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Joint Growth Hormone and Cortisol Spontaneous Secretion Is More Asynchronous in Older Females Than in Their Male Counterparts

London Center for Pediatric Endocrinology, University College London (E.C., P.C.H.), London W1T 3AA, United Kingdom; Guilford (S.M.P.), Connecticut 06437; Diabetes Research Laboratories, Radcliffe Infirmary (D.R.M.), Oxford OX2 6HE, United Kingdom; and Medical Research Council Environmental Epidemiology Unit (E.D., C.H.D.F.), Southampton SO16 6YD, United Kingdom

Address all correspondence and requests for reprints to: Evangelia Charmandari, M.D., Pediatric and Reproductive Endocrinology Branch, National Institute of Child Health and Human Development, National Institutes of Health, 10 Center Drive, Building 10, Room 9D42, Bethesda, Maryland 20892-1583.

Abstract

In humans, cortisol and GH are secreted in a pulsatile manner, and an interaction between GH and the hypothalamic-pituitary-adrenal axis has been established. In view of the sexually dimorphic pattern in GH secretion, we investigated the GH-cortisol bihormonal secretory dynamics in male and female healthy older individuals. We studied the GH and cortisol secretory patterns in 83 healthy subjects (45 men and 38 women; age range, 59.4–73.0 yr) by determining serum GH and cortisol concentrations at 20-min intervals for 24 h. The irregularity of GH and cortisol secretion was assessed using approximate entropy (ApEn), a scale- and model-independent statistic. The synchrony of joint GH-cortisol spontaneous secretion was quantified using the cross-ApEn statistic. Cross-correlation analysis of GH and cortisol patterns was computed at various time lags covering the 24-h period.

Mean 24-h serum GH concentrations were significantly higher in females (mean, 1.31 mU/L; SD, 0.87) than in males (mean, 0.88 mU/L; SD, 0.42; P = 0.009), whereas mean 24-h serum total cortisol concentrations were higher in males (mean, 9.0 µg/dL; SD, 1.4) than in females (mean, 7.3 µg/dL; SD, 1.4; P = 0.0001). GH secretion was more irregular in females (mean ApEn, 0.81; SD, 0.23) than in males (mean ApEn, 0.60; SD, 0.20; P < 0.001). No significant difference in the regularity of cortisol secretion was noted between sexes. Cross-ApEn values of paired GH-cortisol were higher in females (mean, 1.15; SD, 0.18) than in males (mean, 1.01; SD, 0.16; P = 0.0003). Stepwise multiple linear regression analysis indicated that estradiol and insulin-like growth factor-binding protein-3 concentrations were independently related to GH ApEn values (r² = 0.14; P = 0.01), whereas cross-ApEn values of paired GH-cortisol were best predicted by FSH concentrations (r² = 0.37; P = 0.003). Cross-correlation analysis revealed a significant positive correlation between GH and cortisol, peaking at lag time of 4.7 h in males (r = 0.30; P < 0.0001) and 4.3 h in females (r = 0.14; P < 0.0001), with GH leading cortisol by these time intervals. In addition, a significant negative correlation between the two hormones was noted over time, peaking at 4.7 h in males (r = -0.21; P < 0.0001) and 6.3 h in females (r = -0.25; P < 0.0001), with cortisol leading GH by these time intervals.

The above results indicate that in the elderly, females have a more disordered GH secretory pattern and a more asynchronous joint GH-cortisol secretion than their male counterparts. These observations most likely reflect bidirectional interactions between the GH and hypothalamic-pituitary-adrenal axis in humans as well as diminution of subsystem integrity and synchronous control of interconnected hormonal systems with advancing age.

IN HUMANS, CORTISOL and GH are secreted in a pulsatile fashion, and physiological peak concentrations are observed at different times. At the pituitary level, GH secretion is regulated by GHRH and somatostatin (SS), whereas cortisol secretion from the adrenal cortex is under the control of ACTH and vasopressin. A number of studies have investigated the interaction between GH and the hypothalamic-pituitary-adrenal (HPA) axis, and there is an increasing body of literature to suggest a mutual bidirectional interaction between GH and the HPA axis in humans (1, 2, 3, 4, 5, 6, 7).

A sexually dimorphic pattern in GH secretion has been demonstrated in rodents and healthy subjects, and the most prominent gender differences in the regulation of GH axis that have been reported include 1) higher mean serum GH concentrations due to greater GH secretory burst mass in women than in men, with no apparent gender differences in the frequency of GH secretory bursts or the GH half-life in plasma; 2) relatively reduced suppressibility of GH by oral glucose administration in women compared with men; and 3) an approximately 2-fold greater sensitivity of men compared with women to the negative effects of age and increased percent body fat, and the positive impact of physical fitness on mean serum GH concentrations (8). In addition, the regularity of GH secretion has been shown to be sexually dimorphic, with females exhibiting a marked increase in the irregularity or disorderliness of GH secretion compared with their male counterparts (8, 9, 10, 11, 12, 13, 14).

In humans, aging is characterized by disturbances of feedback control and disruption of orderly patterns of hormone release. Recent data suggest a general model of early neuroendocrine aging, wherein aging is marked by a variable disruption in the time-delayed feedback and feedforword interconnections among the neuroendocrine glands, thus disrupting the joint synchrony of hormone release (15). A number of clinical studies that implemented an array of new analytical tools to evaluate the neuroregulation of endocrine axes in aging suggest a progressive fall in the individual orderliness of GH, LH, and insulin in older men and women, a disrupted joint ACTH-cortisol synchrony in healthy older men and women, and a marked decline in the synchrony between LH and testosterone secretion in older men (15, 16).

In a previous study we investigated the GH secretory dynamics in older healthy volunteers and showed that there was sexual dimorphism in the mean, peak, and trough concentrations of 24-h GH secretion as well as in the regularity of GH secretion (9). The aim of the present study was to examine the pattern and regularity of cortisol secretion in the same population and to investigate the synchrony of joint GH-cortisol spontaneous secretion in older healthy males and females.

Subjects and Methods

Subjects

Eighty-three healthy volunteers (45 men and 38 women; age range, 59.4–73.0 yr) were studied prospectively. The cohort was drawn from a larger population study of risk factors for cardiovascular disease comprising 3000 individuals. Anthropometric measurements and social profiles did not differ between the individuals and the United Kingdom population. No subject was receiving medications known to influence GH secretion and corticosteroid-binding globulin concentrations or to induce mixed function oxidase enzymes. All women were postmenopausal, and none was receiving hormone replacement therapy. Standard anthropometric measurements were obtained by a single trained observer.

All subjects were admitted to the Clinical Investigations Unit of the Middlesex Hospital 1 day before the study to allow a period of adaptation, and an indwelling venous catheter for blood sampling was inserted soon after admission. Patients were allowed normal ambulatory activity during the day. Smoking was not permitted. Standard hospital meals were delivered at 0800, 1230, and 1730 h. While in the hospital, patients stayed awake during the day and slept between 2200–0700 h. The depth of sleep of each subject was evaluated by assessing rapid eye movements and was similar in males and females.

On the day of the study, blood samples for measurement of GH and cortisol concentrations were collected at 20-min intervals for a period of 24 h. At 0600 h, an additional blood sample was drawn for the measurement of insulin-like growth factor I (IGF-I), IGF-binding protein-3 (IGFBP-3), corticosteroid-binding globulin (CBG), T₄, LH, FSH, PRL, testosterone, and estradiol concentrations. The study was approved by the University College London Hospitals committees on the ethics of human research, and written informed consent was obtained in all cases.

Assays

GH. GH concentrations were measured using the Nichols chemiluminescent assay for human GH (Nichols Institute Diagnostics, San Juan Capistrano, CA). The sensitivity of the assay was 0.036 mU/L, and a limit of detection of 0.04 mU/L was used throughout. Eight of the 45 males had GH values below the detection limit (in 1–4 samples of the 73 samples obtained for measurement of GH concentrations), but none of the females had values this low. The between-assay coefficients of variation (CVs) were 12.1%, 12.3%, and 9.0% at serum concentrations of 3.3, 6.3, and 18.0 mIU/L, respectively. The within-assay CVs were 5.5%, 6.8%, 10.5%, and 10.8% at serum concentrations of 0.4, 10.0, 18.6, and 23.3 mU/L, respectively.

Total cortisol. Serum total cortisol concentrations were measured using the Coat-A-Count RIA (Coat-A-Count, Diagnostic Products, Los Angeles, CA). This is a solid phase RIA with a sensitivity of 0.2 µg/dL. The within-assay CVs were 5.7% and 2.6% at serum concentrations of 1.0 and 20.0 µg/dL, respectively. The between-assay CVs were 6.3% and 4.5% at serum concentrations of 5.0 and 10.0 µg/dL, respectively.

CBG. CBG was assayed with the CBG-RIA-100 Diagnostic kit (Biosource Technologies, Inc., Fleurus, Belgium). The minimum detectable concentration of transcortin (CBG) was 0.25 µg/mL. The within-assay CVs were 7.7% and 3.3% at serum concentrations of 33.1 and 109.4 µg/mL, respectively. The between-assay CVs were 5.0% and 4.5% at serum concentrations of 31.9 and 105.0 µg/mL, respectively.

Free cortisol. Free cortisol was calculated according to Biosource Technologies, Inc., protocol using the formula: U = (Z² + 0.0122C)^1/2 - Z µM, where Z = 1/2K + (T - C)/2(1 + N) = 0.0167 + 0.182(T - C) µM. In this equation, U represents the molar concentration of unbound cortisol, C is the molar concentration of total cortisol, and T is the concentration of CBG. K corresponds to the affinity of transcortin for cortisol at 37 C, and N to the proportion of albumin bound to non-CBG-bound cortisol.

IGF-I. Serum IGF-I concentrations were measured using an in-house polyclonal RIA with acid/alcohol extraction. The sensitivity of the assay was 13 ng/mL. The within-assay CVs were 11.3%, 6.5%, and 4.7% at serum concentrations of 44.6, 238.6, and 684.8 ng/mL, respectively. Between-assay CVs were 10.5%, 12.1%, and 5.1% at serum concentrations of 73.7, 192.1, and 684.8 ng/mL, respectively.

IGFBP-3. Serum IGFBP-3 concentrations were measured using a radioimmunometric assay (Diagnostics Systems Laboratories, Inc., Webster, TX) with a sensitivity of 0.5 ng/mL. The within-assay CVs were 3.9%, 3.2%, and 1.8% at serum concentrations of 7.4, 27.5, and 7.8 ng/mL, respectively. The between-assay CVs were 7.6% and 4.2% at 5.4 and 27.2 ng/mL, respectively.

Other measurements. The concentrations of testosterone, estradiol, and T₄ were measured using standard commercial RIA kits. Gonadotropin concentrations were measured using immunoradiometric assay systems.

Analysis of hormone pulsatility

Approximate entropy (ApEn) analysis. To quantify serial irregularity we used ApEn, a scale- and model-independent statistic that has provided new insights both mathematically and in various biological applications (17, 18, 19, 20, 21, 22, 23). ApEn is complementary to pulse detection algorithms widely employed to appraise hormone secretion-time series. It evaluates both dominant and subordinant patterns in data and detects changes in underlying episodic behavior not reflected in peak occurrences or amplitudes. In addition, it provides a direct barometer of feedback system alterations in many coupled, theoretical mathematical systems (18, 24). ApEn assigns a nonnegative number to a time series (17), with larger values corresponding to greater apparent process randomness, and smaller values corresponding to more instances of recognizable patterns of features. The value is derived from the logarithmic likelihood that runs of patterns that are close (within r) for m contiguous observations remain close (within the same tolerance width r) on the next incremental comparison. Profiles were analyzed with m = 1 and r = 20% of the SD of the individual subject time series. These values produce good statistical reproducibility in theoretical (17) and endocrine practice (21, 22, 23).

Cross-ApEn analysis. To quantify asynchrony (conditional irregularity) we used cross-ApEn (19). Cross-ApEn can be employed to compare sequences from two distinct yet intertwined variables in a network, herein applied to the joint secretion of GH-cortisol time series. Larger cross-ApEn values indicate greater joint signal asynchrony. The precise mathematical definition of cross-ApEn is thematically similar to that of ApEn (19, 21).

Cross-correlation studies. To search for a time-ordered relationship between GH and cortisol, analysis of correlations between the absolute values of the time series of each hormone was computed at 20-min intervals at various time lags covering the 24-h period of the study. All data were stationarized and processed as a three-point moving average to reduce assay noise as previously described (25, 26). Cross-correlation was computed after lagging (shifting) the concentration-time series of cortisol relative to the concentration-time series of GH. If r_t is the coefficient of correlation between GH and cortisol at a lag time t for one subject, then the mean r_t for all subjects was considered significant when it exceeded zero by more than 2 SE of the mean. The SE was calculated from the individual values of r_t for all individuals at the lag time t.

Statistical analysis

Nonnormally distributed data were logarithmically transformed before analysis. Comparisons between two groups were performed using Student’s t test. Stepwise multiple linear regression analysis was used to investigate independent predictors of GH ApEn values as well as cross-ApEn values of joint GH-cortisol spontaneous secretion. Independent variables tested included sex, body mass index, mean 24-h GH and cortisol concentrations, IGF-I, IGFBP-3, FSH, LH, testosterone, and estradiol concentrations.

Results

Sample population

The clinical characteristics and biochemical parameters determined in all subjects are listed in Table 1. The mean ages of males and females were similar, and the mean height and weight measurements showed the differences expected between sexes. Gonadotropin concentrations were significantly higher in females because of the postmenopausal state and the low plasma estradiol concentrations. Serum PRL and T₄ concentrations were normal in all individuals.

View larger version (22K): [in this window] [in a new window]   Figure 1. Mean 24-h serum GH concentrations in male and female subjects. Y bars represent the SEM. Mean 24-h GH concentrations were higher in women than in men.

View larger version (18K): [in this window] [in a new window]   Figure 2. Mean 24-h serum cortisol concentrations in male and female subjects. Y bars represent the SEM. Mean 24-h serum cortisol concentrations were higher in men than in women.

For GH, ApEn values were significantly higher in females (mean, 0.81; SD, 0.23) than in males (mean, 0.60; SD, 0.20; P < 0.001). There was no significant difference in cortisol ApEn values between sexes (males: mean, 1.01; SD, 0.15; females: mean, 1.04; SD, 0.15; Table 2).

Cross-ApEn values of paired cortisol-GH (GH leading cortisol) were significantly higher in females (mean, 1.15; SD, 0.18) than in males (mean, 1.01; SD, 0.16; P = 0.0003). Cross-ApEn values of paired GH-cortisol (cortisol leading GH) were also significantly higher in females (mean, 1.27; SD, 0.17) than in males (mean, 1.18; SD, 0.23; P = 0.038; Table 2).

Stepwise multiple linear regression analysis

Multivariate analysis indicated that GH ApEn values were independently related to estradiol and IGFBP-3 concentrations (r² = 0.14, P = 0.01) whereas cross-ApEn values of joint GH-cortisol secretion were best predicted by FSH concentrations (r² = 0.37, P = 0.003) (Table 3).

The graphs depicting the first, second (median), and third quartile coefficients of correlation from the cross-correlation analysis over the 24-h period between GH and cortisol concentrations are shown in Fig. 3. In males, there was a significant negative correlation between GH and cortisol at lag time 0 min (r = -0.066; P < 0.01), peaking at 4.67 h (r = -0.209; P < 0.0001), with cortisol leading GH by this time interval. Also, a significant positive correlation between the two hormones was observed over time, peaking at lag time 4.67 h (r = 0.307; P < 0.0001), with GH leading cortisol by this time interval.

View larger version (18K): [in this window] [in a new window]   Figure 3. Cross-correlation analyses between cortisol and GH in older men (a) and women (b).

Discussion

The above results demonstrate clear differences in the pattern of spontaneous GH and cortisol secretion as well as differences in the synchrony of the joint GH and cortisol secretion in older subjects. We have previously reported on the sexually dimorphic pattern of GH secretion in the elderly and discussed the possible pathophysiological mechanisms underlying the differences in mean, peak, and trough concentrations of 24-h GH secretion as well as the increased irregularity of GH secretory pattern in the females compared with the males (9).

The sexual dimorphism in the pattern of GH secretion demonstrated in both humans and rodents (8, 9, 10, 11, 12, 13, 14, 27) is primarily dependent on the interplay between GHRH and SS. Several neuropeptides can, in turn, modify GH secretion by acting on the central nervous system to modulate the hypothalamic secretion of GHRH and SS. A number of studies confirmed a sexually dimorphic pattern in both SS and GHRH synthesis and release as well as modulation of GH secretion by alterations in circulating gonadal steroid concentrations (28, 29, 30, 31). The masculinization of the GH secretory pattern in ovariectomized rats treated with dihydrotestosterone (DHT) and the parallel rise in SS and GHRH messenger ribonucleic acid (mRNA) levels suggest that testosterone may exert its effect on SS tone before its aromatization to estradiol, whereas the rise in SS but not GHRH mRNA levels in ovariectomized and hypophysectomized animals also treated with DHT indicates that it acts at the hypothalamic, rather than the pituitary, level (30). In addition to DHT, testosterone has been shown to result in masculinization of the pattern of GH secretion by increasing SS mRNA levels in the periventricular nuclei (PVN) of the hypothalamus (32). On the other hand, short-term exposure of gonadectomized adult male rats to estradiol results in increased trough GH concentrations, decreased interpeak interval, and a GH secretory profile very similar to that in female rats in terms of periodicity. Furthermore, estradiol exposure abolishes the time-dependent difference in GH responsiveness to GHRH between sexes, thus suggesting that estrogens alter the pattern of hypothalamic SS secretion from a cyclic to a more continuous mode of release, which is likely to account for the feminization of the male pattern of spontaneous and stimulated GH secretion (29).

In addition to GH secretion, a sexually dimorphic pattern has been suggested for the secretion of CRH in humans, because the CRH gene has been shown to be a potentially important target of ovarian steroids and a potential mediator of gender-related differences in HPA axis activity (33). Data obtained in rats demonstrating that chronic estradiol treatment of ovariectomized animals stimulates the PVN CRH mRNA levels (34) and increases ACTH and corticosterone secretion basally and in response to stress (35) and the demonstration of elevated PVN CRH mRNA in the afternoon of proestrous at the approximate time of the estrogen-induced preovulatory surge of LH (36) support this concept. These observations explain the slightly increased basal and stress-stimulated HPA axis function observed in females and may also explain the lower 24-h mean cortisol concentrations in female subjects of the present study, who were not receiving hormone replacement therapy.

Having established the regularity of spontaneous GH and cortisol secretion in the older males and females, we proceeded to quantify the synchrony of joint GH and cortisol secretion in these patients using the cross-ApEn statistic, which facilitates analysis of the network aspects of interconnected hormone systems. The present findings indicate that beyond the previously reported individual nodal changes in GH secretory irregularity in females compared with males (8, 9, 10, 11, 12, 13, 14), there is also a highly significant disruption in the joint GH-cortisol secretory dynamics in older females compared with their male counterparts.

That older females demonstrate a more asynchronous joint GH-cortisol spontaneous secretion than their male counterparts may be the result of greater irregularity in the GH secretory pattern, as no significant difference in the regularity of cortisol secretion was noted between sexes. It is likely that the greater irregularity in GH secretion in females relates to a differential effect of gonadal steroids on the pattern of GH secretion, given that there is enough evidence to suggest that estrogens decrease regularity of GH secretion, whereas testosterone restores it (29, 30, 32). This concept is supported by the negative relationship between the GH ApEn values and estradiol concentrations as well as the positive relationship between cross-ApEn values and FSH concentrations. It is thus inferred that the cessation of reproductive capacity in older females, in contrast to the continued, albeit diminished, function in older males, may play an important role in the regulation of GH secretion, further influencing the synchrony of other interconnected hormone systems.

Although a number of studies have investigated the interaction between HPA and GH axes, the GH-cortisol interrelation has not been fully elucidated. The temporal relationship between circulating cortisol and GH concentrations under physiological conditions is a complex one. While chronic exogenous or endogenous hypercortisolism results in reduced GH secretion and growth suppression (5, 6, 7) as well as attenuation of GH response to exogenous stimuli (2, 3, 4), patients with idiopathic ACTH deficiency need appropriate glucocorticoid replacement to reestablish the normal pattern of GH release in response to provocation, suggesting that normal glucocorticoid concentrations are required to ensure adequate GH secretion (37). On the other hand, GH-deficient patients have been shown to have low basal and stimulated cortisol concentrations, which are subsequently normalized after treatment with exogenous GH administration (1). In vitro studies that attempted to elucidate further the mechanism of glucocorticoid action on the GH axis by evaluating the effect of dexamethasone on hypothalamic SS and GHRH mRNA levels suggested an inhibitory GH-mediated effect of dexamethasone on SS mRNA levels in the periventricular nucleus and an inhibitory direct effect of dexamethasone on GHRH neurons in the arcuate nucleus (38).

The results of the present study revealed a significant positive correlation between cortisol and GH concentrations, peaking at lag time 4.67 h in males and 4.33 h in females, with GH leading cortisol by these time intervals. These findings are in agreement with previous studies that documented a positive correlation between mean 24-h cortisol concentration and mean 24-h GH concentration, the sum of 24-h GH pulse amplitudes, and the number of GH pulses over a 24-h period (39) and confirmed that pretreatment with hydrocortisone significantly augments the GH response to GHRH (40). That the positive correlation between the two hormones is stronger and remains statistically significant for a greater length of time in males compared with females may be the result of greater irregularity in the GH secretion in female individuals.

Also, a significant negative correlation between cortisol and GH was observed over time, peaking at lag times of 4.67 and 6.33 h in males and females, respectively, with cortisol leading GH by these time intervals. The negative correlation between cortisol and GH observed over time is probably the result of inhibition of GH release by CRH (40, 41, 42, 43). The fact that the GH-cortisol negative correlation is also stronger in males than in females reflects a greater effect of CRH on GH secretion in male subjects, who probably had higher CRH concentrations, as evidenced by the higher circulating mean cortisol concentrations throughout the 24-h period.

CRH, although initially reported to be a potent and specific stimulus for ACTH release with no effect on other pituitary hormones (44), was subsequently found to exert an inhibitory effect on GH secretion, which was attributed to increased release of SS (42, 43, 44). A differential suppressive effect of CRH on GH secretion was demonstrated between sexes, with females showing greater sensitivity to the inhibitory effects of CRH than males, which was thought to be related to gender differences in the neuroregulation of GH secretion.

We conclude that in the elderly, females have a more disordered GH secretory pattern and a more asynchronous joint GH-cortisol secretion than their male counterparts. These observations are likely to evolve as a result of a gradual decline in the integrity and synchronous control of interconnected hormone systems with advancing age, and they reflect bidirectional interactions among GH, the HPA axis, and the hypothalamic-pituitary-gonadal axis. These findings also reinforce the importance of employing techniques, such as cross-ApEn and cross-correlation function, that can potentially detect changes in bivariate data behavior.

Received January 9, 2001.

Revised March 9, 2001.

Accepted March 16, 2001.

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