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Am J Physiol Regul Integr Comp Physiol 285: R1240-R1249, 2003. First published July 17, 2003; doi:10.1152/ajpregu.00086.2003
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COMPLEX FUNCTION OF THE CENTRAL NERVOUS SYSTEM, SLEEP AND LOCOMOTION

Joint pituitary-hypothalamic and intrahypothalamic autofeedback construct of pulsatile growth hormone secretion

Leon S. Farhy1 and Johannes D. Veldhuis2

1Division of Endocrinology and Metabolism, Department of Internal Medicine, School of Medicine, University of Virginia, Charlottesville, Virginia 22908; and 2Division of Endocrinology and Metabolism, Department of Internal Medicine, Mayo Medical and Graduate Schools of Medicine, General Clinical Research Center, Mayo Clinic, Rochester, Minnesota 55905

Submitted 19 February 2003 ; accepted in final form 10 July 2003


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 DISCLOSURES
 REFERENCES
 
Growth hormone (GH) secretion is vividly pulsatile in all mammalian species studied. In a simplified model, self-renewable GH pulsatility can be reproduced by assuming individual, reversible, time-delayed, and threshold-sensitive hypothalamic outflow of GH-releasing hormone (GHRH) and GH release-inhibiting hormone (somatostatin; SRIF). However, this basic concept fails to explicate an array of new experimental observations. Accordingly, here we formulate and implement a novel fourfold ensemble construct, wherein 1) systemic GH pulses stimulate long-latency, concentration-dependent secretion of periventricular-nuclear SRIF, thereby initially quenching and then releasing multiphasic GH volleys (recurrent every 3-3.5 h); 2) SRIF delivered to the anterior pituitary gland competitively antagonizes exocytotic release, but not synthesis, of GH during intervolley intervals; 3) arcuate-nucleus GHRH pulses drive the synthesis and accumulation of GH in saturable somatotrope stores; and 4) a purely intrahypothalamic mechanism sustains high-frequency GH pulses (intervals of 30-60 min) within a volley, assuming short-latency reciprocal coupling between GHRH and SRIF neurons (stimulatory direction) and SRIF and GHRH neurons (inhibitory direction). This two-oscillator formulation explicates (but does not prove) 1) the GHRH-sensitizing action of prior SRIF exposure; 2) a three-site (intrahypothalamic, hypothalamo-pituitary, and somatotrope GH store dependent) mechanism driving rebound-like GH secretion after SRIF withdrawal in the male; 3) an obligatory role for pituitary GH stores in representing rebound GH release in the female; 4) greater irregularity of SRIF than GH release profiles; and 5) a basis for the paradoxical GH-inhibiting action of centrally delivered GHRH.

feedback; mathematical model; somatotropic axis; hormone pulsatility; somatostatin; growth hormone-releasing hormone; hypothalamus

THE SECRETION OF GROWTH HORMONE (GH) is pulsatile in the human, monkey, sheep, swine, guinea pig, rat, and mouse (10, 20, 21, 30, 34, 37, 40, 48, 49). In the rodent, episodic GH release directs somatic growth, cellular gene expression, and autonegative feedback (3, 20, 31, 34, 37, 42). A distinctive feature of pulsatile GH secretion is the dual representation of 1) multiburst volleys, which recur every 3-3.5 h in the adult male rat and every 1.5-2.5 h in men and women, and 2) rapid discrete GH pulses, which arise every 30-60 min within an individual volley (19-22, 30, 37, 38, 42, 48, 49). Such complex patterns of GH release are evident by high-frequency (0.5- and 5-min) sampling paradigms in the unanesthetized rat, sheep, and healthy human (19, 22, 23, 37, 38, 42, 49). The mechanisms that generate composite low-frequency volleys and high-frequency GH bursts are not established.

Our earlier construction of a regulatory basis for combined GH volleys and discrete GH pulses incorporated prompt autofeedback by secreted GH on GH-releasing hormone (GHRH) outflow (thereby eliciting rapidly recurrent events) and delayed feedforward by GH on somatostatin (SRIF) release (thus terminating a volley). In essence, this notion defines two systemic-hypothalamic oscillators with distinguishable sensitivities and periodicities (14). The resultant GH secretory pattern is self renewing, emulates that of the adult male rat, and is adaptable to female dynamics by gender-specific relaxation of GH-induced SRIF release (15). However, the purely systemic-central nervous system (CNS) feedback structure fails to account for other fundamental experimental observations. The latter include 1) continued GH pulsatility under constant systemic GHRH stimulation, 2) a paradoxical suppressive effect of central GHRH action, and 3) peripheral SRIF withdrawal-induced rebound-like secretion of GH in the adult female rat (13, 20, 27, 30, 34, 42).

The present work formulates and implements an alternative model of GH autoregulation, which combines four distinct mechanisms: 1) long-loop, time-delayed stimulation of SRIF release by blood-borne GH (systemic-CNS control); 2) periventricular SRIF-dependent inhibition of pituitary GH release but not synthesis (CNS-pituitary regulation); 3) arcuate-nucleus GHRH-stimulated somatotrope GH synthesis and storage in a releasable pool (hypothalamo-pituitary pathway); and 4) short-loop, rapid, and reciprocal signaling within the hypothalamus between GHRH and SRIF, which sustains GHRH/GH pulse renewal. This construct forecasts self-regenerating GH oscillations within a volley, illustrates a mechanism for GH pulsatility in the face of continuous GHRH drive, and explicates post-SRIF rebound GH secretion in the female.


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 DISCLOSURES
 REFERENCES
 
Core GH network. The core ensemble comprises seven principal feedforward and feedback linkages among GH, GHRH, and SRIF (Fig. 1). At any given moment, GH output reflects these primary physiological interactions, which are transduced by implicit effector dose-response interface functions. Individual peptide elimination rates are assumed to be distinct and stable. The primary network-like connections (and their experimental derivation) are 1) GHRH's acute stimulation of GH release from somatotrope cells (8, 18, 26, 30, 37, 42, 43, 45, 46), 2) SRIF's antagonism of GHRH-induced GH secretion (18, 20, 34, 42), 3) GH's delayed feedforward on SRIF release (6, 9, 29, 31, 34, 35, 37), 4) SRIF's inhibition of GHRH secretion (8, 12, 16, 24, 30), 5) GH's repression of GHRH outflow (7, 9, 16, 31, 32), 6) GHRH's time-lagged induction of pituitary SRIF secretion (1, 2, 11, 24, 27, 29, 32-34, 37, 46), and 7) GHRH's induction of the de novo synthesis and accumulation of (releasable) GH in the pituitary gland (20, 34, 42, 45, 46). This ensemble formulation extends an earlier basic construct by including intrahypothalamic GHRH-evoked SRIF outflow and GHRH-stimulated synthesis and accumulation of GH stores (see DISCUSSION). The interconnections defined by the above interfaces (nos. 1-7) yield two coupled oscillators: an intrahypothalamic GHRH-SRIF oscillator (connections 4 and 6 above) and a pituitary-hypothalamic GH-SRIF oscillator (driven via linkage 3).



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  		Fig. 1. Schema of primary feedback connections linking core hypothalamic centers, the anterior pituitary gland and the systemic circulation. Inhibitory interfaces and elimination processes are denoted by lines terminating in solid circles; stimulatory interactions are defined by T endings. Formalized interactions are identified by circled Arabic numerals 1-7; triangles containing T and D denote the time delays in the corresponding relationships (see METHODS). GH, growth hormone; GHRH, GH-releasing hormone; SRIF, somatostatin.

 

The foregoing bipartite model provides a platform to examine the present new postulates that a putative CNS GHRH-SRIF oscillator will yield a high frequency of self-sustaining GH pulses within a volley, and the systemic-hypothalamic GH-SRIF oscillator will confer infrequent multiphasic volleys. Concomitantly, we tested GH pulse automaticity under (simulated) continuous GHRH infusion and the contribution of GHRH-enhanced (releasable) pituitary GH stores to postSRIF rebound-like GH secretion.

Connectivity is encapsulated in the following core equations. The prime notation denotes the time derivative (or rate of change of concentration) under feedback and feedforward inputs

(1)

(2)

(3)

(4)

GH, SRIF, and GHRH (italicized) signify the concentration of each peptide; Pool defines the GH concentration in releasable pituitary stores; M is the maximal attainable GH concentration in the pool; Smin designates minimal baseline "tonic" SRIF release; {alpha} is a scaling constant to relate the distribution volumes of the pituitary and systemic circulation; k1, k2, and k3 are rate constants of peptide elimination; and kr,1, kr,2,gh, kr,2,ghrh, kr,3, and kr,4 are rate constants of release or synthesis. n0, n1, n2, n4, n5, n6, and n7 and t0, t1, t2, t4, t5, t6, and t7 are Hill coefficients and thresholds, respectively, for the dose-response interfaces numbered in Fig. 1. D is the time delay for GH's feedback on SRIF, T is the time-delay for GHRH's feedforward on SRIF, and t3 is the Michaelis-Menten constant defining sensitivity of SRIF feedback on GH.

In this formulation, the dynamics of the GH pool depend simultaneously on time-varying synthesis and release of GH. Algebraically, synthesis is represented by the first term at right in Eq. 4. Synthesis (but not release) of GH is stimulated by GHRH (through the corresponding Hill function), even in the presence of SRIF competition, and depressed as the pool approaches saturation (the term "M - Pool" in Eq. 4). Pool saturation denotes that the maximal GH concentration attainable remains below a certain asymptotic limit (the constant M). Actual GH release is described by the second term at right in Eq. 4. Release is antagonized by SRIF and stimulated by GHRH depending on GH pool size.

Deterministic features. The following assumptions are implicit in the interactive network represented algebraically by Eqs. 1-4. 1) A pulse of GH requires all three of the following: releasable GH stores, stimulation by GHRH, and relative relief of SRIF restraint (designated in the term in brace parentheses after kr,1 in Eq. 1). 2) GH and GHRH each stimulate SRIF release (defined by the terms after kr,2,gh and kr,2,ghrh, respectively, in Eq. 2). 3) GHRH secretion proceeds under combined withdrawal of GH feedback and relief of SRIF inhibition (given in the term after kr,3 in Eq. 3). 4) The releasable pituitary GH pool is depleted partially and saturated fully (parameter M in Eq. 4). 5) GHRH-driven synthesis of GH expands the releasable pool in inverse proportion to nearness to saturation (multiplier fraction after kr,4 in Eq. 4). And 6) GH- and GHRH-stimulated SRIF outflow suppresses GHRH and GH secretion (Eqs. 1 and 3), i.e., SRIF inhibits both the hypothalamus and pituitary gland.

GHRH's drive of SRIF release is stated for notational simplicity as proportionate to GHRH concentration (Eq. 2). Any of numerous other neurotransmitters that mediate GHRHergic transsynaptic control, if relevant, would replace GHRH in acting on internuncial and/or SRIFergic neurons.

Parameter definition. A detailed justification of the choice of interface parameters is given in Refs. 14 and 15. Incomplete experimental data require indirect estimation of kinetics for the unobserved pituitary GH pool: t0, n0, {alpha}, kr,4, t7, n7, and M. A priori criteria are pulsatile GH release without store exhaustion and a threshold t5 that ensures concentration-dependent suppression of GHRH secretion by GH. Table 1 shows parameters used in the present analyses.


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  		Table 1. Nominal parameter set applied in male rat reference model

 

Justification of accumulation of pituitary GH stores. In vitro and in vivo SRIF blocks the release, but not GHRH-stimulated synthesis and accumulation, of GH in somatotrope cells (18, 20, 35, 45, 46). Equations 1 and 4 incorporate this precept by allowing GHRH to promote the (saturable) accumulation of releasable GH stores when SRIF is present. Second, we test the implications of an allowance that systemic SRIF suppresses GHRH release in the arcuate nucleus (see DISCUSSION).

Rebound GH release. The network connectivity of Fig. 1 permits an evaluation of the impact of feedback-dependent unleashing of acute GH secretion by sequential exposure to and withdrawal of systemic SRIF. We assess the consequences of SRIF to block GH release but not inhibit GHRH-dependent synthesis and accumulation of GH stores (20). The primary postulate is that post-SRIF rebound secretion of GH arises by way of increased GH stores (due to SRIFergic inhibition of GH release despite ongoing GH synthesis) and elevated GHRH release (due to decreased hypothalamic SRIF outflow associated with reduced GH availability for feedback) (6, 7, 16, 20, 28, 32, 37). A complementary prediction is that hypothalamic GHRH secretion during peripheral SRIF infusion would remain pulsatile, unless circulating SRIF can enter the CNS and fully suppress GHRH release (12).

Continuous infusion of GHRH. The macromolecules injected intravenously accumulate promptly in the median eminence and arcuate nucleus but not in the periventricular nucleus (20, 34). Thus we compare the impact of constant systemic GHRH stimulation under the assumption of either no or variable access of infused GHRH to SRIF neurons. A truncated transcript of the GHRH gene is expressed in the foregoing two hypothalamic nuclei, as quantitated by RTPCR, sequencing of the cDNA product, and Northern blot hybridization (47); and, central delivery of synthetic GHRH stimulates SRIF release acutely in vivo in the adult male rat and in vitro from incubated fragments of the median eminence (1, 2, 11, 24, 27, 29, 32-34, 37).

Simulation of SRIF or GHRH infusion. To simulate systemic or central delivery of SRIF or GHRH, we define the changing concentration of the infused substance as

(5)

where C is the time-varying predicted and instantaneous concentration of the exogenous peptide (GHRH or SRIF), k is the corresponding elimination rate constant, and Inf is the peptide infusion rate. The (infused) C term is additive to the endogenous concentration term, SRIF or GHRH, in Eqs. 1-4, solely if exogenous peptide gains access to the particular endogenous peptide pool (e.g., if exogenous SRIF comingles with hypothalamic SRIF).


   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 DISCLOSURES
 REFERENCES
 
Basic model output. Figure 2 depicts simulated (reference) profiles of time-varying concentrations of GH, SRIF, and GHRH (Fig. 2A) and releasable pituitary GH stores (Fig. 2B) in the adult male model. In the present formulation, successive GH pulses evolve as follows. GHRH is released into portal blood during relatively permissive outflow of hypothalamic SRIF. GHRH stimulates prompt GH secretion from releasable pituitary stores, as GHRH-on-GH dose-responsive stimulation of somatotropes traverses the steeply ascending portion of the agonist-response interface, defined by the action threshold (t1). Concomitantly, GHRH feedforward begins to augment de novo synthesis of GH. Neuronal GHRHergic activity (denoted algebraically by the rising GHRH concentration; Eq. 3) evokes central SRIF release after a short time delay T. The latency, T, is required for GHRH to attain the dose-response threshold t6 of strong feedforward drive. As a result, SRIFergic outflow increases toward the cognate inhibitory threshold (t4), whereby arcuate-nucleus GHRH secretion is repressed. Concurrently, SRIF secreted to the pituitary gland antagonizes the release, but not synthesis or storage, of GH by somatotrope cells. Attendant elimination of GHRH peptide (by diffusion and distribution into the systemic circulation and cerebrospinal fluid and irreversible metabolism) contributes to ending the first GH secretory peak within a volley. Attenuation of GHRHergic drive withdraws the latter intrahypothalamic stimulus to SRIF secretion. Subsequent rapid elimination of SRIF from the periventricular SRIFergic synaptic contacts made with arcuate-nucleus GHRH neurons disinhibits GHRH release, thus initiating another GHRH pulse that continues the multiburst secretory volley. Recurrent cycling of GHRH and SRIF with phase disparity allows somatotrope accumulation of GH stores (Fig. 2). Accumulation proceeds when GHRH signaling, GH gene transcription, and/or mRNA stability maintain GH biosynthesis and SRIFergic effects inhibit somatotrope exocytosis.



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  		Fig. 2. A: simulated time series driven by the reference (male) model (see Table 1 and Fig. 1). Plots are simultaneously evolving SRIF, GHRH, and GH concentrations generated every 30 s by the network shown in Fig. 1 and then discretized to 5-min intervals. B: changing relative size of GHRH-releasable pituitary GH pool (arbitrary maximum). Time series were allowed to unfold for 20 h before the indicated 18-h record.

 

The foregoing formulation illustrates that reciprocal interactions between hypothalamic GHRH and SRIF could sustain recurrent GHRH and GH peaks within a volley. The volley unfolds until GH concentrations increase sufficiently in the circulation and hypothalamus to stimulate release of periventricular SRIF after a distinct time delay D. The resultant outflow of SRIF restricts pituitary GH release and hypothalamic GHRH secretion (5). These twofold actions quench GH and GHRH pulses within a volley. Accordingly, the duration of any given volley reflects the de facto delay required for systemic GH-hypothalamic SRIF feedback. Concentrations of GH in blood and interneuronal fluids decline at a slow rate. The attendant delay enforces prolonged intervolley release of SRIF. The latter interval exceeds intravolley recovery times, which would mirror interneuronal synaptic (reciprocal SRIFGHRH) signaling latencies. GH stores accumulate so long as release and/or pituitary effects of GHRH persist in stimulating GH synthesis in the transitional intervals, when 1) GH induces SRIF outflow by autofeedback, but has not yet inhibited GHRH (ending a volley); and 2) SRIF outflow wanes releasing restraint on GHRH (initiating a new volley; Fig. 2B).

Simulations further illustrate that high-frequency GHRH-SRIF oscillations expressly require GHRH stimulation of SRIF. Depletion of this pathway leaves low-frequency (~3-h) pulses driven by the long-latency GH-SRIF oscillator. High-frequency GH oscillations also disappear if T = 0 (time delay for GHRH to stimulate SRIF outflow), since instantaneous SRIF release damps the intrahypothalamic GHRH-SRIF oscillator. Thus feedback delay in this model is obligatory to sustain rapid GHRH/GH pulsatility within a volley.

Theoretical considerations and empirical observations indicate that feedback connections within an interlinked network control the serial orderliness (or sequential regularity) of output patterns (39, 41). One objective ensemble regularity measure is the approximate entropy (ApEn) statistic, as justified earlier to compare the relative orderliness of limited time series and thereby quantitate the relative admixture of deterministic and stochastic processes (19, 38). Table 2 gives ApEn and normalized ApEn ratio for simulated (noise-free) GH, GHRH, and SRIF release profiles in the adult male model. For ApEn normalization, each time series is shuffled randomly 200 times to generate a distribution of random (null) ApEn (50, 52). Normalized ApEn is defined here as the mean ratio of observed ApEn (a single value per series) to each of 200 null ApEn values. Series are generated by 5-min discretization (265 apparent samples over 22 h) of the primary 30-s concentrations. ApEn ratios are cited for simultaneously evolving GH, SRIF, and GHRH concentrations and their first differences (stationarized series). First-differenced ApEn values yield comparable inferences to those for native profiles. ApEn was quantitated for pattern recurrence (template) vector lengths of m = 1 and a scalar tolerance (threshold) range of r = 0.2 SD, where SD is the standard deviation of the data set (for details, see Refs. 19 and 38). Higher ApEn ratios approaching 1.0 approximate empirically mean random (equivalent to shuffled, null ApEn) and therefore define greater disorderliness (less subpattern reproducibility). Thus SRIF was the most irregular and GH the least irregular, with GHRH exhibiting an intermediate degree of relative orderliness.


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  		Table 2. Comparative regularity (orderliness) of hormone concns monitored by scale-independent ApEn

 

SRIF-induced rebound GH release. Systemic SRIF delivery and withdrawal was simulated as described in METHODS (see Simulation of SRIF or GHRH infusion) by adding a new Eq. 5 to the core system. The infusion term Inf(t) differs from zero only during the anticipated infusion period, when it equals 5,000 pg·ml-1·h-1. The same elimination rate constants are assumed for endogenous and exogenous SRIF. Under a simplifying model assumption that exogenous SRIF does not inhibit GHRH neurons [the "infusion" C(t) (Eq. 5) is added to SRIF(t) in Eqs. 1 and 4 but not Eq. 3], pulsatile GHRH release continues despite peripheral inhibition of GH output, thereby increasing GH synthesis and storage. Withdrawal of short-term (4-h) SRIF inhibition from the circulation in this model induces prompt rebound-like release of GH (Fig. 3A). The resultant post-SRIF GH secretory burst partially depletes releasable GH stores. Rebound is accompanied by elevated release of GHRH peptide (exemplified in Fig. 3 by a horizontal line passing through the peak GHRH value during the rebound). Elevated GHRH release has been documented in similar context by direct central (hypothalamo-pituitary portal) venous sampling in the awake ram (31).



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  		Fig. 3. Predicted effect of sequential infusion and withdrawal of systemic SRIF on GH and GHRH output and the GH pool. A: simulated 4-h SRIF infusion (timeline: 1600-2000) based on the feedback parameters summarized in Table 1. B and C: abbreviated vs. prolonged SRIF infusion (2.5 h in B and 7 h in C) when the contribution of the GH pool is augmented (2-fold decrease in t0, 2-fold increase in kr,1, and 2-fold decrease in {alpha}; see METHODS). Top curves depict pituitary GH pool size. Cessation of a simulated SRIF infusion ({leftrightarrow}) abruptly 1) diminishes GH pool size, 2) initiates rebound-like GH release, and 3) allows responsiveness to GHRH output (B). Horizontal line demarcates elevation in SRIF-induced GHRH release compared with preinfusion GHRH outflow.

 

Figure 3, B and C, illustrates predicted responses to a relatively abbreviated and extended SRIF infusion (2.5 and 7 h compared with 4 h). These simulations forecast that relative expansion of the GH pool augments rebound GH release until pool size approaches saturation asymptotically. The foregoing outcome was modeled by augmenting the contribution of the GH pool to postSRIF-induced rebound GH release under equivalent GHRH release (2-fold decrease in t0, 2-fold increase in kr,1, and 2-fold decrease in {alpha} to preserve {alpha}kr,1 unchanged; see METHODS).

Additional simulations show that in this model system, SRIF infusion does not disrupt GHRH pulse timing. Therefore, the magnitude of rebound GH release postSRIF depends on the quantity of releasable GH stores, concomitant GHRH concentration, and the rates of infusion and elimination of SRIF. Incomplete withdrawal of exogenous SRIF during the first postinfusion GHRH spike would limit maximal GH release. Thus for uniformity, simulations depicted in Fig. 3 illustrate termination of SRIF infusion during a GHRH zenith.

Figure 4A illustrates the predicted effect of a single GHRH stimulus imposed after cessation of a continuous (4-h) infusion of SRIF (with allowance for SRIF elimination). Continuous SRIF infusion was modeled as described, and bolus GHRH was injected by a delimited burst of peak rate of 120,000 pg·ml-1·h-1. The agonist/antagonist sequence amplifies rebound GH release, as reported in vivo and in vitro for the adult male rat pituitary (8, 20, 34, 46). In contrast, prolonging the (post-SRIF) interval before delivering a GHRH pulse elicits a smaller GH secretory response because of depletion of the releasable GH pool under endogenous GHRH action (not shown). Likewise, delivery of a GHRH stimulus 0.5 h before ending the SRIF infusion is ineffectual (Fig. 4B). These simulations assume that infused GHRH does not stimulate SRIF-producing neurons [the GHRH infusion C(t) (Eq. 5) is added to GHRH(t) in Eqs. 1 and 4 but not Eq. 2]. The latter proviso does not exclude delayed GH drive of SRIF induced by the first peak and expected hypothalamic GHRH stimulation of SRIF.



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  		Fig. 4. A: predicted impact of a single GHRH stimulus (arrow on the "Time" axis) administered shortly (20 min) after abrupt interruption of a simulated 4-h infusion of SRIF (1600 to 2000). Rebound-like release of GH is accentuated markedly by an appropriately timed GHRH signal (see Fig. 3A). B: model-based response to a controlled exogenous GHRH pulse (arrow on the "Time" axis) introduced 30 min before withdrawal of a simulated 4-h infusion of SRIF. Rebound amplitude is unchanged compared with the output depicted in Fig. 3A (post-SRIF rebound without a GHRH stimulus).

 

SRIF withdrawal-induced rebound secretion of GH in the female-like model. To examine post-SRIF-induced rebound release of GH in a female-like construct, we attenuated GH-dependent stimulation of SRIF secretion in the male model. This adaptation is described algebraically in Ref. 15. We then compared the magnitude of post-SRIF rebound-like GH release in the presence (as above) and absence of a time-varying GH pool by replacing the release-control function

with a constant in Eq. 1. Figure 5 illustrates that inclusion of a releasable GH pool allows rebound-like GH secretion in the female-like formulation.



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  		Fig. 5. Dependence of a female-like (GH feedback-muted) construct on a replenishable (A) vs. fixed (B) pituitary GH pool in generating rebound-like GH release at the end of a brief SRIF infusion ({leftrightarrow}).

 

Continuous GHRH infusion. Continuous systemic GHRH delivery was simulated at a rate of 1,600 pg·ml-1·h-1 with allowance for variable access of exogenous GHRH to SRIF neurons after a finite time delay. For graphical purposes, the 20-h infusion started at 1000 and ended at 3000. Because CNS access of exogenous GHRH is an unknown property that could influence hypothalamo-pituitary responsiveness, we explored the impact on GH output of variable uptake of GHRH into the hypothalamus (Fig. 6). Figure 6, A-D, illustrates outcomes of an assumed relative availability of GHRH to the hypothalamus vis-à-vis anterior pituitary gland of 100 (1:1), 75, 50, and 25%. Unrestricted access of GHRH to SRIF-releasing neurons in this construct represses GH pulse amplitude by delayed feedforward on SRIF. The latter phenomenon is observed after in vivo intracerebroventricular infusion of biosynthetic GHRH in the mature male rat and after in vitro incubation of GHRH with fetal hypothalamic neurons or adult median-eminence neural tissue (1, 2, 11, 27, 29, 32, 33). In further simulations, we observed that the onset of continuous GHRH infusion initially induces high-amplitude GH pulses. Damping of GH pulse size thereafter reflects the assumed delay in cyclical GHRH-stimulated and systemic GH-induced SRIF release. The sensitivity of suppression of GH secretion to the amount of infused peripheral GHRH was explored by elevating the infusion rate by two- and eightfold (Fig. 7). In this experiment, the hypothalamic uptake of the circulating peptide was assumed to be 100%, and the feedforward latency was prolonged by fourfold to match the delay in GH-on-SRIF drive. The twofold increase in GHRH delivery rate (Fig. 7A) yielded a pseudofeminized GH pattern of low-amplitude pulses (because of secreted GHRH-driven SRIF release) and elevated interpulse concentrations (because of infused GHRH). The eightfold increase in the GHRH infusion rate (Fig. 7B) obliterated GH pulsatility and resulted in rebound-like GH secretion thereafter. The fourfold extended lag time enhanced the magnitude of GHRH dose-dependent rebound. The latter occurred at the predicted time of cyclical GHRH secretion release and was associated with partial depletion of GH stores. Appropriate timing of elevated GHRH release is due to low GH-driven SRIF outflow compared with the GHRH infusion dose.



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  		Fig. 6. Predicted outcome of peripherally infused GHRH (1000-3000) under assumptions of hypothalamic uptake of 100 (A), 75 (B), 50 (C), and 25% (D) of circulating peptide. Central actions of GHRH include paradoxical inhibition (100%) and absent stimulation (75%) of GH secretion.

 


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  		Fig. 7. Sensitivity of suppression of GH secretion to elevation (with respect to the experiment depicted in Fig. 6) of the simulated GHRH infusion rate by 2-fold (A) and 8-fold (B). The feedforward (GHRH-on-SRIF) latency was increased by 4-fold, and the hypothalamic uptake of the circulating peptide was assumed to be 100%.

 


   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
DISCLOSURES
 REFERENCES
 
The present analyses demonstrate that reciprocal intrahypothalamic oscillations between SRIF and GHRH provide a mechanistic model that reproduces physiological features of in vivo GH release patterns. Specifically, unlike an earlier alternative formulation (14), the present ensemble construct correctly forecasts 1) rapid GH pulses within a multiphasic secretory volley, 2) rebound-like GH release after sequential SRIF exposure and withdrawal, 3) sustained GH pulsatility under continuous (exogenous) GHRH stimulation, 4) accumulation of GHRH-releasable pituitary GH stores, and 5) paradoxical GH-inhibiting action of central GHRH uptake. Each of these regulatory principles is well established experimentally in the rodent, and several are inferable indirectly in the human (20, 25, 34, 37).

Detailed simulations predicted several pivotal regulatory mechanisms. First, saturable accumulation of GHRH-releasable somatotrope stores is crucial to the generation of recurring high-amplitude GH pulses within a multiphasic release episode (volley) in the male model. Indeed, simulated depletion of the saturable pituitary GH pool damps the amplitude of successive GH secretory bursts in an evolving volley. Second, GHRH-stimulated GH synthesis under SRIF-inhibited GH release potentiates postSRIF-induced GH secretion in the male-like construct. Moreover, the replenishable GH pool model is obligatory to simulate post-SRIF rebound release of GH in the female formulation, wherein GH autofeedback is attenuated. Both projected outcomes agree with experimental data in the adult rat (37, 42, 45, 46). And, third, systemic exposure to SRIF inhibits GH secretion, which in the present construct limits endogenous SRIF restraint and (on SRIF withdrawal) induces rebound-like GH release. Elevated GHRH release has been demonstrated directly by frequent hypothalamo-pituitary portal-venous sampling in the unanesthetized ram and inferred indirectly by passive GHRH immunoneutralization in the adult male rat (8, 30).

Clinical investigations have also unveiled SRIF-induced rebound GH secretion, which in one study was not blocked by administration of a GHRH-receptor antagonist peptide (3, 4, 13, 22, 26, 43, 51). The latter paradoxical outcome could signify a species difference in the post-SRIF rebound mechanism. On the other hand, according to the simulations described here, failure to inhibit rebound GH release in the human administered high concentrations of a GHRH antagonist could denote central stimulatory effect directly on the hypothalamic GHRH-SRIF oscillator. The latter notion follows from extensive experimental data documenting (paradoxical) inhibition of GH secretion via GHRH-specific central neural stimulation of SRIF release (1, 2, 5, 11, 16, 27, 30, 34) and structural evidence of bidirectional GHRH-SRIF connectivity (24, 26). Simulated central (SRIF) access of infused GHRH also paradoxically suppresses pulsatile GH secretion (Fig. 6). On the basis of this representation, (minimal) CNS uptake of a GHRH-receptor antagonist would enhance rather than repress post-SRIF rebound-like GH release by opposing central GHRH drive of SRIF outflow.

The current computer-assisted simulations show that intrahypothalamic oscillations between SRIF and GHRH afford a plausible mechanistic basis for the paradox of unchanged GH pulse frequency during constant GHRH infusion. For example, GH pulsatility clearly persists, but remains unexplained to date, in rare patients with ectopic (tumoral) GHRH production and in healthy individuals given constant intravenous infusion of biosynthetic GHRH (13, 20). Patients harboring a complete inactivating (truncational) mutation of the GHRH-receptor gene also retain a normal daily frequency of GH pulses, albeit of 30-fold reduced amplitude (44). The present analyses forecast a stable GH pulse frequency in the first two contexts, so long as systemic GHRH and GH do not directly restrain the putative hypothalamic SRIF/GHRH oscillator mechanism purported to set pulse timing. The hypothesis that the central GHRH-SRIF oscillator is isolated from systemic GHRH and GH autonegative feedback could be tested expressly by hypothalamo-pituitary portal-venous sampling of pulsatile GHRH release in the intact awake animal during constant infusion of (heterologous) GHRH and after bolus injection of GH. Important nonexclusive considerations are 1) GHRH neurons stimulate SRIFergic pathways via nonGHRH receptor-dependent neurotransmitters, thus allowing GHRH-SRIF interactions and GH pulse renewal to proceed at a normal frequency in patients with loss-of-function mutations of the GHRH receptor (44); and 2) redundant or collateral signals (such as neuropeptide Y or galanin) maintain GH pulse frequency in the face of excessive or diminished GHRH-dependent oscillations.

In the present model, the inferred descending rank order of ApEn ratios (most irregular to most regular) is SRIF > GHRH > GH for both untransformed and stationarized time series. In our earlier model (14), predicted GH, GHRH, and SRIF profiles emerge from different feedback connectivity, which yields a descending order of ApEn ratios of GHRH > SRIF > GH. Available experimental data do not unequivocally distinguish the relative (quantifiable) regularity of SRIF and GHRH release. However, we report greater irregularity of SRIF than GH release using 5-min sampling of cavernous-sinus blood in the conscious unrestrained ewe (SRIF and GH ApEn values were 94 ± 4.3 and 72 ± 8.1%, respectively, of the mean irregularity of 1,000 individual random-shuffled cognate series; P = 0.034; Ref. 49).

The current mechanistic formulation of high-frequency GH pulses within multiphasic volleys differs from an earlier notion (14, 15). Specifically, the initial model does not include intrahypothalamic bidirectional coupling between GHRH and SRIF to drive high-frequency pulse renewal. Rather, GH is envisioned to act briefly and reversibly via pituitary secretion to the arcuate-nucleus (36), which suppresses GHRH secretion at a threshold too low to induce SRIF release (14, 15). However, both representations of autoregulation require a longer time delay for systemic GH concentrations to stimulate periventricular SRIF release and quench (otherwise indefinite) continuation of a multiphasic volley (6, 9, 20, 31, 34, 35, 37, 42). SRIF release from nerve terminals in the median eminence terminates a volley by blocking somatotrope exocytosis (7, 9, 12, 16, 20, 24, 30, 32, 34, 37, 42). GH feedback-induced outflow of SRIF into portal blood maintains low intervolley somatotrope secretion until GH concentrations decline by metabolic elimination in the circulation and CNS. Two constructs allow examination of other mechanistic considerations. For example, in future studies, a testable postulate is that central GH drive of periventricular SRIF release may repress putative intrahypothalamic oscillations between GHRH and SRIF. Repression would be relieved by waning GH concentrations, thereby triggering rebound-like GHRH and GH secretion. The foregoing dynamics are concordant with selected biological oscillatory mechanisms that require implicit or explicit involvement of delayed negative feedback (17).

Intervolley (nadir) GH concentrations in the adult male rat are undetectable in most current assays, consistent with prominent periventricular SRIF secretion induced by GH autofeedback (5, 6, 8, 9, 20, 29, 32). In the female rodent, lesser GH-induced SRIF outflow would unmask activity of the proposed intrahypothalamic GHRH-SRIF oscillator mechanism otherwise made unapparent (albeit present) by pituitary inhibition because of cycles of autofeedback (14, 15, 20, 34, 35, 37). Experimental data show that GH-dependent feedback on SRIF neurons is attenuated, but not abolished, in the adult female rat (15, 19, 20, 31, 34, 37, 38, 42). In the current formulation, partial, rather than complete, muting of GH autoinhibition in the female animal predicts occasional epochs of pluriphasic GH release, as observed under intensive (5-min) and extended (6- to 24-h) monitoring of GH secretion in the female rodent and ruminant (19, 38, 42, 49). A comparable inference of disinhibited GHRH-SRIF oscillatory activity would apply to the nearly continuous train of GH secretory bursts in the presumptively low SRIF milieu associated with fasting or deep sleep in the human (22, 26).

Perspectives

Silencing of CNS SRIF subtype 1-specific receptor function by intracerebroventricular infusion of specific antisense oligodeoxynucleotide represses GH pulse amplitude in the adult male rat (28). Such data demonstrate CNS autoregulation via SRIF receptors but do not establish the particular locus (loci) involved. In principle, topographically specific models of SRIF action could embody primarily arcuate (intra-) nuclear SRIF/GHRH connectivity or periventricular/arcuate (inter-) nuclear SRIF/GHRH linkages (12, 20, 24, 34, 35, 37, 42). For example, in the latter perspective, a pulse of GH would evoke periventricular SRIF release into hypothalamo-pituitary portal blood (thus blocking GH exocytosis) and concomitantly exert SRIFergic transsynaptic inhibition of arcuate-nucleus GHRH neurons (thereby repressing GHRH pulse amplitude). Distinguishing between the foregoing formulations (and possible hybrid models that include each) is not facile. Indeed, interconnectivity may be redundant or complementary, inasmuch as immunoreactive peptidergic neuronal terminals and cognate receptors for GHRH and SRIF are each detected in both the periventricular and the arcuate nucleus (1, 2, 8, 11, 24, 27, 29, 32, 33, 42, 47). In light of the foregoing complex issues, the present analyses underscore the expected complementarity of experimental data and model-assisted predictions to probe physiological regulation.


   DISCLOSURES
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 DISCLOSURES
REFERENCES
 
This work was supported in part by National Institutes of Health Grants K25-HD-01474 (to L. S. Farhy) and RO1-AG-14799 and AG-19695 (to J. D. Veldhuis) and General Clinical Research Center Award NCRR-M01-00585 (to Mayo Clinic and Foundation).


   ACKNOWLEDGMENTS
 
The authors acknowledge the expert manuscript assistance of J. Plote and the statistical advice of Drs. D. Keenan (Charlottesville, VA) and S. Pincus (Guilford, CT).


   FOOTNOTES
 

Address for reprint requests and other correspondence: J. D. Veldhuis, Division of Endocrinology and Metabolism, Dept. of Internal Medicine, Mayo Medical and Graduate Schools of Medicine, General Clinical Research Center, Mayo Clinic, Rochester, MN 55905 (E-mail: veldhuis.johannes{at}mayo.edu).

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.


   REFERENCES
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 DISCLOSURES
 REFERENCES
 

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