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Endocrinology Vol. 140, No. 4 1552-1558
Copyright © 1999 by The Endocrine Society

ARTICLES

Increases in Circulating Insulin-Like Growth Factor I Levels by the Oral Growth Hormone Secretagogue MK-0677 in the Beagle Are Dependent upon Pituitary Mediation1

K.-D. Schleim, T. Jacks, P. Cunningham, W. Feeney, E. G. Frazier, G. W. Niebauer, D. Zhang, H. Chen, R. G. Smith and G. Hickey

Departments of Physiology and Biochemistry (K.-D.S., T.J., E.G.F., H.C., R.G.S., G.H.), Biometrics Research (D.Z.), and Laboratory Animal Resources (P.C., W.F.), Merck Research Laboratories, Rahway, New Jersey 07065; and University of Pennsylvania School of Veterinary Medicine (G.W.N.), Philadelphia, Pennsylvania 19104

Address all correspondence and requests for reprints to: Dr. K.-D. Schleim, Department of Physiology and Biochemistry, Merck Research Laboratories, P.O. Box 2000, Rahway, New Jersey 07065.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
It has been well established that the spiroindoline sulfonamide MK-0677 stimulates GH secretion from the pituitary both in vitro and in vivo. MK-0677 has also been shown to increase serum insulin-like growth factor I (IGF-I) and cortisol levels in vivo; these increases are assumed to be driven by the increased serum GH and ACTH levels, respectively. However, such increases could also be due to a direct stimulatory action of MK-0677 at the level of the liver and adrenal cortex. To address this possibility, we investigated whether MK-0677 increased IGF-I and cortisol levels in hypophysectomized dogs.

Baseline GH, IGF-I, and cortisol responses to MK-0677 (1 mg/kg, orally) were initially determined. Hypophysectomy (hypox; n = 7) or sham surgery (sham; n = 5) was then carried out. Six days postsurgery, the GH and cortisol responses to MK-0677 were reevaluated in each dog. In addition, each dog was treated with porcine GH (PST; 0.1 IU/kg, sc) to confirm the responsiveness of the GH-IGF-I axis.

The mean peak GH increases in response to MK-0677 in the pre-sham dogs (83.7 ± 19.2 ng/ml), post-sham dogs (108 ± 26.2 ng/ml), and pre-hypox dogs (121.2 ± 13.6 ng/ml) were not significantly different. Mean peak GH levels were unchanged after MK-0677 administration in the hypox dogs (2.3 ± 0.7 ng/ml). Before surgery, serum IGF-I levels increased to 243 ± 27 and 224 ± 47 ng/ml in the sham and hypox groups, respectively, after MK-0677 administration. Surgery was associated with a marked (>=50%) decrease in serum IGF-I levels. MK-0677 administration increased IGF-I levels in the sham dogs from 78 ± 14 to 187 ± 31 ng/ml, whereas IGF-I levels remained unchanged (17.7 ± 2.4 ng/ml) in the hypox dogs. PST treatment increased IGF-I levels in the sham dogs from 162 ± 30 to 325 ± 32 ng/ml. In the hypox dogs PST treatment restored IGF-I to physiological levels (from 17.7 ± 2.4 to 199 ± 41 ng/ml).

Cortisol was increased after MK-0677 administration 3.7-fold in the pre-sham, 3.6-fold in the post-sham, and 3.6-fold in the pre-hypox dogs, but no increase was seen in the post-hypox dogs. ACTH GEL administration (2.2 U/kg, im) to hypox dogs returned cortisol to normal physiological levels, demonstrating the functional integrity of the adrenal cortex.

This study demonstrates that the GH secretagogue MK-0677 does not directly stimulate an increase in serum IGF-I or cortisol levels, but depends upon the presence of an intact pituitary.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
THE GH SECRETAGOGUE (GHS) MK-0677 is a member of the functional class of GHSs that includes L-692,429, L-692,585, and GH-releasing peptide-6 (1, 2, 3, 4, 5). This class of secretagogues stimulates GH release from somatotrophs through a receptor and second messenger system different from those of GHRH (6). GHS activity has been demonstrated in vivo across a wide range of species, including chicken (7), rat (8), dog (3, 9), pig (9, 10), horse (11), cattle (12), sheep (13), and man (14).

We have recently reported that oral administration of MK-0677 to beagles resulted in immediate and marked increases in GH levels, which were maintained for up to 8 h after treatment (2). Serum insulin-like growth factor I (IGF-I) levels were also significantly increased 6–8 h after treatment. Given the magnitude of the GH response to MK-0677, and that GH is a major regulator of IGF-I secretion, the increased IGF-I levels after MK-0677 administration were expected. In MK-0677 dose titration studies in dogs, we demonstrated a dose-dependent increase in both GH secretion and IGF-I levels.

We noted that the magnitude of the GH response to repeat daily administration of MK-0677 is markedly decreased, although not eliminated, compared with that of the first day response (15). However, circulating IGF-I levels remain consistently elevated or increase further with daily MK-0677 treatment. This apparent dissociation between circulating GH and IGF-I levels was unexpected based on previous observations after repeated iv treatments with L-692,585, when the GH response was relatively stable (3). We therefore hypothesized that the increased IGF-I levels may be explained by MK-0677 having a direct stimulatory activity on IGF-I secretion that is independent of GH. To test this hypothesis, we investigated the effect of MK-0677 on IGF-I levels in beagles after surgical hypophysectomy.

MK-0677, like other members of this functional group of GHSs stimulates a rapid, but transient, increase in cortisol secretion in the dog (2, 3). To determine whether this activity could be due to a direct stimulation of MK-0677 at the level of the adrenal gland, we compared the cortisol responses in dogs before and after surgical hypophysectomy.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
All experiments were performed following standards established by the Animal Welfare Act and NIH Guide for the Care and Use of Laboratory Animals, Publication 85–23, observed by Merck & Co., Inc. institutional animal care and use committee.

Twelve normal male beagles were used for the experiment. The dogs were 16–17 months of age and ranged in weight from 10–14 kg. The dogs were fed at noon each day and were fasted 15 h before treatment. The treatments were administered at 0800 h each day. For oral application of MK-0677, a solution was prepared in distilled water (vehicle) at a concentration of 0.2 mg/ml and administered at a rate of 5.0 ml/kg BW via stomach tube, resulting in a drug dosage of 1 mg/kg.

The study was divided into a presurgical and a postsurgical evaluation (Fig. 1Go). Dogs were randomly assigned to either the hypophysectomized (hypox; n = 7) or sham-operated (sham; n = 5) group.



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  		Figure 1. Experimental schedule. A, Vehicle treatment (5 ml/kg·day, orally) for 4 days; B, MK-0677 (1 mg/kg·day, orally) for 4 days; C, PST (0.1 IU/kg·day, sc) for 4 days; D, ACTH GEL (2.2 U/kg, im).

 
The evaluation of IGF-I levels was based on a calculation of the percent change at 8 h after 4 days of treatment from baseline (baseline = mean of -0.33 and 0 h points) on day 1 of each treatment period. Thus, individual animals for each treatment served as their own controls.

Preoperative evaluation
All dogs were treated orally for 4 days with vehicle at a rate of 5 ml/kg BW. This was followed by four daily oral administrations of 1 mg/kg MK-0677 in the same volume of vehicle.

Blood samples for GH, IGF-I, and cortisol analyses were collected from the jugular vein on the first day of each treatment period. The time points for the first day were -0.33, 0, 0.33, 0.66, 1.0, 1.5, 2.0, 3.0, 4.0, 6.0, and 8.0 h (schedule 1). On the fourth day of each treatment period, blood samples were collected for IGF-I at -0.33, 0, 6.0, and 8.0 h (schedule 2) after dosing. The serum from each blood sample was obtained and stored at -20 C for hormone analyses.

Hypophysectomy
The surgical procedures were performed 3 days after completion of the presurgical treatment. Before surgery, a cephalosporin antibiotic was administered im (cefazolin sodium, 250 mg, three times daily; Marsam Pharmaceutical, Inc., Cherry Hill, NJ).

Dogs were premedicated with atropine (Phoenix Pharmaceuticals, Inc., St. Joseph, MO; 0.02 mg/kg, im) and oxymorphone (Numorphan, DuPont Merck Pharmaceutical, Inc., Wilmington, DE; 0.05 mg/kg, im). General anesthesia was induced with a 2% thiamylal sodium solution (Bio-Tal, Boehringer Ingelheim Animal Health, Inc., Ridgefield, CT; iv to effect), and after endotrachial intubation, it was maintained by isoflurane (AErrane, Anaquest, Inc., Madison, WI) in oxygen. A balanced electrolyte solution (Normosol-R, Abbott Laboratories, North Chicago, IL) was administered iv during surgery at a rate of 10 ml/kg·h.

Complete hypophysectomies were performed in 7 of the 12 dogs. A transsphenoidal approach was used, employing a technique described previously (16). Briefly, palatomies were performed, and radiographic markers were placed in the exposed sphenoid bone to facilitate localization of the hypophysis by sinus venography. The transsphenoidal approach to the sellae turcicae was completed by drilling an elliptical hole in the basisphenoid bone. Hypophysectomies were then carried out by suction extraction, during which the entire hypophysis could be visualized. The bone defect was sealed with bone wax (Ethicon, Inc., Somerville, NJ), and the incision was sutured in 2 layers with 3–0 polyglactin 910 (Vicryl, Ethicon, Inc.), using an inverted suture pattern. In the sham group, surgeries were performed in the same manner as described above, but the hypophysis was only exposed and not removed.

Postoperatively, desmopressin acetate (DDVAP, Rhone-Poulenc Rohrer Pharmaceutical, Inc., Collegeville, PA) was administered intraconjunctivally for 5 days to promote stabilization of water and electrolyte balance associated with loss of corticoid regulation. The desmopressin (vasopressin) supplementation was reduced on days 2–4 and was discontinued 5 days postsurgery (17). In the final two dogs of the sham group, desmopressin treatment was not administered, and animals were monitored closely. Antibiotic therapy was continued for an additional 3 days with cefadroxyl orally (Cefa-Tabs, Ft. Dodge Laboratory, Inc., Ft. Dodge, IA; 10 mg/lb, twice daily). Recovery in all animals was uneventful.

Postoperative evaluation
Six days after surgery, the same 8-day treatment regimen as the described in the presurgical evaluation was followed. In addition, on days 9–12, each dog was treated with porcine GH (PST) at 0.1 IU/kg sc (0.056 mg PST/0.2 ml 0.05 mol NaHCO3, at a rate of 0.2 ml/kg BW). PST was used as a control because of the limited availability of dog GH and because dog GH messenger RNA (mRNA) encodes a mature protein that is identical to PST (18). Dogs were bled on days 9 and 12 according to schedule 2 for serum IGF-I determination.

On day 14, all dogs were challenged with ACTH GEL (Butler , Dublin, OH) at 2.2 U/kg, im, and were bled at -0.083, 0, 0.083, 0.25, 0.5, 0.75, 1, 1.25, 1.5, and 2 h after treatment for serum cortisol determination.

The dogs were then killed, and a gross necropsy was performed to confirm the presence or absence of the pituitary gland in the sham and hypox groups, respectively.

Hormone analyses
The hormone analyses were performed by RIA. The GH RIA was performed at Merck Research Laboratories (Rahway, NJ). Assays for IGF-I, LH, and cortisol were performed at the Veterinary Diagnostic Laboratory, Cornell University (Ithaca, NY). All assays have been validated for dog sera, and their respective sensitivities and the intra- and interassay coefficients of variance were previously reported (3).

Statistics
Peak concentration and trapezoidal area under the hormone response curve (AUC) over time for GH and cortisol and the percent change in IGF-I concentration were computed for each dog after each treatment before and after surgery. ANOVA techniques were used to assess the significance of differences in peak and AUC hormone release for GH and cortisol, and the significance of differences in the percent change in IGF-I release between two surgeries and two treatments. The paired t test was used to assess the differences before and after surgery within each treatment group. Hartley’s Fmax test was used to verify that the data adhered to homogeneous variance assumption, and the Shapiro-Wilk test was used to check that the data were normally distributed. The data were transformed to the natural logarithm scale to better meet the normality and homogeneity of variance assumptions required by the ANOVA and t test techniques.

Desmopressin treatment postsurgery did not affect responses to treatment; therefore, all sham animals were included in the statistical analysis.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Preoperative evaluation
The preoperative GH responses to vehicle and MK-0677 were similar in the sham and hypox dogs (Table 1Go and Figs. 2Go and 3Go). All animals had marked increases in GH levels after MK-0677 administration, with mean fold increases (GH AUC, nanograms per ml/h) of 9.1 and 15.9 in the sham and hypox groups, respectively, over the vehicle control value.


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  		Table 1. Effect of oral MK-677 administration on GH in beagles before and after hypophysectomy

 


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  		Figure 2. Effect of MK-0677 (1 mg/kg, orally) on GH in beagles before and after hypophysectomy. GH values are the geometric mean ± SE.

 


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  		Figure 3. Effect of hypophysectomy on IGF-I in beagles treated with MK-0677 (1 mg/kg, orally). IGF-I values are the geometric mean ± SE.

 
The percent changes in preoperative IGF-I levels after 4-day administration of vehicle and MK-0677 were similar in sham and hypox groups (Table 2Go).


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  		Table 2. Effect of oral MK-677 or GH administration on serum IGF-I levels in beagles before and after hypophysectomy

 
Preoperative cortisol responses to vehicle and MK-0677 were similar in the sham and hypox dogs (Table 3Go and Fig. 4aGo). All animals had increased cortisol levels after MK-0677 administration, with mean fold increases (cortisol AUC: µg/dl·h) of 1.6 and 1.8 in the sham and hypox groups, respectively, over those in the vehicle group.


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  		Table 3. Effect of oral MK-677 administration on cortisol in beagles before and after hypophysectomy

 


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  		Figure 4. a, Effect of MK-0677 (1 mg/kg, orally) on cortisol in beagles before and after hypophysectomy. b, Effect of ACTH (2.2 U/kg, im) on cortisol in beagles after hypophysectomy. Cortisol values are the geometric mean ± SE.

 
Postoperative evaluation
Basal GH levels were similar to preoperative levels in the hypox and sham groups (Table 1Go and Fig. 2Go). MK-0677 administration did not affect GH levels in the hypox group; in contrast, a marked increase occurred in the sham group.

Surgery was associated with a decrease in IGF-I levels in both groups. In the sham group on day 1, baseline IGF-I decreased from 150 ± 34 ng/ml before surgery to 60.3 ± 17.5 ng/ml post surgery, whereas in the hypox group, IGF-I levels decreased from 145.2 ± 35.9 to 16.7 ± 2.3 ng/ml. MK-0677 administration did not affect IGF-I levels in the hypox group; in contrast, a marked increase was noted in the sham group (from 77.8 ± 14.1 to 186.9 ± 31.4 ng/ml).

Circulating IGF-I levels were increased after sc administration of PST in both the sham and hypox groups (Table 2Go). PST treatment increased IGF-I levels in the hypox group from subphysiological (17.7 ± 2.4 ng/ml) to physiological (199.1 ± 41.0 ng/ml) by the fourth day of treatment.

Hypophysectomy was associated with a decrease in basal cortisol levels; levels in the sham-operated group were unchanged compared with presurgical levels (Table 3Go and Fig. 4aGo). MK-0677 treatment did not affect cortisol in the hypox group; a marked increase in cortisol occurred in the sham group. Serum cortisol levels were increased to physiological and superphysiological levels after ACTH challenge in the hypox and sham groups, respectively (Fig. 4bGo).


   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
It is well established that a major site of action for GHS, as exemplified by GH-releasing peptide-6, is the pituitary (19, 20). In characterizing the in vivo activity of the GHS, we have shown that hypothalamic input is critical to the GH and cortisol responses; hypophyseal stalk transection results in a marked reduction, although not an ablation, of the GH and cortisol responses (10). We concluded from that study that in vivo, GHS had a direct, but very limited, stimulatory effect on the somatotroph; the minimal cortisol response could be due to stimulation of the corticotroph and/or adrenal cortex.

We have reported that MK-0677 is a potent, orally active, long acting GHS that increases serum GH and cortisol levels (1, 2, 4). In addition, this is the first GHS for which repeat daily treatment has been associated with sustained elevations in circulating IGF-I levels while GH and cortisol responses decrease (15). To more fully characterize the in vivo activity of MK-0677, we investigated in the current study whether IGF-I and cortisol increases could occur independent of pituitary mediation.

Surgical hypophysectomy was carried out without complication, and all animals recovered uneventfully. Surgery was associated with a marked decrease in serum IGF-I levels. There was a greater than 50% decrease in the sham group, whereas the hypox group had a more than 80% decrease. Fasting as well as the stress connected with surgery have been associated with decreased IGF-I levels (21, 22). Serum IGF-I levels increased in the sham group postoperatively during placebo treatment. This increase was presumably due to recovery postsurgery as well as return to a normal diet.

Surgery did not affect the endocrine responsiveness of the animals, as evidenced by the robust IGF-I and cortisol responses to PST and ACTH, respectively, in the hypox group; pre- and postsurgery responses to MK-0677 were similar in the sham group.

Our results indicate that MK-0677 did not directly increase serum IGF-I levels and that MK-0677-induced IGF-I elevation is dependent upon pituitary mediation, presumably by increasing GH secretion. We had previously shown that elevation of IGF-I by administration of exogenous GH resulted in a marked decrease in the subsequent GH response to MK-0677. These findings support a role for GHS as a set-point modulator in the GH-IGF-I axis; GHS promotes higher circulating GH and IGF-I levels; however, IGF-I appears to feedback and regulate the magnitude of the GH response. This is in contrast to GHRH-mediated increases in IGF-I levels, where there is no reduction of GH output to the secretagogue in face of elevated IGF-I levels (23, 24, 25).

As MK-0677-induced IGF-I elevation is dependent upon pituitary mediation, it raises the question of how IGF-I levels are maintained while the GH response decreases with repeated treatment. In a previous study (15) in which the GH response to MK-0677 was measured during daily treatment for 4 days, it was shown that the day 1 response was clearly greater than the day 4 response, but the day 4 response was approximately 2-fold greater than the vehicle baseline value. The day 4 response was associated primarily with episodes of elevated GH secretion out to 8 h rather than a consistent increase in the baseline secretory rate. This lack of an acute GH response on day 4 suggests an amplification of the endogenous pulsatile GH profile. We believe that this sustained increase in the physiological pulsatile GH secretion induced by MK-0677 is why it is so effective in maintaining elevated IGF-I levels during repeated dosing.

The current study also indicates that MK-0677 did not directly stimulate serum cortisol levels. Therefore, MK-0677-induced cortisol increases are dependent upon pituitary mediation. We have previously reported that L-692,429, a member of the GHS family, increases ACTH secretion in the dog. This earlier finding along with the current results would suggest that the cortisol response to MK-0677 is indirect and mediated by increasing ACTH secretion. It cannot be ruled out that MK-0677 may have a direct effect at the level of the adrenal gland but requires the presence of ACTH.

A limitation of the current study design is that we have not selectively removed GH or ACTH mediation, i.e. all of the pituitary hormone output has been abolished with hypophysectomy. Therefore, we cannot rule out that the IGF-I and cortisol responses to MK-0677 involve the mediation of pituitary hormones in addition to GH and ACTH, respectively. Specific suppression of the two tropic factors, possibly by immunoneutralization, would provide greater insight and expand upon the present findings.

Serum GH levels were not abolished after hypophysectomy. A decrease in GH levels is suggested by the greater decline in serum IGF-I concentrations in the hypox group compared with the sham-operated group. A possible explanation lies in the technical difficulty of quantifying such low levels in dog sera (26). In addition, the minimal number of samples taken would be insufficient to document any reduction that may have been present in pulsatile secretion of GH. Lastly, it is possible that some residual pituitary tissue remained adjacent to the stalk after surgical removal. However, the lack of a detectable GH response to MK-0677 indicates the physiological disconnection of any residual tissue, if present.

Preliminary screening of rat tissues by a sensitive ribonuclease protection analysis using specific complementary RNA probes have indicated that the liver and adrenal gland do not contain GHS receptor mRNA (Howard, A., personal communication). Although the rat is not the most sensitive species to GHS activity, the absence of GHS receptor mRNA in these tissues is in line with the lack of IGF-I or cortisol responses to MK-0677 in the hypox dogs of the current study.

In summary, the potent, orally active GHS MK-0677 does not directly stimulate IGF-I or cortisol secretion in dogs. MK-0677-induced increases in IGF-I and cortisol are dependent upon pituitary mediation and are presumably due to GHS-stimulated increases in GH and ACTH secretion, respectively.


   Acknowledgments
 
The authors gratefully acknowledge the technical assistance of B. Friscino, L. Harris, D. Hora, Jr., and J. Stone.


   Footnotes
 
1 Data have been previously reported in abstract form at the 10th International Congress of Endocrinology Meeting, 1996 (Abstract P-603). Back

Received July 31, 1998.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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Endocrinology Endocrine Reviews J. Clin. End. & Metab.
Molecular Endocrinology Recent Prog. Horm. Res. All Endocrine Journals