1 Department of Zoology, North Carolina State University, Raleigh, North Carolina 27695; and 2 Division of Endocrinology and Metabolism, Department of Internal Medicine, Department of Veterans Affairs Medical Center and the University of Michigan Medical Center, Ann Arbor, Michigan 48109
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ABSTRACT |
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Growth hormone-releasing hormone (GHRH) is a main inducer of growth hormone (GH) pulses in most species studied to date. There is no information regarding the pattern of GHRH secretion as a regulator of GH gene expression. We investigated the roles of the parameters of exogenous GHRH administration (frequency, amplitude, and total amount) upon induction of pituitary GH mRNA, GH content, and somatic growth in the female rat. Continuous GHRH infusions were ineffective in altering GH mRNA levels, GH stores, or weight gain. Changing GHRH pulse amplitude between 4, 8, and 16 µg/kg at a constant frequency (Q3.0 h) was only moderately effective in augmenting GH mRNA levels, whereas the 8 µg/kg and 16 µg/kg dosages stimulated weight gain by as much as 60%. When given at a 1.5-h frequency, GHRH doubled the amount of GH mRNA, elevated pituitary GH stores, and stimulated body weight gain. In the rat model, pulsatile but not continuous GHRH administration is effective in inducing pituitary GH mRNA and GH content as well as somatic growth. These studies suggest that the greater growth rate, pituitary mRNA levels, and GH stores seen in male compared with female rats are likely mediated, in part, by the endogenous episodic GHRH secretory pattern present in males.
pituitary; growth; pulsatility; sexual dimorphism
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INTRODUCTION |
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SOMATIC GROWTH DEPENDS ON a multitude of complex and often interrelated mechanisms, including genetic factors, nutrition, and adequate hormone milieu. Among these factors, growth hormone (GH) secretion by somatotrophs is central to regulating growth. In all vertebrates studied to date, GH is secreted in a pulsatile fashion (for review see Ref. 13). The episodic pattern of GH release is thought to be central in regulating a variety of GH-mediated processes, including hepatic epidermal growth factor receptors, corticosteroid binding globulins, and serum cholesterol, apoprotein, and lipoprotein concentrations (18, 22, 24, 32). In the adult rat, the markedly higher growth rates of males compared with females is regulated, in part, by the more episodic pattern of GH secretion seen in males (7, 19, 30).
Growth hormone secretion in male rats is characterized by secretory bursts that occur every 3-3.3 h with low, almost undetectable levels between peaks, whereas females have a more continuous secretion with substantially higher baseline GH levels (11, 38). The pulsatile pattern of GH secretion is governed mainly by GH-releasing hormone (GHRH) and somatostatin (SRIF). Studies in rats with use of antisera to either peptide or GHRH antagonist demonstrate that GHRH induces GH pulses, whereas low interpulse GH levels are maintained by SRIF (29, 34, 37). Indeed, both GHRH and SRIF are thought to be secreted 180 degrees out of phase, leading to the highly episodic pattern of GH secretion in males (37). In the intact adult female rat, administration of exogenous GHRH every 3 h imitates the male pattern of GH secretion and promoted growth, whereas continuous GHRH administration in the same dose was less effective (7). This study clearly demonstrates that the manner of GHRH stimulation may be more important than the total amount in promoting somatic growth.
In addition to greater growth rates, adult male rats have higher pituitary GH mRNA levels, pituitary GH content, and elevated circulating insulin-like growth factor I (IGF-I) levels compared with age-matched females (17, 40). Although the pattern of GHRH administration is a major determinant of episodic GH secretion and somatic growth, there is little information with regard to its in vivo regulation of GH gene expression. The present investigation was undertaken to determine whether GHRH pulse amplitude and/or frequency might be critical to masculinizing several aspects of the somatotrophic axis of intact female rat. To this end, we evaluated whether the pattern of GHRH when administered in a pulsatile male-like fashion might be a primary mediator of the elevated pituitary GH mRNA levels, pituitary GH stores, plasma IGF-I concentrations, and greater growth rates one sees in male compared with female rats.
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MATERIALS AND METHODS |
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Animals and experimental procedures.
The protocol was approved by the Animal Studies Committee of
the Veterans Affairs Medical Center. Male (12 wk old) and young female
Sprague-Dawley rats (6 wk old, 140-170 g) were purchased from
Charles River Laboratories (Wilmington, MA) and housed separately in
individual cages and acclimated for 3-4 days in a temperature (22°C)-, humidity-, and light-controlled (12:12-h light-dark cycle, lights on between 0600 and 1800) environment before surgery. Animals were given unlimited access to water and food (Purina Rat Chow, Richmond, IN) before and throughout the experiment. Animals were anesthetized under ketamine-xylazine (87 and 13 mg/kg sc,
respectively), and a right-jugular venous catheter was implanted and
exteriorized through a plastic cap and spring (to protect catheter)
attached between the shoulder blades. The spring was connected to a
swivel, permitting continuous venous infusion or sampling and allowing free movement within the cage. The catheter consisted of PE 50 tubing
tipped on the venous end with 1.5-cm Silastic medical grade tubing
(0.012 in. ID, 0.025 in. OD). Animals were weighed, returned to their
cages, and allowed to recover before infusions. Only those animals that
attained presurgical body weight or resumed growth were used in the
experiments. At the start of the experiment, animals were weighed and
then infused (Autosyringe AS2C) with human GHRH-(144) intravenously
(Bachem, Torrance, CA) continuously or in a series of pulses every 1.5, 3, and 6 h at total daily doses of 32, 64, or 128 µg/kg body wt.
Control animals received a vehicle of 0.9% saline solution containing
protease-free 0.02% BSA and 5 U/ml of heparin as a continuous
infusion. All animals were infused with an equal volume of solution
over a 24-h period. After 7 days of infusion, animals were weighed and
then killed by decapitation. Trunk blood was collected, and plasma was
separated by centrifugation and stored at
20°C until
subsequent IGF-I and GH RIAs. Anterior pituitaries were immediately
removed, snap frozen in liquid nitrogen, and stored at
70°C.
Total RNA isolation.
Pituitary cytoplasmic RNA was isolated according to previously
described methods (17, 33). In brief, pituitaries were thawed on ice,
weighed, and homogenized in 10 mM Tris, 0.5% Nonidet P-40, and 1 mM
EDTA (pH 7.4). The homogenate was centrifuged for 5 min (13,000 g), and an aliquot of cytosol was stored at 20°C for
GH determinations. The nuclear pellet was measured for DNA by using a
fluorometric assay (27). Total RNA was extracted with a
phenol-chloroform-isoamyl alcohol mixture (100:100:1) and quantified by
absorbance at 260 nm. In all samples, the optical density ratios
(A260/A280) were between 1.7 and 2.0. The
integrity and quantitation of pituitary cytosolic RNA preparations
(20-µg aliquots) from randomly selected samples representing
treatment groups were confirmed by visual inspection of ethidium
bromide-stained 18S and 28S ribosomal RNA bands after electrophoresis
through 1.25% agarose-2.2 M formaldehyde gels (28).
Pituitary GH mRNA quantitation.
The GH cDNA (800-bp Hind III fragment inserted into
pBR322 vector), kindly provided by Drs. S. Melmed (University of
California, Los Angeles) and N. Eberhardt (Mayo Clinic) was linearized
under standard conditions and purified by electroelution. Labeled GH cDNA was prepared with a random primed DNA labeling kit (Boehringer Mannheim Biochemicals, Indianapolis, IN) with
[32P]dCTP (specific activity >3,000 Ci/mmol;
Amersham, Arlington Heights, IL) and separated from unincorporated
[32P]dCTP by gel filtration through a Sephadex
G-50 (Sigma, St. Louis, MO) quick-spin column. Specific activities
obtained were in the order of 2.45 × 109 cpm/µg.
Plasma hormone determinations. Plasma and pituitary cytosolic GH levels were measured separately by RIA against the reference standard preparation rGH-RP-2 by using materials obtained from the NIDDK, as previously described (23). All samples were run in duplicate in a single assay. The coefficients of variation between replicates were <10% for both plasma and pituitary cytosolic GH RIAs (assay sensitivity = 1.85 ng/ml). Plasma IGF-I samples were measured in triplicate in a single assay by RIA after acid-ethanol extraction (10) with antiserum (provided by Drs. J. J. Van Wyk and L. Underwood and distributed by the National Hormone and Pituitary Program, NIDDK) and recombinant human IGF-I (Mallinckrodt, St. Louis, MO) as a standard. Intra-assay CV was <10% (assay sensitivity = 108 ng/ml).
Statistical analysis. Differences among means were evaluated by use of one-way ANOVA followed by Fisher's least significance difference test for predetermined comparisons (36). Data are shown as means ± SE.
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RESULTS |
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Male and female GH secretory profiles.
Before evaluating the dosages of GHRH that induce male-like GH
pulses in female rats, we examined the typical GH blood profiles of
each sex. Figure 1 shows the typical daily
GH secretory pattern of young female rats that we used in our
subsequent studies and of adult male rats. Animals were sampled every
30 min. The male GH profile is characterized by high amplitude pulses
that reach ~180 ng/ml on average. In some individual animals, pulses
were >600 ng/ml. These pulses occur every 3 h and are interspersed by
low basal GH levels. Compared with males, females show a relatively apulsatile GH secretory pattern with low amplitude, irregular peaks,
and overall higher basal GH concentrations.
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Dose-response effect of GHRH on GH secretion.
We verified that the GHRH concentrations used in female rats
were those that produce physiological GH pulses typical of the endogenous male GH secretory pattern. Therefore, effects of the first
injection of GHRH were measured in a subset of individuals from the
GHRH pulsatility experiment. Female rats were injected intravenously
with 4, 8, or 16 µg/kg of GHRH, and GH was measured from blood
collected 5 min later. There was a clear dose-response relationship
between the amount of GHRH injected and plasma GH levels (Table
1). The lowest 4 µg/kg dose increased
plasma GH concentration by ~260 ng/ml, which is typical of the rise
seen in males during an endogenous pulse (Fig. 1). Administration of the highest GHRH dose (16 µg/kg) resulted in GH concentrations of 620 ng/ml, which falls in the range of endogenous pulse peaks measured in
individual adult males. It was difficult to maintain catheter patency
for blood withdrawal without persistently disturbing animals or
interrupting the varied patterns of GHRH administration; therefore, we
did not routinely measure GH secretory responses to GHRH over the
course of the experiment. However, collection of trunk blood 5 min
after the last injection of the 8 µg/kg of GHRH dosage revealed
plasma GH levels virtually identical to those after the first
injection. This suggests that the female rat continues to show
one-on-one GH secretory bursts with no refractoriness in response to
bolus GHRH injections, even after 7 days. This confirms an earlier
finding showing that GH secretory bursts occur in response to each GHRH
bolus injection with no desensitization for up to 12 consecutive days
of treatment (7).
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Pattern of GHRH administration on pituitary GH mRNA and GH stores.
To determine whether the pattern of GHRH administration is an
important determinant of pituitary GH mRNA expression, 6-wk-old female
rats were given GHRH as a continuous infusion or as bolus injections of
4-16 µg/kg every 3 h or 8 µg/kg of GHRH every 1.5, 3, or 6 h.
Continuous infusion of GHRH at daily doses ranging from 32 to 128 µg/kg did not significantly alter GH mRNA levels compared with
animals infused with saline (Fig. 2).
Administration every 3 h of 8 µg/kg of GHRH significantly elevated GH
mRNA levels above those seen in pituitaries of animals receiving
continuous infusion of saline or GHRH at the same total daily dosage of
64 µg/kg (P < 0.05). Changing the frequency of GHRH
administration also significantly altered GH mRNA levels. Injection of
8 µg/kg of GHRH every 90 min caused a twofold increase in GH mRNA
levels compared with animals receiving saline control infusions
(P < 0.001), continuous GHRH infusion (P < 0.001),
or a bolus GHRH injection of 16 µg/kg every 3 h at the same daily
dose of 128 µg/kg (P < 0.01).
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Pattern of GHRH administration on somatic growth and serum IGF-I
concentrations.
Continuous infusion of GHRH at total daily doses of 32, 64, and
128 µg/kg did not alter weight gain compared with saline infused animals (Fig. 3). Delivery of increasing
doses of 8 and 16 µg/kg of GHRH at a constant frequency of 3 h
increased somatic growth compared with those animals receiving either a
continuous infusion of saline or GHRH at equivalent total daily GHRH
dosages. Likewise, delivery of 8 µg/kg of GHRH at different
frequencies (every 1.5, 3, or 6 h) significantly enhanced somatic
growth compared with those animals receiving a continuous infusion of
saline or GHRH at the same total daily dose.
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DISCUSSION |
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An earlier study clearly showed that administration of human GHRH to immature female rats at 40-, 90-, or 180-min frequencies produced one-on-one, male-like GH secretory bursts with no desensitization in the GH response (8). Due to its uniformity in GH responses to exogenous GHRH and relatively hypopulsatile spontaneous GH secretory profile (11, 21, 37), the female rat provides an appropriate model for assessing the role that endogenous GHRH pulsatility plays in regulating the somatotrophic axis. This is the first report demonstrating that pituitary steady-state GH mRNA levels are dependent, in part, on the pattern of GHRH secretion. We found that pulsatile administration of GHRH is more effective than a continuous mode of delivery in inducing pituitary GH mRNA accumulation and GH protein stores as well as promoting somatic growth in female rats. The doses of GHRH used in this study produced acute GH responses within the amplitude range of endogenous GH pulses measured in adult male rats (see Fig. 1 and Table 1). Thus the degree of GHRH stimulation was likely within the physiological range.
Compared with females, male rats possess higher pituitary GH and GH
mRNA levels and exhibit plasma GH secretory profiles with high-amplitude peaks that occur at 3-h frequencies interspersed with
low, almost undetectable, interpeak GH levels (11, 15, 17, 21, 40). The
latter is likely due to the highly pulsatile pattern of hypothalamic
GHRH secretion, because GH pulses are abolished in animals and humans
treated with GHRH antiserum or GHRH receptor antagonist (20, 29, 34,
37). The importance of the pulse pattern of neurohormone secretion on
gene induction of its respective pituitary target hormone(s) has been
clearly demonstrated for gonadotropin-releasing hormone and
follicle-stimulating hormone/luteinizing hormone (14). Whether the same
is true for GHRH-GH interactions is unknown. The present study suggests
that, in addition to effects on GH secretion, pulsatile GHRH is central for inducing elevations in GH mRNA and GH content and could be responsible, in part, for the higher levels observed in pituitaries of
male compared with female rats. We found that bolus injections of GHRH
every 1.5 h, or at a 3.0-h frequency to mimic the male pattern of
endogenous GHRH secretion, increased pituitary GH mRNA levels over
those animals receiving similar total daily dosages of GHRH as a
continuous infusion (Fig. 2). Moreover, rapid (Q1.5h) GHRH pulse
delivery significantly elevated pituitary GH stores in parallel with
its induction of GH mRNA. Interestingly, "physiological" (Q3.0h)
GHRH pulses increased GH mRNA but not pituitary GH content, suggesting
a different time course effect of GHRH on these parameters. Indeed, a
similar dosage of GHRH-(129)NH2 (
9 µg/kg body wt of GHRH-(1
44), delivered at 3-h frequencies for 12 days, elevated pituitary GH stores in female rats of a similar age and size to those
used in this study (7). Exposure to dihydrotestosterone (DHT) increases pituitary GH stores and mRNA levels in
ovariectomized female rats in vivo, whereas the opposite occurred when
animals were treated with estrogen (6). Because DHT, but not estrogen, increased hypothalamic GHRH mRNA and peptide expression (1, 15), this
serves as additional support for the crucial role played by pulsatile
GHRH in augmentation of GH synthesis and sexually dimorphic expression
of pituitary mRNA and protein stores. Our studies, however, do not rule
out a potentially important role for pulsatile SRIF in modulating
GHRH-induced sex differences in GH mRNA expression. Nevertheless, it
appears GHRH may induce GH synthesis by acting directly on the
somatotroph, because it was previously shown to stimulate GH gene
transcription, GH mRNA accumulation, and GH stores in pituitary cell
cultures (3, 4, 12).
The frequency rather than the amplitude component of GHRH pulses is more effective in elevating pituitary GH mRNA and GH content, whereas either is sufficient for inducing somatic growth. We found that injections of GHRH at 1.5-h intervals increased pituitary GH mRNA and GH content over levels observed in animals given the same daily dosage at 3-h intervals, whereas both frequencies similarly stimulated weight gain. It is possible that GHRH may augment pituitary GH and GH mRNA stores via increased GH synthesis in a manner distinct from its stimulatory effect on GH secretion and somatic growth. GHRH was shown to stimulate GH gene transcription independently of its induction of GH release in primary pituitary cell cultures (3). The physiological relevance of enhanced GH mRNA and GH stores seen with GHRH pulse frequencies beyond the 3-h intervals typically observed in male rats is unclear; nevertheless, our findings suggest that GHRH delivery at more rapid pulse frequencies could serve the additive effect of enhancing growth while simultaneously stimulating GH synthesis in GH-deficient subjects. Future studies should address whether GHRH pulse frequency might be a mediator of in vivo somatotroph hyperplasia and proliferation, which accompany the pathophysiological conditions associated with GHRH hypersecretion (2, 5, 25, 31).
Pulsatile GHRH treatment increased body weight gain by as much as 60%, whereas the same total daily dose administered as a continuous infusion for 7 days had no effect (Fig. 3), confirming an earlier study (7). This potent action (8% body wt gain/day) of GHRH is independent of the frequency or amplitude of GHRH administration as long as the peptide is given in a pulsatile fashion. Previous studies have shown that deprivation of GHRH or treatment with GHRH antagonist, conditions that abolish plasma GH secretory peaks, impair body weight gain (7, 17, 25, 29). Likewise, intermittent delivery of GH to hypophysectomized rats was shown to be more effective than a continuous GH infusion in stimulating growth (19, 30). Consistent with these observations, our results demonstrate that GH secretory spikes, derived mainly through episodic increases in GHRH secretion, are central to mediating the greater growth rates observed in male compared with female rats.
Despite its stimulation of body weight gain, pulsatile GHRH did not significantly alter circulating IGF-I in this study (Fig. 3). These findings differ from that of a previous report (26), where chronic administration of GHRH antagonist for 2 wk caused a small albeit significant decline in circulating IGF-I in female rats. Because hepatic IGF-I production is dependent on GH, it is not surprising that the inhibition of endogenous GH secretion with GHRH antagonist would reduce circulating IGF-I. However, our results suggest that additional increases in plasma GH after exogenous GHRH treatment may not suffice to increase hepatic, and therefore plasma IGF-I, above levels already elevated by endogenous GH present in normal animals. Recent studies using molecular approaches to selectively knock out IGF-I gene expression in the liver indicate that the paracrine, rather than endocrine, source of IGF-I is critical for postnatal body growth (35, 39, 41). We postulate that pulsatile GHRH delivery, by generating an episodic pattern of GH secretion, enhances somatic growth by preferentially inducing IGF-I production at peripheral tissues rather than at the liver. This hypothesis is supported by a previous investigation showing that pulsatile GH treatment is more effective than continuous GH infusion in stimulating IGF-I mRNA levels in rib growth plate and skeletal muscles, two major targets for the growth-promoting actions of GH (19).
In summary, our results show for the first time that pulsatile GHRH administration is more effective than continuous infusion in elevating pituitary GH mRNA levels. Increases in pituitary GH mRNA levels were accompanied by similar rises in GH content, suggesting that pulsatile GHRH may be an important inducer of GH gene expression and GH synthesis in vivo. Although all parameters of pulsatile GHRH delivery stimulate growth, the frequency rather than the amplitude component was more effective in inducing pituitary GH stores and gene expression. Exogenous GHRH did not alter circulating IGF-I concentrations, regardless of the pattern of delivery. The lack of concordance between somatic growth and serum IGF-I levels after GHRH administration supports the notion that pulsatile GH acts preferentially to induce local production of IGF-I to promote growth as opposed to increasing systemic IGF-I derived from the liver. Taken together, these studies suggest that the frequency of GHRH pulsatility is an important regulator of GH gene expression, and the greater growth rate, pituitary GH content, and mRNA levels in male compared with female rats are likely mediated by the highly episodic secretion of GHRH seen in males.
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ACKNOWLEDGEMENTS |
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This work was supported by a Merit Review from the Veterans Affairs Medical Research Service and National Institutes of Health Grant R01-DK-38449 to A. L. Barkan, and by the Agriculture Research Service, National Institutes of Health National Research Service Award Research Fellowship Grant F32-DK-09008, and National Science Foundation Grant IBN-9810326 to R. J. Borski.
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FOOTNOTES |
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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. §1734 solely to indicate this fact.
Address for reprint requests and other correspondence: R. J. Borski, Department of Zoology, Box 7617, North Carolina State University, Raleigh, NC 27695-7617 (Email: russell_borski{at}ncsu.edu).
Received 14 July 1999; accepted in final form 30 November 1999.
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