been termed sarcopenia, is greatest in the muscle compartment of BCM, a change that leads to weakness, frailty, and loss of independence (7). It is important to recognize that sarcopenia occurs in healthy adults with age, even in the absence of disease, and occurs in the absence of cachexia, wasting, or indeed any clinical illness (7, 8). Because these changes in body composition are similar to those that occur in GH deficiency, and at least in men can be reversed with GH treatment (9), a plausible postulate is that sarcopenia is due to the age-related decline in GH secretion (10). If this hypothesis is correct, it would be expected that in any age cohort, BCM would be highest in individuals with the highest GH secretion, and conversely, BCM should be lowest when GH production is most reduced. Despite the changes seen over the entire age range, there are no data on the relationship among BCM, fat mass, and GH secretion in a group of healthy elderly people. To test the hypothesis that low GH is associated with low BCM, we measured GH secretion in a group of healthy elderly postmenopausal women and correlated it with measurements of body composition. As a further indicator of body adipocyte mass, measurements were made of serum leptin concentrations. Leptin is a cytokine secreted by adipocytes, and its level in the blood has been shown to be a function of the fat cell mass in humans (11, 12, 13).


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Subjects

Fifteen healthy, independently living, postmenopausal women, aged 52–80 yr, were studied. None was taking any prescription medications or hormone replacement therapy. All women had normal physical examinations, complete blood counts, TSH levels, hepatic transaminases, serum creatinine, electrocardiograms, and chest radiographs. Their weight had been stable for at least 6 months before admission, and dietary energy, protein, and fat intake met or exceeded the Recommended Daily Allowances as determined by 3-day food records.

Study protocol

Subjects were admitted to the Metabolic Research Unit of the Jean Mayer USDA Human Nutrition Research Center on Aging or to the General Clinical Research Center of New England Medical Center on the afternoon before starting the study. An indwelling catheter was placed in a forearm vein for blood withdrawal beginning at 0730 h. One milliliter of blood was withdrawn every 20 min for 24 h for determination of GH secretory kinetics. Plasma was obtained after a 12-h fast at 0800 h for measurements of leptin, IGF-I, and IGF-binding protein-3 (IGFBP-3). The study was approved by the human investigations review committee of Tufts-New England Medical Center (Boston, MA), and written informed consent was obtained from all participants.

Measures

BCM was measured by calculating total body potassium (TBK) using endogenous 40K in a whole body counter as reported previously (14). We have previously shown that this measure is tightly correlated with muscle mass and whole body strength (r = 0.9; P < 0.0001) (15). Body fat was measured either by dual energy x-ray absorptiometry on a Hologic QDR2000 instrument (Waltham, MA) using the manufacturer’s software version 5.64A (n = 9) or by neutron inelastic scatter (n = 6) (16). The correlation between body fat determined by the two methods based on a separate study of eight postmenopausal Caucasian women, aged 60–79 yr, was 0.87 (P < 0.0001). Subjects undergoing dual energy x-ray absorptiometry underwent a whole body scan using the array mode. GH was measured by chemiluminescence using a commercial assay (Nichols Institute Diagnostics, San Juan Capistrano, CA). The intraassay coefficients of variation (CV) at concentrations of 0.5, 1.4, and 5.0 ng/mL were 4.1%, 1.7%, and 4.6%, respectively. The interassay CVs at these concentrations were 2.0%, 8.3%, and 4.8%, respectively.

IGF-I was measured after acid-ethanol cryoprecipitation using a single Nichols IGF-I extraction RIA. IGFBP-3 was measured with a single immunoradiometric assay (Diagnostic Systems, Webster, TX). All measurements were made in duplicate. The intraassay CV was 0.7% for IGF-I and 5.0% for IGFBP-3.

Plasma leptin levels were measured in a solid phase sandwich enzyme immunoassay, as previously described (17), using a monoclonal antibody immobilized in microtiter wells. The affinity-purified antibody was raised against recombinant human leptin. Bound leptin was detected with affinity-purified rabbit polyclonal antibody conjugated to horseradish peroxidase and quantified with a chromogenic substrate (3,3',5,5'-tetramethylbenzidine/peroxide). Leptin concentrations were calculated from standard curves generated for each assay using recombinant human leptin. The minimal leptin detection limit was 70 pg/mL. The intra- and interassay coefficients of variation were 3% and 8%, respectively.

Calculations and statistical analysis

Deconvolution analysis was applied to compute the number, amplitude, duration, and mass of significant GH secretory bursts and estimate the apparent endogenous GH half-life in blood sampled at 20-min intervals over 24 h. Weighted intraseries SDs for the chemiluminescence series were used in the estimate of the variance and covariance matrices (18, 19, 20). Basal secretion indicates the linear secretion term, if any. Half-duration measures the width of the calculated secretory burst and is equal to the duration of the calculated secretory event at half-maximal amplitude. Half-life is calculated as the monoexponential half-life of apparent metabolic removal in minutes. Peak amplitude indicates the maximal value attained within the computed secretory event, not the hormone concentration peak in the serum. Mass secreted per burst is the integral of the secretory events. Daily production rate is the product of mass per burst x the number of bursts, plus any 24-h basal secretion. Approximate entropy is a measure of the serial subpattern reproducibility of the data and is often altered in disease states even when hormone concentrations are similar. BCM was expressed as grams of TBK. The distribution of each continuous variable was examined graphically and statistically for normality. Scatterplots and Pearson correlation coefficients were used to examine the association among GH kinetic parameters, age, and BCM. The primary outcome was set a priori as the 24-h integrated GH concentration, and this was the only outcome tested statistically. Correlations between body composition parameters and other GH measures were calculated as secondary outcomes, but they were not tested statistically because they are not independent events. Associations were tested using univariate linear regression and were considered statistically significant when the two-tailed P value was less than 0.05.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
The characteristics of the study subjects are shown in Table 1Go. The mean ± SD age of the 15 women was 66.9 ± 7.8 yr, and all were Caucasian. Mean total body potassium was 86.5 ± 12.6 g, whereas body mass index (BMI; kg/m2) was 24.6 ± 3.2, and the percent body fat was 36.2 ± 8.5%. The range of BCM in the study participants was from the 25th to the 75th percentile of the expected range for healthy volunteers of this age at our center (21).


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  		Table 1. Demographic and endocrinologic attributes of study population

 
BCM correlated directly with fatness, expressed either as a percentage of body fat or as grams of fat (Fig. 1aGo; r = 0.51; P < 0.05). Twenty-four-hour integrated serum GH concentrations did not change with age within this elderly population (r = 0.11; P = 0.69), but were significantly lower than those we have previously seen in younger subjects (22). However, women with the lowest BCM had the highest 24-h GH levels (Fig. 1bGo; r = -0.51; P < 0.05). Similar relationships were seen between BCM and several other parameters of GH kinetics, including secretory burst amplitude, basal secretion, mean GH concentration, and GH production rate, but not half-life of GH; however, these were not tested statistically (Table 2Go). These associations did not change significantly after adjustment for stature. No association was found between IGF-I or IGFBP-3 and BCM, age, or GH parameters in this population.



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  		Figure 1. a, Association between percent body fat and BCM (total body potassium, grams). b, Association between 24-h integrated GH and body cell mass, measured in grams of TBK (r = -0.51; P < 0.05). c, Association between integrated 24-h GH and percent body fat (r = -0.51; P < 0.05). TBK, total body potassium.

 

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  		Table 2. Pearson correlation matrix for GH kinetic and body composition parameters

 
As expected, serum leptin levels were positively correlated with the percent body fat (r = 0.79; P < 0.0001). Integrated 24-h serum GH concentrations were inversely correlated with percent body fat (Fig. 1cGo; r = -0.51; P < 0.05). Similar correlations with percent fat were also seen for amplitude of the secretory bursts (r = -0.53) and for GH production rate (r = -0.49; Table 2Go). A strong inverse association was found between serum leptin and integrated 24-h GH levels (Fig. 2Go; r = -0.67, P < 0.006). This association was confirmed by similar correlations with basal GH secretion, burst mass, burst amplitude, GH production rate, and mean 24-h GH levels, but no correlation was found between leptin and GH half-life, half-duration, or approximate entropy (Table 2Go).



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  		Figure 2. Association between serum leptin and integrated 24-h GH levels (r = -0.67; P < 0.006).

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
In this study of healthy postmenopausal women, aged 56–80 yr, we found that 24-h GH secretion was inversely correlated with BCM. These data suggest that within a relatively homogeneous group of healthy postmenopausal women, BCM is not determined by GH secretion. This finding appears to be contrary to the widely held hypothesis that the sarcopenia of aging is due to the age-related decline in GH secretion. This observation by no means excludes the possibility that reduced GH secretion in earlier years could have a strong influence on body composition later, but it emphasizes the importance of identifying non-GH causes of sarcopenia of aging.

We believe that the most likely explanation for the inverse association between GH secretion and BCM is the confounding influence of fat mass on GH secretion. The subjects who had higher BCM also had higher fat mass. GH levels were inversely correlated with body fat and serum leptin levels. Reduced GH secretion in obese humans has long been recognized (23, 24, 25). Obese individuals secrete smaller amounts of GH at night (26) and have reduced responses to injections of GHRH (27, 28). Weight reduction improves these abnormalities (29, 30). The subjects in this study demonstrated a range of BCM from the 25th to the 75th percentile of normal (21), and they were not obese, with a mean BMI under 25 kg/m2. Only two of the subjects had BMIs above 27 kg/m2 (both 29 kg/m2), compared to a mean BMI in the comparably aged Framingham Heart Study cohort of 28.0 kg/m2 (31). Nevertheless, these subjects had relatively high fat masses compared to younger adults of the same weight, an observation that is well established in other populations (21, 31, 32). Women with chronic illness were excluded, as disease itself may alter GH secretion (33). The association between fat mass and GH secretion was evident even within the relatively narrow range of fat seen in our population.

In this study, body fat mass was shown to correlate significantly with serum leptin levels, a relationship that has been reported previously (34, 35, 36). Serum leptin levels were inversely correlated with GH secretion, a finding that confirms several recent reports (37, 38, 39). The mechanism by which leptin and GH are inversely correlated has not been determined. They may be independently regulated covariables, GH may inhibit leptin secretion by a direct action on fat cell secretion or fat mass, or leptin may inhibit GH secretion. GH administration has been reported to lower leptin concentrations in GH-deficient individuals (37), but because fat mass was also reduced by this treatment, it is not possible to distinguish between direct effects on leptin secretion and indirect effects on fat mass.

It is possible that leptin acts to reduce GH secretion by direct inhibition of the pituitary or by an action on the hypothalamus to inhibit GHRH secretion or to stimulate somatostatin secretion. It is now well established that full-length leptin receptors are present on neurons in the hypothalamus (40, 41), that leptin administration in rats inhibits the expression of neuropeptide Y in the hypothalamus (40), that leptin advances puberty in mice by stimulating the secretion of hypothalamic GnRH (42), and that leptin reverses starvation-induced thyroid inhibition in the rat through its actions on TRH-secreting neurons of the paraventricular nucleus (41). However, the limited data now available relating somatostatin secretion to leptin suggest that leptin may be suppressive, as inferred from studies in cultured and perfused rat hypothalamic preparations (43).

With weight gain, approximately 25% of the additional weight is lean mass, so that obese persons have higher BCM than lean persons (44). Because these women also have more BCM, it appears that higher BCM is associated with lower GH. We believe that this finding is an example of the epidemiologic concept of confounding (45), because GH is causally related to the exposure (fat mass, possibly mediated by leptin), but noncausally related to the outcome (BCM). This hypothesis should be tested in larger studies of humans as well as in animal studies to examine whether leptin can affect GH secretion in the intact animal.

Moderate degrees of weight (and fat) gain with age have been associated with decreased all-cause and cardiovascular mortality, although not all studies are in agreement with this finding (46, 47, 48, 49). The current observations suggest that higher fat mass, higher BCM, and lower GH levels may be consistent with successful aging. Furthermore, these data emphasize the importance of considering fat mass (and corresponding blood leptin levels) in studies of factors that regulate GH secretion and of the relationship between GH and body composition. Although we studied a relatively small group of subjects, by selecting healthy, ambulatory, free-living, postmenopausal women, it is likely that we have studied a representative group of successfully aging Caucasian women. The relationship between GH and BCM may be different in clinically obese or wasted patients. In addition, because these are cross-sectional observations, the relationship between GH and BCM in a group of women followed longitudinally could differ from the current results. However, limited data on the change in BCM with age indicate that longitudinal and cross-sectional declines in BCM with age are parallel, without evidence of a cohort effect (50). Further research on the relationship between GH and sarcopenia in men, non-Caucasian women, and premenopausal women is needed to generalize these findings to other populations. These data also indicate the need to reassess non-GH-related mechanisms of sarcopenia. A better understanding of the decline in BCM with age should allow design of strategies to reduce frailty and dependence with age and improve quality of life in this growing segment of the healthy population.


   Footnotes
 
1 This work was supported by General Clinical Research Center Grant RR-00054, USDA Contract 53–3K06–5-10, an Arthritis Foundation Clinical Science Grant (to R.R.), and the NSF Center for Biological Timing (to J.D.V.). The contents of this publication do not necessarily reflect the views or policies of the USDA, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. government. Back

Received October 20, 1997.

Revised January 15, 1998.

Accepted February 3, 1998.


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 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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