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From the Clinical Research Centers |
Division of Endocrinology (J.D.V.), Department of Internal Medicine, National Science Foundation Center for Biological Timing, University of Virginia Health Sciences Center, Charlottesville, Virginia 22908; Pediatric Endocrinology (D.L.M.), University of British Columbia, Vancouver, BC V6H 3V4, Canada; Genentech, Inc. (P.M.M.), South San Francisco, California 94080; Nemours Children’s Clinic (N.M.), Jacksonville, Florida 32207-8426; Department of Pediatrics (J.R.K.), East Tennessee State University, Johnson City, Tennessee 37614-0578; Department of Pediatrics (B.K.), University of Texas Medical Branch, Galveston, Texas 77555-0363; Department of Pediatrics (A.D.R.), University of Virginia Health Sciences Center, Charlottesville, Virginia 22908; and (S.M.P.) Guilford, Connecticut 06437
Address all correspondence and requests for reprints to: Johannes D. Veldhuis, Division of Endocrinology, Department of Internal Medicine and National Science foundation Center for Biological Timing, University of Virginia Health Sciences Center, Charlottesville 22908. E-mail: JDV{at}Virginia.Edu
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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-dihydrotestosterone, a nonaromatizable androgen, failed to produce
a significant ApEn increase (P > 0.43). We
conclude from these three distinct experimental contexts that
aromatization of testosterone to estrogen in boys, or estrogen itself
in girls, is likely the proximate sex-steroid stimulus amplifying
secretory activity of the GH axis in puberty. In addition, based on
inferences derived from mathematical models that mechanistically link
increased disorderliness (higher ApEn) to network changes, we suggest
that sex-steroid hormones in normal puberty modulate feedback within,
and hence network function of, the
hypothalamo-pituitary/GH-insulin-like growth factor I axis. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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As an indirect estimate of feedback control within an axis, approximate entropy (ApEn) has been applied in a variety of mathematical and biological settings, such as aging, tumoral hormone secretion, feedback withdrawal, and gender-specific patterns of hormone secretion (17, 18, 19, 20, 21, 22, 23, 24, 25). For example, ApEn quantifies greater disorderliness of GH release over time in the female than male in both the human and rat (24). In addition, ApEn measures show that the disorderliness of GH, LH, and testosterone release increases during healthy aging in adults (19, 25). ApEn, as a measure of regularity, also reveals marked disruption of the orderliness of ACTH, GH, and aldosterone release in Cushing’s disease, acromegaly, and aldosteronoma, respectively (17, 18, 20). Consequently, ApEn offers a discriminative tool with which to assess the loss of coordinated regulation of neurohormone release.
Theoretically, ApEn provides an overall index of feedback behavior in quite a variety of well-determined networks (26, 27, 28, 29, 30). The ApEn metric has good statistical replicability in evaluating both dominant (pulsatile) and subordinate (nonpulsatile) features of hormone release over time (31, 32). Thus, ApEn can be used to infer changes in network function; e.g. feedback among the hypothalamus, pituitary gland, and target organ. This is significant, because the feedback activity of endocrine axes cannot be measured directly in clinical experiments.
Given the above framework, we have used ApEn here to test the clinical
hypotheses that feedback regulation of the human SRIH/GHRH-somatotropic
(GH)-IGF-I axis is altered during normal human puberty and that such
altered regulation is effected via one or more specific sex-steroid
hormones. To this end, we used three experimental paradigms, namely: 1)
a cross-sectional evaluation of 24-h serum GH concentration profiles in
53 boys and young men stratified into 5 groups defined by prepuberty,
early puberty, mid-late puberty, postpuberty, and adulthood (33); 2)
short-term sex-steroid hormone (estrogen) treatment of 7 prepubertal
girls with gonadal dysgenesis (Turner’s syndrome) (34) to test the
impact of estrogen on feedback control of GH release; and 3) 5
androgen-deficient boys with constitutionally delayed puberty studied
both at baseline and after im administration of testosterone, as an
aromatizable androgen, and 5 -dihydrotestosterone (DHT), as a
nonaromatizable androgen (35). We hypothesized that estrogen and
testosterone, but not a nonaromatizable androgen, would govern the
orderliness of the GH release process, and hence, by inference,
modulate feedback regulation of the hypothalamo-somatotroph-IGF-I
axis.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Cross-sectional studies of boys at different stages of puberty. The normal boys studied here were described in an earlier analysis of their pulsatile GH data, which we now evaluate for the first time by way of ApEn measures (33). Fifty-three healthy boys were studied, 10 in prepuberty as defined by Tanner Stage I, 12 in early puberty (Tanner Stage II), and 16 in mid-to-late puberty (defined as pubic hair development in Tanner Stages III and V, but clearly unfused epiphyses on hand x-ray). In addition, 8 boys were tested in early postpuberty as defined by chronological ages less than 18 with fused epiphyses and clinical Tanner Stage V; and, lastly, 7 subjects were recruited in young adulthood, defined as reproductively mature and 21–30 yr old. All volunteers underwent blood sampling at 20-min intervals for 24 h on 1 occasion each. Serum GH concentrations were assayed in duplicate by immunoradiometric assay (IRMA) (33).
Girls with Turner’s syndrome. Seven untreated prepubertal girls with Turner’s syndrome underwent blood sampling at baseline and after 1 week and 5 weeks of daily oral ethinyl estradiol (100 ng/kg) treatment. Blood was sampled at 20-min intervals from 2000 h to 0800 h overnight and submitted to GH IRMA. GH pulse analysis was reported earlier for these subjects (34).
Boys with constitutional delay of puberty. Five boys with clinically defined constitutional delay of puberty were recruited from the outpatient clinic and studied 4 times each; namely, at baseline; 7 days after an im testosterone enanthate (80 mg, Delatestryl, Gynex Pharmaceuticals, Inc.) injection; at second baseline; and lastly, 7 days after DHT enanthate (80 mg) im. Admissions were spaced at least 5 weeks apart. Androgen injections were randomly ordered. Volunteers underwent 12-h overnight (2000–0800 h) blood sampling at 10-min intervals during each admission. Prestudy testing showed morning concentrations of plasma IGF-I, and serum T4, TSH, (prepubertal) LH and FSH, all of which were normal for bone age, as well as normal biochemical indices of metabolic, hematological, renal, and hepatic function. History and physical examination were unremarkable except for a (mean ± SEM) chronological age of 15.5 ± 0.4 yr, bone age of 12.8 ± 0.4 yr, height z-score of -2.2 ± 0.2 for chronologic age and -0.1 ± 0.2 for bone age, testes vol of 3–5 mL, pubic hair Tanner stages I-II, and a.m. serum total testosterone concentrations of 94 ± 39 ng/dL (3.3 ± 1.4 nmol/L). Volunteers participated with their assent, and after informed consent was obtained from their parents, as approved by the IRB of the University of Virginia. These boys’ data have not been presented previously.
ApEn calculations
ApEn is a model-independent regularity statistic developed to quantify the orderliness of sequential measures (26, 36), such as hormonal time series. Larger ApEn values correspond to greater randomness (irregularity). Technically, ApEn measures the logarithmic likelihood that runs of patterns that are similar remain so on next incremental comparison. The basic derivation and calculation of ApEn have been presented earlier (29, 32). Two input parameters, m (window length) and r (tolerance), must be specified to compute ApEn. For this study, we calculated ApEn values for each GH profile with window length m = 1, and tolerance parameter r = 20% of the average SD of the individual subject’s GH time-series. Thus, this calculated ApEn is denoted as ApEn (1,20%). Previous theoretical analyses and clinical applications have demonstrated that these input values produce good statistical validity of ApEn for time series of 50 or more data points (18, 24, 28, 29). Mathematically stated, the ApEn application with m = 1 is said to estimate the rate of entropy for a first-order (m = 1) approximating Markov chain to the underlying true process (37).
In choosing the r input parameter (tolerance) in ApEn as a fixed percentage of each data set’s SD, we normalize ApEn for each profile. This so-called normalized ApEn is both translation and scale invariant (adding to or multiplying each data value in the hormone profile by a constant would produce an identical ApEn value) (32). This point is important when different absolute hormone levels are expected, as they are here.
ApEn is stable to small changes in noise characteristics and infrequent, albeit significant, outliers (26, 28). This statistic evaluates a variety of dominant and subordinate patterns in the data; for example, ApEn can detect and quantify changes in underlying regularity of hormone release that are not necessarily reflected in changes in peak frequency or amplitude (28). Additionally, ApEn provides a barometer of feedback changes in many coupled systems (28, 30).
ApEn is a family of statistics which individually provides a relative, not absolute, measure of process regularity. ApEn thus can show significant variation in absolute value with changing m or r input parameters, N (data series length), and/or noise characteristics (experimental variability) (29). Because ApEn will generally increase with increasing N and noise (and hence, increasing intraassay coefficients of variation), it is important to compare data sets with similar N and assay CV’s, as we do here. Technical and statistical properties of ApEn, including so-called mesh interplay, relative consistency of (m, r) pair choices, asymptotic normality under general assumptions, statistical bias, and error estimation for general processes are discussed elsewhere (38).
Deconvolution analysis
The serum GH time series were deconvolved, as described earlier (39, 40).
Statistical analysis
One-way ANOVA, followed by Duncan’s multiple comparison test, was used to evaluate the null hypothesis that mean ApEn measures of the 24-h serum GH concentration time series are statistically unrelated to pubertal stage across the five study groups (prepuberty, early and mid-late puberty, postpuberty, and adulthood). Similar comparisons were made among mean ApEn values in the prepubertal girls with Turner’s syndrome (treated for 1 or 5 weeks with estradiol), as well as in boys with constitutional pubertal delay (treated with DHT or testosterone). In the latter study, because the two baseline sets of ApEn values were statistically indistinguishable (by paired Student’s t test), they were combined.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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, mean ApEn
measures of 24-h serum GH concentration profiles in boys studied
cross-sectionally at various stages of puberty showed a maximal
absolute value (denoting highest pattern irregularity) in mid-late
puberty, and minimum values (greatest orderliness, or least
irregularity) in postpuberty and adulthood (P =
0.0008). ApEn values in the individual boy’s GH time series were quite
well determined statistically, because randomly varying the apparent
sample GH concentrations within each time series by Monte Carlo
simulations (300 realizations/series) with Gaussian variability
matching the intrasample SD of the GH assay yielded
coefficients of variation of ApEn of approximately 7–13% for any
given GH profile (absolute ApEn SD approximately
0.05–0.12). The lowest ApEn value for the boys and men studied here
occurred in young adulthood and was approximately one-half that seen in
mid-late puberty. Thus, the difference in the relative orderliness of
GH release between adulthood and puberty was large, namely
approximately 4–5 SD’s of individual ApEn values.
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for comparison of the latter
vs. baseline within-subject values. In this study, absolute
ApEn values reflected overnight blood sampling, and thus (although
validly compared within and between subjects in this substudy) should
not be directly related in absolute terms to 24-h data (pubertal boys,
above).
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. The corresponding mean (12-h) serum GH
concentrations (µg/L) were 2.5 ± 0.41 (baseline 1), 3.2 ±
0.82 (baseline 2), 2.3 ± 0.54 (DHT), and 4.9 ± 1.0
(testosterone, P < 0.05 vs. DHT).
Testosterone, but not DHT, increased plasma IGF-I and GH
deconvolution-calculated secretory rates (P < 0.01).
An illustrative set of four individual 12-h serum GH concentration
profiles and their calculated secretion rates and ApEn values are shown
in Fig. 4.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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One mechanistic hypothesis is that greater regularity (lower ApEn) of hormone release corresponds to greater subsystem autonomy. For the GH axis, subsystems of control are likely represented by hypothalamic regulatory signals (e.g. GHRH, SRIH, etc.), the pituitary somatotropes, GH itself, and the IGF-I (and its binding protein) system. This general hypothesis has been explored theoretically via analyses of several very different (stochastic and deterministic) mathematical models, which established a robustness of the hypothesis (28, 30). Stated technically, ApEn (or relative disorderliness) typically increases with greater within-system coupling, accelerated positive feedback, and greater external influences, at least as inferred from analyses of coupled stochastic differential equations (30), several composite oscillator-noise models, e.g. Refs. 26 and 30, and stochastic control systems or queuing networks. According to such analyses, the present clinical instances of increased disorderliness or irregularity of GH release would indicate a more complex network directing GH secretion. Higher complexity could reflect more critical interacting factors within the GH feedback axis and/or a greater intensity of particular interactions, e.g. among GHRH-SRIH-GH-IGF-I.
The demonstration of greater disorderliness of GH release in midpuberty, compared with young adulthood, and the ability to reproduce such ApEn differences qualitatively by treatment with estrogen or aromatizable androgen, further suggests to us that estrogen per se critically controls feedback (or network) activity within the hypothalamo-pituitary-IGF-I axis in the human. The fact that plasma GH and IGF-I concentrations rise together in the sex-steroid-rich milieu of puberty (41) is consistent with a corollary hypothesis of decreased sensitivity of the hypothalamo-pituitary/GH unit to IGF-I’s negative-feedback actions during puberty. Concurrent elevations in plasma GH and IGF-I concentrations otherwise arise only in acromegaly, wherein tumoral GH hypersecretion is less sensitive to IGF-I’s feedback restraint (18). The present ApEn data allow the conjecture that puberty is associated with effectively reduced IGF-I negative feedback, resulting in decreased orderliness of GH release; i.e. GH secretion becomes quantifiably more irregular.
Our observations, in a pubertal context, are similar to those reported recently in another setting of withdrawn IGF-I negative feedback, namely fasting-induced decrements in plasma IGF-I concentrations (18). This open-loop (feedback-withdrawn) GH axis exhibits higher ApEn values (greater disorderliness of GH release) in men, but not women; the latter’s ApEn values are already significantly higher in the fed state than those in men (24). More generally, reduction of relevant target-tissue negative-feedback signaling in other neuroendocrine axes, such as in the gonadotropic (LH) and thyrotropic (TSH) axes via experimentally lowered serum testosterone and L-T4 concentrations, also brings about significant (and reversible) increases in ApEn (22, 42). Replacement of the target-organ hormones, namely T4 in the case of the TSH axis and testosterone for the LH axis, restores elevated ApEn to baseline values. Such observations in other neuroendocrine axes reinforce our interpretation that ApEn provides a useful clinical correlate of within-axis feedback integration.
Another plausible explanation for the greater disorderliness of GH release in midpuberty, and in children treated with estradiol or testosterone, is reduced coordination within the somatotropic axis, e.g. among the hypothalamus, pituitary gland, and IGF-I-synthesizing tissues. Reduced coordination among key interacting control points within the GHRH/SRIH-GH-IGF-I axis has been inferred in acromegaly, wherein more disorderly (higher ApEn measures of) GH secretion occurs by (autonomous) GH-secreting pituitary adenomas (17). Similar inferences apply to ACTH- and aldosterone-secreting tumors (18, 20).
A third plausible interpretation of our data is that puberty and/or administration of estrogen or testosterone awakens more complex hypothalamic SRIH/GHRH interactions, as indeed are postulated to mediate the male/female gender differences in GH release in the rat and human (6, 24, 43, 44, 45, 46). For example, in both the rodent and human, the female shows greater quantifiable irregularity of GH release than the male (24). This gender contrast is postulated to reflect inter alia decreased GH autofeedback inhibition of the somatotropic axis in the female rat (47) and/or greater rhythmic hypothalamic SRIH release in the male animal (48, 49). Changes in hypothalamic GHRH and SRIH signaling to the somatotroph population may mediate the amplification of GH secretion and the significantly higher GH ApEn values observed in midpuberty, as well as after estradiol or testosterone treatment.
And fourth, we postulate that decreased autoregulation of GHRH release could result in increased ApEn, taken as a measure of the disorderliness of GH release. This notion is supported by recent experiments in which synthetic GHRH peptide was administered iv every 90 min, as fixed pulses over 3 days, to normal men of varying ages and body compositions. Unvarying GHRH injections consistently increased ApEn (50), thus quantifying greater irregularity of subordinate (nonpulsatile) 24-h GH release. A plausible mechanism for such increased disorderliness of the GH time series is a reduction in endogenous feedback control within the GH axis. For example, GHRH infusions may disrupt normal physiological moment-to-moment GHRH/SRIH interactions, which otherwise reciprocally adjust each other’s release (16, 51). Merely increasing GH secretion is not relevant to increased ApEn, because ApEn is scale-invariant. Thus, a doubling of daily GH secretion rates via pyridostigmine stimulation in young men does not alter the orderliness of GH release (52). Based on the GHRH infusion data, one can speculate that a relatively intense or autonomous hypothalamic GHRH stimulus might be delivered to somatotrope cells in late puberty. This could result from either SRIH-withdrawal and/or augmented GHRH release. There are insufficient data at present to distinguish among these explanations, all of which are consistent with the (above) biostatistical considerations.
The current cross-sectional observations in boys each studied only once and stratified according to different stages of puberty (compared with young adults) do not demonstrate causality. For example, we do not know whether any given healthy boy or girl studied longitudinally throughout normal puberty would show progressively more disorderly GH release (higher ApEn) in mid-to-late puberty and then manifest a monotonic decline in ApEn in young adulthood. Sequential evaluation of the same child before and throughout puberty and again in young adulthood will be required to address this issue definitively. However, the present sex-steroid replacement studies indicate that an individual girl or boy responds to short-term estrogen or testosterone (but not DHT) treatment with increased irregularity of GH secretion akin to that identified in midpuberty. Similarly, a recent longitudinal study of prepubertal boys with idiopathic hypogonadotropic hypogonadism, treated with a very small (25 mg) dose of testosterone enanthate im, disclosed increased GH ApEn within 2 weeks (53).
Our cross-sectional data in boys and young men may not be quantitatively representative of differences expected in girls across different stages of puberty and/or in young women. Although valid in boys and men, our studies do not explicate why ApEn falls postpubertally in young adulthood after an apparent maximum in mid-late puberty, even though sex-steroid hormone concentrations remain increased. One interpretation is that the GH axis escapes mechanistically from the sex-hormone stimulus during sustained sex-hormone exposure and/or in response to adult maturation and its metabolic consequences.
Available data also do not yet clarify whether the ApEn-implied variations in GH feedback control in puberty are singularly applicable to the somatotropic axis or also apply in the LH, FSH, ACTH, etc., feedback axes. However, an interesting parallel finding is that aging beyond the young adult years results in a slowly progressive rise in GH ApEn (19), which indicates a more disorderly GH release pattern with rising age. Diminishing regularity of neurohormone release with increasing age is also evident for LH/testosterone (25), ACTH/cortisol (20), and insulin (23). The exact mechanisms by which midpuberty and aging evoke a loss of orderliness of GH (and other hormone) release remain to be identified but likely involve alterations in the coordination and/or complexity of within-axis feedback control.
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Acknowledgments |
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Footnotes |
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search Career Development Award 1-KO4-HD-00634 (to J.D.V.); the NIH-supported Clinfo Data Reduction System; the University of Virginia Pratt Foundation and Academic Enhancement Program; the National Science Foundation Center for Biological Timing (NSF Grant DIR-89-20162); NIH P-30 Center for Reproduction Research (NICHD) HD-28934); Post-Doctoral Research Training in Diabetes and Hormone Grants 5T32-DK-07320 and DK07642 (to the University of Virginia); and NIH NIA R01 AG14799 and RO3 AG 14873 (to J.D.V.).
Received April 22, 1997.
Revised July 2, 1997.
Accepted July 14, 1997.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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