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From the Clinical Research Centers |
Division of Endocrinology and Metabolism, Department of Internal Medicine, University of Michigan Medical Center, and Department of Veterans Affairs Medical Center, Ann Arbor, Michigan 48109-0354
Address all correspondence and requests for reprints to: Ariel L Barkan, M.D, 3920 Taubman Center, Box 0354, University of Michigan Medical Center, Ann Arbor, Michigan 48109-0354. E-mail: abarkan{at}umich.edu
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The neuroendocrine mechanisms of somatopause are uncertain. Some early studies suggested that it is the pituitary itself that undergoes senescent changes (8, 9). However, other data refute this explanation. First, there is no apparent decrease in the number of somatotrophs in the pituitaries with age (10, 11). Second, even though older rats have diminished responses to GHRH in vivo, the in vitro pituitary responsiveness to GHRH does not decline with age (12). Perhaps the strongest argument against a primary pituitary mechanism of somatopause is the ability of exogenous GHRH (13, 14) or GH-releasing peptide (GHRP) analogs (15, 16) to rejuvenate GH output and plasma IGF-I levels in elderly humans. Thus, the focus of investigations has shifted to potential alterations of the hypothalamic regulation of GH secretion.
Two hypothalamic peptides, GHRH and somatostatin (SRIH), have been firmly established as crucial for the regulation of pituitary somatotroph proliferation and the synthesis and secretion of GH (17, 18, 19). The putative endogenous ligand for the GHRP receptor (20) has not yet been identified and its precise role and significance are not yet known. Aging-associated GH decline has been ascribed to hypothalamic SRIH excess, GHRH deficiency or both (1, 3). However, these studies were invariably performed in the rat model and species specificity does not allow these results to be automatically applied to humans (21). Direct experimental approaches, such as pituitary-portal blood sampling (22), are impractical in humans for obvious reasons, and measurements of GHRH and SRIH in the peripheral blood do not reflect their hypothalamic output. Therefore, insights into hypothalamic mechanisms governing GH secretion in humans have been derived exclusively from indirect studies of the discrete parameters of GH pulsatility and pharmacological manipulations of GH secretion. The interpretation of data obtained by these methodologies is confounded by complexity of GH neuroregulation and the potential interactions between GHRH and SRIH (23). Moreover, the conclusions have often conflicted with data from more direct experimental models (24, 25).
Recently, Hall et al. (26) suggested an alternative approach to the study of hypothalamic neurohormonal output. Using graded doses of GnRH antagonist, they found differential inhibition of LH secretion during various stages of the menstrual cycle, suggesting cycle-related variability of hypothalamic GnRH secretion. This model is based on simple and well established principles of pharmacodynamics (27) and was also validated by the assessment of the endogenous endorphin tone with a specific opiate antagonist, naloxone (28, 29).
In this study we validated a model for semiquantification of endogenous hypothalamic GHRH secretion. This model uses graded infusions of a specific competitive GHRH receptor antagonist (N-Ac-Tyr1,D-Arg2)GHRH-(1–29). Implementation of this model suggests the existence of relative GHRH deficiency in elderly men.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The studies were approved by the institutional review board of the University of Michigan Medical School and the Department of Veterans Affairs Medical Research Service. Each subject signed a consent form before this participation in the protocol.
Sixteen young (19–30 yr old) and 10 elderly (60–81 yr old) men were
recruited from the community. All were healthy, as documented by
medical history, physical examination, and routine hematological and
biochemical testing. Specifically, none had evidence of cardiovascular,
hepatic or renal disease, or diabetes mellitus. Young subjects were not
taking any medications on a regular basis, and some elderly men took
multivitamin supplements, prophylactic aspirin, and/or other
medications (diuretics, lipid-lowering agents, antacids, and
bronchodilating inhalers) that were known not to influence GH
secretion. All subjects were night sleepers, and none of them had
transmeridian travel within 3 weeks before study. Body mass index (BMI)
was below 29 kg/m2 in all participants. Young men
were physically active college students, who did not engage in
intercollegiate competitive sports. Elderly men were physically active
and engaged in daily physical exercise (running up to 3 miles/day,
swimming, bicycling, cross-country skiing, rollerblading,
etc.). The demographic data are summarized in Table 1
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Each subject underwent four to six in-patient overnight studies at the General Clinical Research Center of the University of Michigan. They all had a baseline study with normal saline infusion and three to five studies with varying doses of GHRH antagonist. Subjects were given a standard hospital meal at 1800 h and then remained fasting, except for water, until the end of the study. Heparin-filled venous cannulas were placed in each arm (one for infusion and another for blood sampling). Blood sampling was performed every 10 min from 2000 h on day 1 until 1100 h on day 2. Continuous iv infusion of either normal saline or GHRH antagonist (diluted in normal saline) was administered at a rate of 15 ml/h from 2100 h on day 1 until 1100 h on day 2. Intravenous boluses of 0.1, 0.33, and 1.0 µg/kg BW GHRH-44 (Peninsula Laboratories, Inc., Belmont, CA) were given at 0500, 0700, and 0900 h, respectively. Human serum albumin (1%) was added to all infusions to prevent adherence of the peptide to the plastic. Lights were turned off at 2300 h and on at 0700 h. Sleeping was not allowed before 2300 or after 0700 h.
In the young subjects, the GHRH antagonist doses were 0.033, 0.1, 0.33, 1.0, 3.3, 10, and 33 µg/kg·h. In the elderly subjects, only the four lowest doses were infused. In the early phase of the study, nine subjects (four young and five elderly) were given GHRH antagonist infusion at the rate of 0.033 µg/kg·h. When it became obvious that this dose was ineffective in suppressing GH output in the young, it was omitted in subsequent studies and eliminated from the analysis. The actual data with this dose are, nevertheless, presented in the appropriate figures. In each individual, the order of the studies (saline vs. different doses of GHRH antagonist) was randomized, and a minimum of 3 days elapsed between consecutive studies. This time frame was based on our earlier data showing disappearance of the GHRH antagonist effect within 12–24 h after its administration (30).
GHRH antagonist (N-Ac-Tyr1,D-Arg2)GHRH-(1–29) was manufactured by Bachem (King of Prussia, PA) according to the GMP conditions and administered under IND 33,255. The antagonist was prepared by the investigational pharmacy of the University of Michigan as 2 mg/ml solution in normal saline. The stock solution was stored at -20 C, thawed immediately before administration, and diluted in normal saline containing 1% human serum albumin to the target concentration.
Body composition
Body composition was assessed in 14 of the young and 9 of the elderly subjects (body fat, lean body mass, and bone mass) using a total body dual energy x-ray absorptiometry scan (DEXA; IQ analysis software version 4.1, Lunar Corp., Madison, WI). The three subjects in whom DEXA was not performed had BMIs within 1.2 SD of the mean of their age group.
Assays
Blood samples were centrifuged, and plasma was stored at -20 C until assayed. All assays were run in duplicate. Plasma GH was measured by a chemiluminescent assay (Nichols Institute, Inc., San Juan Capistrano, CA). The assay sensitivity was 0.01 µg/L, and the mean intraassay coefficient of variation (CV) was 9% between 0.01–0.1 µg/L and 5% between 0.1–40 µg/L. The interassay CV was 7% at 9 µg/L. Insulin-like growth factor-binding protein-3 (IGFBP-3), IGF-I, testosterone (T), and estradiol (E2) were measured in a sample made by pooling plasma obtained every 10 min from 2100–2200 h during the normal saline infusion. Total IGF-I was measured after acid-ethanol extraction by an immunoradiometric assay (Diagnostics Systems Laboratories, Inc., Webster, TX) with a sensitivity of 0.03 µg/L. IGFBP-3 was measured using RIA kits (Diagnostics Systems Laboratories, Inc.) with a sensitivity of 0.05 mg/L. Plasma E2 was measured using commercial assay (Coat-A-Count, Diagnostics Products, Los Angeles, CA) with a sensitivity of 8 ng/L. Plasma T was measured using commercial assay (Coat-A-Count, Diagnostics Products) with a sensitivity of 0.04 µg/L. All samples with measured concentrations below the sensitivity of the assay were assigned the value of the assay sensitivity.
Calculations
The integrated GH concentration (IGHC; micrograms per min/L) was calculated by the trapezoidal rule. Maximal GH (micrograms per L) was defined as the highest GH level measured during the specific time interval. Spontaneous output was defined as the IGHC during the 2100–0500 h interval. Previous data have shown that IGHC during this time period accounts for approximately 80% of the total daily IGHC in young men (31). The responses to GHRH stimulation were defined as IGHC and maximal GH over the 2 h after the GHRH bolus injection. Only IGHC data are shown, as they represent a more reliable estimate of GH output than a single GH value. Reanalysis of the data using maximal GH values produced similar results, with minor differences in P values that did not affect the conclusions of the study.
In each subject, GH output (spontaneous or GHRH induced) during each GHRH antagonist dose was calculated as a percentage of the corresponding GH measurement during baseline saline infusion (percent residual output). Percent inhibition was calculated as 100% - % residual output.
Statistical analysis
The percent inhibition of GH output (spontaneous and GHRH
stimulated) by different doses of GHRH antagonist was analyzed by
repeated measures ANOVA to detect potential shifts in dose-inhibition
curves for the age groups. A similar analysis was performed to
investigate the effect of GHRH antagonist on the GH response to GHRH
boluses. Only data points common to both groups were included in these
ANOVAs, except 0.033 µg/kg·h as noted above. Post-hoc
testing was performed using Tukey-Kramer adjustments as appropriate.
Repeated measures ANOVA was used to compare GH responses to GHRH
boluses on the baseline saline day. All other parameters were analyzed
by paired or unpaired Student’s t tests after logarithmic
transformation when appropriate. Data are presented as the mean ±
SE. Statistical significance was assumed for
P 
0.05.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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and 2)Young and elderly subjects had similar heights and weights. However, despite virtually identical mean BMI values, their body compositions were different, with a higher percentage of body fat (P = 0.05) and a lower lean body mass (P = 0.01) in the elderly. In elderly subjects, plasma IGF-I concentrations were approximately half of the average value observed in the young group (P = 0.0001). Mean IGFBP-3 was approximately 20% lower in the elderly (P = 0.04). Plasma E2 and T concentrations were similar between the two groups (P = 0.75 and P = 0.95, respectively).
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and Table 2)
GH data from the entire experiment are shown as the mean ±
SE in Fig. 1. Elderly subjects had lower spontaneous
maximal GH concentrations (8.8 ± 2.1 vs. 14.3 ±
2.2 µg/L; P = 0.04) than young subjects. Although the
elderly had 32% lower nocturnal spontaneous IGHC (924 ± 199
vs. 1350 ± 228 µg/min·L) than the young, this
difference did not reach statistical significance (P =
0.15).
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) elicited similar
IGHC responses in both age groups (P = 0.47). There was
a dose-response relationship between the magnitude of the GHRH stimulus
and IGHC response (P = 0.008).
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Inhibition of GH responses to standard amounts of exogenous GHRH
(Fig. 3). Higher doses of GHRH
antagonist produced higher percentages of IGHC inhibition at each GHRH
bolus (P = 0.006–0.03), indicating the ability of
graded infusions of GHRH antagonist to inhibit the IGHC response in a
dose-dependent manner. At each dose of GHRH, the ability of GHRH
antagonist to inhibit IGHC responses did not differ between the young
and elderly groups (P = 0.15–0.80). We were therefore
able to pool the young and elderly data for each particular GHRH dose.
This pooling increased the power of the subsequent analysis in which we
determined whether there were differences between the dose-inhibition
curves when known amounts of exogenous GHRH were given (Fig. 4).
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) for all three GHRH boluses. The ability of GHRH
antagonist to suppress IGHC responses to known doses of GHRH depended
on the magnitude of GHRH stimulus (P = 0.01),
indicating that there was a dose-related shift in the dose-inhibition
curves. Pairwise comparisons of dose-inhibition curves in Fig. 4 showed
that the dose-inhibition curve for 1 µg/kg GHRH was significantly
shifted to the right compared to those for 0.33 µg/kg GHRH
(P = 0.005) and 0. 1 µg/kg (P =
0.004). The dose-inhibition curves for GHRH boluses of 0.1 and 0.33
µg/kg were not significantly different (P = 0.84)
from each other by pairwise comparisons.
Inhibition of spontaneous nocturnal GH output. Mean GH data
during saline and GHRH antagonist infusions are shown in Fig. 1. Visual
inspection suggested no apparent inhibition of GH output in young
individuals by GHRH antagonist doses below 1 µg/kg·h. Higher GHRH
antagonist doses appeared to produce dose-dependent inhibition. In
contrast, in the elderly, spontaneous nocturnal GH output appeared to
be inhibited even by the lowest GHRH antagonist dose, with more
prominent inhibition by higher antagonist doses.
Formal analysis of these data is shown in Fig. 5. In both groups, dose-dependent
inhibition of spontaneous GH output was achieved. However, the
dose-inhibition curve for the group of elderly subjects was
significantly (P = 0.01) shifted to the left. This
analysis was conducted after exclusion of the data obtained with the
0.033 µg/kg·h GHRH antagonist dose as explained previously. Had
this point been included in the analysis, the difference between the
curves would have become even more significant (P =
0.0008). At the best discriminating point (GHRH antagonist dose of 0.33
µg/kg·h), the GH suppression in the young was 7 ± 13%
vs. 59 ± 6% in the elderly (P =
0.01).
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As the elderly had significantly higher body fat content despite similar BMI values, we were concerned that the GH data might have been affected by the differences in relative adiposity. Therefore, we performed a secondary data analysis on subgroups matched for percentage of body fat. First, GH data from the three subjects who did not have DEXA scans were omitted from the dataset. In the remaining subjects, the percentage of body fat ranged from 8.2–26.7% in the young and from 14.2–37.9% in the elderly. We further constrained the dataset to encompass all subjects who fell within 1.1% (the precision of measurement as reported by the manufacturer) of the overlapping range (i.e. 13.1–27.8% body fat). This left a group comprised of eight elderly men with the lowest percent body fat and the eight young men with the highest percent body fat. Within these subgroups, there were no age-related differences in percent fat (20 ± 2% vs. 19 ± 2%, elderly vs. young; P = 0.66), height (176 ± 2 vs. 175 ± 2 cm; P = 0.62), weight (67 ± 2 vs. 71 ± 3 kg; P = 0.37), fat mass (13 ± 2 vs. 12 ± 2 kg; P = 0.94), lean mass (50 ± 1 vs. 53 ± 2 kg; P = 0.11), BMI (22 ± 1 vs. 23 ± 1 kg/m2; P = 0.25), spontaneous baseline IGHC (104 ± 23 vs. 80 ± 16 µg/min·L; P = 0.40) and spontaneous maximal GH (9.8 ± 2.5 vs. 8.9 ± 1.6 µg/L; P = 0.77). In addition, there were no significant age-related differences in either GHRH-induced IGHC responses during the baseline study (P = 0.34) or GH/GHRH antagonist dose-inhibition curves to known amounts of GHRH (P = 0.86). Within these subgroups, the dose-inhibition curve of spontaneous IGHC by graded GHRH antagonist infusions in the elderly still showed a strong trend for a leftward shift compared to the younger group (P = 0.07).
Side-effects
No GHRH antagonist-related side-effects were observed in either group. GHRH boluses of 1.0 µg/kg produced short term facial flushing in a few subjects.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Similar to previous studies (6, 7, 14, 15, 16), the elderly subjects had lower spontaneous nocturnal maximal GH concentrations than the young, although IGHC were not statistically different. In earlier studies, GH assays with insufficient sensitivities were used, and precise definition of low GH levels (<1–2 µg/L) was impossible. Moreover, subjects with a wide range of body adiposity were often included (32, 33), and the degree of physical fitness in the elderly was likely to be lower than that in our subject population. In studies with heterogeneous subject populations (5, 32), the relative roles of aging, obesity, and gonadal steroids were inferred from stepwise multiple regression analysis. These intervening variables are interdependent, and the precise role of each was difficult to ascertain. Some of these methodological problems were avoided in our study by enrolling physically active elderly subjects who were similar to the young subjects in terms of BMI and gonadal steroids. Therefore, we were able to isolate the effect of aging as the primary variable. Similarities in BMI and gonadal steroids are the most likely reason that the degree of GH deficiency in our elderly subjects was relatively mild, with only statistical trending toward lower IGHC. Thus, in our attempt to study the effects of aging per se, we most likely selected elderly men with higher than average GH levels for their age, thus introducing a bias against our hypothesis. Interestingly, despite only small differences in GH values, the plasma IGF-I concentrations were significantly lower in the elderly, suggesting that the seemingly minor difference in GH has biological significance.
Many previous studies using the rat model attempted to examine the relative involvements of SRIH and GHRH as mediators of GH deficiency in aging. Increased somatostatinergic tone was postulated, but the actual data are contradictory. Both increased (34, 35) and reduced (1, 8, 36) hypothalamic SRIH contents were found in the hypothalami of aged rats. However, hypothalamic SRIH messenger ribonucleic acid (mRNA) was uniformly found to be decreased in old animals (37, 38, 39, 40). These findings are in disagreement with the hypothesis of high SRIH tone in aging.
Data implicating a fall in hypothalamic GHRH secretion as the cause of the somatopause have been more compelling. A loss of GHRH neurons has been postulated as a cause of GH deficiency in old rats (41), and GHRH content and GHRH mRNA expression in the hypothalami of old animals are low (34, 37, 42, 43). In elderly humans, administration of exogenous GHRH restores normal GH and IGF-I levels (13, 14). Thus, the possibility of GHRH deficiency in aging is supported by several lines of evidence. However, the crucial piece of evidence, a decrease in hypothalamic output of GHRH, has not been demonstrated in any model. Whereas this may be possible to investigate in animals by pituitary-portal blood sampling, such an approach is obviously impractical in humans.
We assessed the magnitude of hypothalamic GHRH output in vivo in humans using the pharmacological model previously developed for semiquantification of hypothalamic GnRH secretion (26) and endogenous opioids (28, 29). The model depends on competition for the GHRH receptor between the endogenous receptor agonist (GHRH) and a competitive receptor antagonist (GHRH antagonist). The magnitude of GH suppression by GHRH antagonist would be inversely proportional to the amount of GHRH present in the system (27). Expression of the data as a percentage of the baseline value allowed comparisons to be made between physiological states with different absolute magnitudes of GH secretion, and the use of graded GHRH antagonist infusions over a 1000-fold range permitted assessment of GH suppressibility at the linear part of the dose-response curve.
First, we validated the model by giving graded doses of GHRH antagonist to suppress the GH responses to known amounts of GHRH. As expected, the dose-inhibition curves for lower boluses of GHRH were significantly shifted to the left compared to those for the higher GHRH dose. Thus, this current model was capable of differentiating the degree of in vivo GHRH exposure over a 3- to 10-fold range. This range is comparable to the differences in hypothalamic GHRH and GHRH mRNA contents observed between young and old rats (40, 42, 43).
Next, we assessed the ability of graded infusions of GHRH antagonist to suppress spontaneous GH secretion. We observed a significant shift to the left of the dose-inhibition curve in the elderly vs. the young subjects. This pattern was similar to the data obtained with different exogenous GHRH boluses. Thus, our data suggest lower endogenous GHRH output in the elderly subjects.
One potential confounding factor in our study was the increased relative adiposity in the elderly subjects as reflected by their higher percentage body fat. A higher body fat content despite similar BMI in the elderly is well described (44). Conceivably, higher relative adiposity and lower lean body mass in the elderly men could have resulted from relative GH deficiency (45). Higher adiposity may result in a heightened SRIH tone (46), which, in turn, could theoretically potentiate the ability of GHRH antagonist to inhibit GH secretion. To overcome this problem, we repeated the analysis in two subgroups of young and elderly men with similar percentages of body fat. In this small subset, there was still a strong trend for GHRH antagonist to inhibit spontaneous GH secretion with higher potency in the elderly than in the young (P = 0.07). Thus, the greater inhibition of GH by GHRH antagonist in the elderly could not be explained by the difference in body composition parameters, and our conclusion of a lowered GHRH milieu in the elderly was further supported.
In other systems, the number and the affinity of ligand receptors may be important determinants of hormonal response. This might also apply to the pituitary response to GHRH and GHRH antagonist. Unfortunately, there is no information regarding the potential dynamics of GHRH receptors in different physiological situations, including aging. An early study using iodinated (Tyr10)GHRH-44 suggested a decline in GHRH binding in aged rats (47). However, the difference was accounted for by low affinity sites that have uncertain physiological relevance. A decline of GHRH receptor mRNA has also been observed with aging (48). However, in other systems there are nonlinear relationships among receptor mRNA, ligand binding, and functional ligand effects. For example, pituitary LH responsiveness to GnRH is maximal in cycling (49) or ovariectomized E2-treated (50) rats just before the LH surge when there is an acute 50% fall in GnRH receptor number. GnRH receptor mRNA content, however, is stable at that time, but falls precipitously after the LH surge (51). Thus, GHRH receptor mRNA content may be an imprecise reflection of actual GHRH receptor number or affinity. Knowledge of receptor parameters is important for the interpretation of data that depend on competitive interactions between the endogenous ligand and the exogenous antagonist. We have addressed this issue indirectly by demonstrating that the dose-response curves for known amounts of GHRH and their inhibition by GHRH antagonist are similar in young and elderly men. Thus, alterations in GHRH receptor parameters are unlikely to play a role in the differential sensitivity of the two groups to receptor blockade. This issue needs to be further addressed in future studies.
Even though SRIH excess is an unlikely cause of GH deficiency in aging, this possibility needs to be considered. Similarly, deficiency of the putative endogenous ligand for the GHRP receptor may explain the lower GH output in aged men (15, 16). Either of these mechanisms could alter pituitary responsiveness to GHRH. However, the similarity of GH responses to GHRH in both age groups makes their contribution unlikely. In fact, similar spontaneous GH output between age groups (especially in the relative adiposity-matched groups) despite evidence of lower GHRH milieu may actually suggest hypothalamic SRIH deficiency in the elderly. This would be compatible with the age-related fall in both hypothalamic SRIH (8, 36) and SRIH mRNA (37, 40) contents observed in some animal studies. This hypothesis can be directly tested in young and old sheep using pituitary portal blood sampling. Future studies using endogenous GHRP ligand and its antagonist(s) as well as SRIH antagonist(s) will be necessary to address these issues in greater detail in humans.
The neuroendocrine mechanisms leading to GHRH deficiency in elderly men are unknown. Relative hypogonadism in old age may play a role (52). Animal studies have shown that gonadal steroids augment GHRH gene expression and that castration leads to a decline in GHRH mRNA and peptide contents in the hypothalamus (53). However, this does not explain the apparent decrease in GHRH in the elderly men, because their plasma sex steroid concentrations were similar to those in the young subjects.
In conclusion, our study validates the model of semiquantification of endogenous hypothalamic GHRH output by using graded doses of GHRH antagonist in vivo in humans. Our data suggest the existence of relative GHRH deficiency in elderly men as a potential cause of the aging-associated decline in GH. This model could be applied to assess the contributions of endogenous GHRH to the regulation of GH secretion in physiological and pathological conditions such as puberty and growth disorders.
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Acknowledgments |
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Footnotes |
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Received April 15, 1999.
Revised July 1, 1999.
Accepted July 8, 1999.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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