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Department of Endocrinology, Christie Hospital (K.H.D., S.M.S.), Manchester, M20 4BX United Kingdom; and Department of Medicine, University of Virginia Health Science Center (S.S.P., M.O.T.), Charlottesville, Virginia 22908
Address all correspondence and requests for reprints to: Dr. Stephen M. Shalet, Department of Endocrinology, Christie Hospital, Wilmslow Road, Manchester M20 4BX, United Kingdom. E-mail: stephen.m.shalet{at}man.ac.uk.
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Abstract |
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 Top Abstract IntroductionPatients and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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In this study we used an ultrasensitive GH assay characterized by a detection limit 100–200 times lower than that of a conventional GH assay. All studies using ultrasensitive assays have shown that the GH concentration never falls to undetectable levels in normal or GH-deficient subjects (12, 13, 14, 15, 16, 17), and that tonic and pulsatile GH secretion are maintained, albeit attenuated, in patients with GH deficiency (13, 15).
Preservation of GH pulsatility and, hence, GH neuroregulation in patients with adult-onset GH deficiency due to pituitary tumors and its treatment have been demonstrated in many studies (15, 16, 17, 18). Although, many of the patients included in these studies had received hypothalamic-pituitary (h-p) irradiation, the actual impact of radiation on GH pulsatility is more difficult to interpret because of the impact of the tumor itself as well as the inclusion of nonirradiated patients (15, 16) and patients with less severe degrees of GH deficiency or even normal GH status (17) according to current diagnostic thresholds (19). More importantly, all of these studies have addressed patients who received irradiation late in adult life. Therefore, the results may not necessarily reflect the actual impact of irradiation administered during childhood; current evidence suggests that the radiosensitivity of the h-p axis is greater in children (20, 21, 22, 23).
A number of studies have examined physiological GH secretion in irradiated children, but failed to provide detailed characterization and uniform conclusions about GH secretory patterns (24, 25, 26, 27, 28, 29). These studies included heterogeneous groups of patients at various stages of pubertal development and used a variable threshold for the biochemical diagnosis of GH deficiency. Furthermore, the use of conventional GH assays and less robust methods of pulsatility analysis blurred the overall conclusions that could be drawn from these studies.
Therefore, the aim of our study was to provide a more clear description of GH dynamics and a better understanding of the long-term impact of radiation damage to the h-p axis sustained in childhood on GH neuroregulatory mechanisms
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Patients and Methods |
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Ten young adult patients (three women and seven men), aged 18–37.7 yr (median, 23.8 yr), with severe radiation-induced GH deficiency were included in this study. GH deficiency was confirmed by the failure to respond to both the insulin tolerance test (ITT) and the combined GHRH plus arginine stimulation test (GHRH+AST) according to well established cut-off levels of peak GH responses of less than 3 and 9 µg/liter, respectively (8, 19, 30). All patients had received whole brain irradiation and/or focal irradiation during childhood for brain tumors anatomically distinct from the h-p region. The radiation field included the h-p axis in all patients, and the biological effective dose of radiation delivered to the h-p axis was calculated as previously described (8) (Table 1
). None of the patients had any other pituitary hormone deficits. Three men had sustained chemotherapy-induced testicular damage (low testosterone with elevated gonadotropins levels), and two patients had primary hypothyroidism; they were all receiving testosterone and/or T4, and their replacement therapies had been optimized for at least 6 months before testing. All patients had long-standing GH deficiency and had achieved a final height below their target height (31). Five of the 10 patients received GH therapy in childhood (finished at least 1 yr before this study), but none had received GH replacement therapy in adult life.
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The normality of GH status in all normal subjects was confirmed by an unequivocally normal response to both the ITT and GHRH+AST (peak GH responses >5 and >9 µg/liter, respectively), as reported previously (8). No patient or normal control was receiving any medications that might influence GH secretion.
Study protocol
The study was approved by the South Manchester local research ethics committee, and informed consent was obtained from all subjects before testing.
Subjects were admitted to the endocrine investigation ward at about 0800 h. An indwelling iv cannula was inserted into a large forearm vein and connected to an extension three-way valve to minimize the subject’s disturbance during blood withdrawal. The cannula was kept patent with normal saline flush after each blood collection or by a very slow iv infusion. Three standard hospital meals were provided at 0830, 1230, and 1800 h. The patients were allowed an extra snack in the evening, and physical activity was restricted to within the ward. Lights on the ward were turned off at 2300 h, and subjects were encouraged to retire to bed and sleep. All subjects were awakened at 0700 h.
Blood sampling started at 0900 h and continued at 20-min intervals until 0840 h the next morning; a total of 72 samples were collected. All samples were allowed to settle for at least 30 min, but not more than 60 min, to allow adequate clotting and generation of the maximal amount of serum upon centrifugation at 3000 rpm. Sera were then separated and immediately frozen at –80 C until the assays were performed. A separate serum aliquot from the last sample in the profile was used for the IGF-I assay.
Women were profiled in the first half of their menstrual cycles, and none had taken any oral contraception for at least 6 months before the study.
Serum GH assay
Serum samples for GH concentrations from each subject’s profile and their GH stimulation tests were analyzed in duplicate in the same assay using the modified Luma Tag hGH chemiluminescence immunometric assay (Nichols Institute, Inc., San Juan Capistrano, CA) (13). The GH standards used in this assay were calibrated against the first International Standard 80/505. The sensitivity of this assay was 0.003 µg/liter. The intraassay coefficients of variation were 11.3, 9.8, and 11.7% for GH concentrations of 8.22, 0.293, and 0.027 µg/liter, respectively. The interassay coefficients of variation at the same GH concentrations were 6.6, 7.7, and 10.4%, respectively.
Serum IGF-I assay
Serum IGF-I was determined by a two-site chemiluminescent immunometric assay. In this technique the serum sample is acidified to separate IGF-I from IGFBPs. Then excess IGF-II is added in the assay to block the IGF-binding protein-binding sites from recombining with the released IGF-I. A C-terminal antibody is used to capture the free IGF-I, and detection of the captured IGF-I is achieved by acridinium ester labeled by a second IGF-I antibody using the Advantage automated immunoassay analyzer (Nichols Diagnostika, Bad Nauheim, Germany). The intraassay coefficients of variation are 4.8%, 5.2%, and 4.4% for IGF-I concentrations of 63, 208, and 766 µg/liter, respectively and the interassay coefficients of variation are 7.1%, 5.7%, and 7.4% for IGF-I concentrations of 62, 215, and 811 µg/liter, respectively.
Analysis of GH concentration profiles
The Cluster algorithm was used to analyze attributes of the GH concentration profiles (32). The mean values of the duplicate GH concentrations for each time point were used, and a fixed coefficient of variation of 10% was assigned before running the Cluster program. The Cluster parameters used (t statistic for an upstroke = 1, t statistic for a downstroke = 1, cluster size for the test peak or nadir = 1) have been shown to provide optimal peak detection with over 90% sensitivity and positive predictive accuracy (32)
In this analytic algorithm, a peak (pulse) is defined as a significant increase, followed by a significant decrease. A nadir is defined as a significant decrease, followed by a significant increase. Significant interpeak intervals (valleys) are identified as regions embracing nadirs without intervening upstrokes, i.e. interpeak regions containing no significant increases or decreases. The absolute peak GH level and absolute GH nadir are the highest and lowest GH concentrations in the profile, respectively. The area under the curve is the time-integrated value for all GH concentrations for the entire sampling period (AUCGH) and is equivalent to the profile mean GH concentration multiplied by the profile duration (1440 min).
Diurnal variation in GH secretion
Cosinor analysis was used to appraise diurnal variation in GH concentrations. This involves fitting a cosine function curve to the data using the least squares method (33). Three parameters were calculated for the fitting curve that defined the diurnal variation according to this equation: GH concentration (t) = mean + amplitude x cosine [2
(t + acrophase)/P] + e, where the mean (mesor) of the curve is the value around which the oscillation occurs, amplitude is the distance from the mean to the peak of the curve, acrophase is the timing of the peak (cosine maximum; Fig. 1), P is the fixed period of the time series (which is 24 h), and e is the residual error in the equation (the difference between the actual and the calculated GH concentration). The relative amplitude (amplitude/mean) is a measure of the amplitude of the diurnal change.
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Pulsatile vs. tonic GH secretion
This was indirectly appraised by analyzing the ratio of the pulsatile AUCGH (number of pulses multiplied by the mean pulse area)/total AUCGH. This ratio should not change significantly if basal and pulsatile GH secretions are reduced proportionally in GH-deficient patients. Although a higher ratio denotes a larger pulsatile component, a lower ratio indicates a higher fractional contribution of tonic GH secretion.
Approximate entropy statistic (ApEn)
ApEn is a scale- and model-independent regularity statistic that assigns a single nonnegative number to a time series to quantify the orderliness or regularity of consecutive hormone concentration measurements; larger ApEn values denote greater apparent process randomness (34, 35). ApEn measures the logarithmic likelihood that runs of patterns that are similar remain similar on the next incremental comparisons. Two input parameters, m and r, must be fixed to compute ApEn. In this study we calculated the ApEn for each profile using the input parameters of m = 1 (series length) and r = 20% (threshold) of the average SD of the GH time series. These input parameters have been shown to provide the most robust and sensitive measure of patterning complexity with good statistical validity for comparing data time series of 50–300 points (34, 35, 36, 37, 38, 39, 40, 41). A higher ApEn value indicates a greater disorderliness (randomness) of moment to moment hormone release, as previously observed in acromegalic patients (37) and in normal women compared with normal men (38).
GH sensitivity
The ratio of IGF-I concentration/AUCGH was used to compare GH sensitivity among the groups. This assumes that non-GH-dependent IGF-I production is not changed in GH-deficient patients. Thus, a higher IGF-I/AUCGH ratio is characteristic of increased tissue responsiveness to the available circulating GH.
Statistical analysis
The data were expressed as the mean ± SD if normally distributed or as the median and range if the data were skewed. Simple correlations to examine the relationship between variables were made using the Spearman rank order correlation test. Student’s t test was used to examine the differences between normally distributed data, whereas a Mann-Whitney rank-sum test was used when the data were nonnormally distributed (skewed). Statistical significance was accepted at P < 0.05.
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Results |
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Pulsatile GH secretion was preserved in all patients. GH was detected in all samples, and pulsatility was evident with the lowest of GH concentrations in all subjects (Fig. 2). Gender-specific comparisons revealed significant reduction in all amplitude-related measurements in the patients (Tables 2 and 3), and similar pattern of results were obtained when comparing all patients with all normal subjects or with the BMI-matched subgroup (Table 4). This is critically important to define the lowest normality limits for some measures, such as the absolute GH peak level and the mean GH level (or AUCGH). As expected, most values for this subgroup occupied the lower end of the spectrum in normal subjects (Fig. 3).
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A clear demarcation between patients and normal subjects was achieved by the absolute GH peak. The separation between the two groups was almost complete using the mean GH level (or the AUCGH); however, two patients had AUCGH values above the lowest level of the normal group (320 µg·min/liter), and one normal subject had a value below the maximum for the GH-deficient patients (358 µg·min/liter). A substantial overlap was noted in the absolute nadir levels (Fig. 3 and Table 4).
Frequency-related measurements (number of pulses, mean pulse duration, interpulse interval, and mean valley duration) did not differ between the patients and the control group (Tables 2 and 3).
The peak GH responses to ITT and GHRH+AST did not significantly correlate with the maximum (absolute) GH peak in the profile or the profile mean GH concentration in normal subjects or patients. However, when both groups were combined, all of these correlations achieved statistical significance (r = 0.7; P = 0.0001).
Pulsatile GH secretion
The ratio of the pulsatile AUCGH/total AUCGH was significantly reduced in the patients by about 40% (Tables 2–4). The results are consistent with greater attenuation in the pulsatile component of GH secretion.
Diurnal variation in GH secretion
Gender-specific comparisons revealed a reduction in the ratio of night AUCGH/total AUCGH in male patients only (Tables 2 and 3). This was echoed by a reduction in the relative amplitude in cosinor analysis, suggesting that nighttime augmentation of GH secretion (amplitude of the diurnal variation) is diminished in male patients. The absence of similar differences in female patients reflects the reduction in the amplitude of the diurnal change in normal women compared with normal men (Table 5). The timing of the diurnal change (acrophase) did not differ significantly among the groups (Tables 2, 3, and 5).
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Considerably higher ApEn values were noted in patients (Tables 2 and 3) and normal women compared with normal men (Table 5). No significant correlation was observed between the ApEn and IGF-I levels, IGF-I SD score (SDS), maximum peak GH levels, or the AUCGH in patients or normal subjects.
Effect of gender on GH secretion
Normal women (n = 9) who were age- and BMI-matched with normal men (n = 21) had higher mean GH levels (or AUCGH) that almost reached statistical significance and significantly higher interpeak (nadir) levels (Table 5). Frequency-related measurements were not different (data not shown). The increase in GH levels reflected a predominant increase in daytime GH levels resulting in a reduced amplitude of the diurnal rhythm, as indicated by a fall in the night AUCGH/total AUCGH ratio and the relative amplitude (Table 5).
Effect of BMI on GH secretion
Using multiple linear regression analysis with AUCGH as the dependent variable and age, gender, and BMI as the independent variables, the BMI contributed significantly to the equation (P = 0.03), whereas the effect of female gender was almost significant (P = 0.06); the effect of age was not significant (P = 0.11).
In normal men, significant negative correlations were noted between the BMI and AUCGH (r = –0.61; P = 0.003), absolute GH peak (r = –0.6; P = 0.004), mean GH peak height (r = –0.5; P = 0.02), and absolute nadir levels (r = –0.56; P = 0.008). Similar correlations were not significant in normal women.
Normal men (n = 15) with lower BMI (median, 21.5; range, 19.4–23.6 kg/m2) had significantly higher amplitude-related measurements compared with normal men (n = 6) with BMI above 24 kg/m2 (median, 25.4; range, 24.1–27.1 kg/m2). Both groups were age-matched (Table 6). The BMI did not affect the pulsatility pattern, relative amplitude, acrophase, or ApEn.
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IGF-I and IGF-I SDS
IGF-I levels and IGF-I SDS (mean ± SEM) were significantly reduced (P < 0.0001) in the patients (Tables 2–4). In the patients, IGF-I SDS negatively correlated with the BMI (r = –0.80; P < 0.0001) and positively correlated with mean GH levels (r = 0.8; P < 0.0001) and absolute GH peak (r = 0.8; P = 0.005), but not with the absolute nadir levels, mean valley nadir levels, or the peak GH responses to the stimulation tests. Similar correlations were not observed in the normal cohort.
GH sensitivity
A higher IGF-I/AUCGH ratio was noted in the patients (Table 4). In normal subjects, men with BMI greater than 24 kg/m2 had the highest ratio, and women had the lowest ratio. In addition, strong negative correlations were observed between the IGF-I/AUCGH ratio and the AUCGH in normal men (r = –0.8; P < 0.0001), normal women (r = –0.73; P = 0.01), patients (r = –0.7; P = 0.01), and all groups combined (r = –0.91; P < 0.0001). This suggests that GH sensitivity is a continuum that increases with the decline in GH production (Fig. 4).
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Discussion |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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Sex, age, and BMI quantitatively influence GH secretion (41, 42). There is no evidence that a change in BMI (or fat mass) can influence GH pulsatility (41). In this study, a BMI match was achieved with eight normal subjects who still had significantly higher GH levels than the patients with clear demarcation.
Our findings regarding GH secretion in women, in particular the increased interpulse GH concentrations, are in accord with previous results (12, 17, 41, 43, 44, 45). Previous studies have demonstrated the dampening effect of obesity on amplitude-dependent GH secretion (41, 46, 47, 48). However, this study demonstrated that an increase in BMI in the nonobese range can also reduce GH levels significantly without any effect on GH pulsatility, diurnal variation, or ApEn scores.
With regard to the dynamics of GH secretion in the irradiated GH-deficient patients, this study has clearly demonstrated that although GH secretion is greatly attenuated, the pulsatile nature of GH release is fully maintained. The reduction in all quantitative attributes of GH secretion, however, was considerable. The absolute GH peak completely separated patients from normal subjects, with the highest patient peak of 2.03 µg/liter compared with the lowest of 2.37 µg/liter in all normal subjects and 4.13 µg/liter in the BMI-matched subgroup. The AUCGH (or mean GH level) also demarcated patients from normal subjects, with only one normal value superimposed within the GH-deficient range. Overall, two normal individuals (6%) had peak GH levels below 4 µg/liter, but they had AUCGH above 500 µg·min/liter (equivalent to mean GH of >3.5 µg/liter), and one normal individual (3%) had AUCGH less than 360 µg·min/liter (GH, <2.5 µg/liter), but had peak GH levels well in excess of 4 µg/liter. Therefore, using these two characteristics in the GH profile, one can diagnose normality by having a peak GH level above 4 µg/liter and/or a GH mean of 0.35 µg/liter or above. Alternatively, severe GH deficiency can be diagnosed with very high sensitivity and specificity by the combined use of an absolute peak GH of 2 µg/liter or less and a mean GH level of 0.25 µg/liter or less.
Previous studies have used deconvolution analysis (49, 50) to directly quantify both components of GH secretion. In normal subjects, pulsatile GH secretion accounts for 92–99% of the daily GH production (13, 15). In GH-deficient patients, the total daily GH production was shown to be reduced to less than 5% compared with age-, sex-, and BMI-matched controls (15, 18). Pulsatile secretion seems to be affected more, with a more than 92–96% reduction (15, 18). In contrast, basal secretion seems to be less affected, with one study reporting a 47% decline (15), and another showing no decline in basal secretion (18); i.e. pulsatile and tonic GH secretions contribute equally (50% each) in GH-deficient patients. Furthermore, the former study showed no change in GH secretory burst frequency compared with the latter study, which showed almost doubling of the GH secretory burst frequency; the researchers concluded that the increased burst frequency in GH-deficient patients is a compensatory mechanism associated with the decline in GH production. The apparent differences between the two studies could be attributed to fundamental differences in the sampling frequency, the GH assays, the severity of GH deficiency, the matching of controls, and perhaps the analytical methods used.
In our study it was possible to draw similar conclusions regarding the pattern of GH production in the patients by demonstrating a substantial reduction in the pulsatile fraction of the AUCGH from 80% in normal subjects to 50% in patients. This observation confirms that basal (tonic) GH secretion still occurred in these patients and that pulsatile GH secretion is relatively more attenuated than nonpulsatile (tonic) GH secretion. Thus, the fractional daily contribution from tonic GH release in the GH-deficient subjects is markedly increased (50%). The reduction in pulsatile secretion is not associated with any change in pulse frequency. These results are consistent with those reported by Toogood et al. (17) in patients irradiated for pituitary tumors using the same assay and pulse detection algorithm. In fact, the concentration pulse frequency in any group is likely to be an underestimation of the true underlying secretory burst frequency. This is particularly true for the nocturnal part of the profile when large and broad pulses dominate; these often represent more than one secretory burst that can only be resolved by deconvolution analysis, ideally with more frequent sampling (32, 49, 50, 51).
In accord with previous studies (13, 18, 51), the timing of the diurnal change (acrophase) seems to be fully preserved, but with a reduction in the relative amplitude. The latter, however, is seen in male patients only. Normal women have attenuated amplitude of the diurnal rhythm compared with normal men, with no additional reduction noted in female patients. Thus, GH-deficient patients have a more feminized pattern of GH secretion, with a higher contribution of interpeak levels and daytime GH to the total, resulting in reduced diurnal fluctuation.
Despite fundamental preservation of GH pulsatility and diurnal variation in the irradiated GH-deficient patients, the overall secretory process is more disordered, as indicated by the much higher ApEn score. Increased ApEn has been consistently documented in almost all physiological, pathophysiolgical, and experimental conditions associated with decreased or increased GH secretion (18, 37, 38, 41, 52, 53, 54, 55, 56, 57). It is postulated that increased ApEn reflects an altered balance between the feedforward and feedback control mechanisms that result in greater disorderliness in subordinate (nonpulsatile) hormone secretion (58).
In irradiated GH-deficient patients, the attenuation in GH secretion is amplitude specific, not frequency specific, and the diurnal rhythm is preserved. Relative preservation of the basal component in GH secretion can be attributed to reduced IGF-I-dependent negative feedback and, more importantly, to radiation-induced reduction in somatostatin tone, leading to enhanced tonic GH release from the residual functioning somatotrophs. In contrast, reduced pulse amplitude is a consequence of reduced hypothalamic GHRH release and/or diminished somatotroph mass. These findings are in concert with the small amount of data from pharmacological manipulation studies that showed that although hypothalamic components of GH pulse generation (GHRH release and somatostatin tone) are reduced, they are not completely abolished (10, 11). Nonetheless, the poorly understood fundamental mechanisms controlling GH pulse generation and sleep-entrained diurnal variation seem to be relatively unaffected by radiation damage to the h-p axis, even when the latter is administered in childhood.
From a clinical perspective the preservation of the normal pulsatile pattern of GH secretion in GH-deficient patients may, in theory, lend itself to pharmacological interventions (with GHRH and/or GH secretagogues) targeted at amplifying the existing secretory pattern. The ultimate aim would be the restoration of GH pulsatile amplitude to normality (59, 60), a potentially more physiological approach in managing GH-deficient patients than a single daily injection of GH.
In the irradiated patients, pituitary responsiveness to the GHRH declines with the time lapse after irradiation (8, 61, 62). This has been attributed to somatotroph atrophy secondary to reduced hypothalamic GHRH release. Reversal of somatotroph atrophy and restoration of responsiveness to GHRH has been reported in patients with idiopathic GHRH deficiency (63). However, the reversibility of somatotroph dysfunction after radiotherapy is unpredictable, because the possibility of permanent time-dependent direct radiation damage to the somatotrophs cannot be excluded. Clinical studies are required to investigate the validity of using GHRH and/or oral GH secretagogues in these clinical settings.
In summary, pulsatile GH secretion and diurnal variation are maintained in patients with radiation-induced GH deficiency acquired after radiation injury to the h-p axis in childhood. Radiation seems to inflict mostly quantitative damage to the h-p axis, leading to amplitude-dependent dampening of GH secretion, with relative preservation of nonpulsatile (tonic) GH secretion. Qualitative perturbation in hypothalamic control of GH release, however, is evident by the increase in ApEn values, reflecting more disordered GH secretion. We conclude that the integrity of the h-p axis and, hence, GH neuroregulation are fundamentally preserved in the irradiated GH-deficient patients, with a GH secretory pattern similar to that observed in normal subjects and in GH deficiency states due to other etiologies.
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Acknowledgments |
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Footnotes |
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First Published Online February 22, 2005
Abbreviations: ApEn, Approximate entropy; AUCGH, area under the curve time-integrated value for all GH concentrations; BMI, body mass index; GHRH+AST, GHRH plus arginine stimulation test; h-p, hypothalamic-pituitary; ITT, insulin tolerance test; SDS, SD score.
Received October 12, 2004.
Accepted February 10, 2005.
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Endocrinology | Endocrine Reviews | J. Clin. End. & Metab. |
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, Median value for each group (combined for all normal women). The horizontal dashed line represents the highest value for the patients.
, patients; 
, normal men (BMI, >24 kg/m2); 
, normal men (BMI, <24 kg/m2); 
, normal women.