1 Divisions of Endocrinology and Metabolism and 3 Gastroenterology, University of Michigan Medical Center, and 2 Department of Veterans Affairs Medical Center, Ann Arbor, Michigan 48109; and 4 Department of Medicine, University of North Carolina, Chapel Hill, North Carolina 27599
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ABSTRACT |
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The importance of gender-specific
growth hormone (GH) secretion pattern in the regulation of growth and
metabolism has been demonstrated clearly in rodents. We recently showed
that GH secretion in humans is also sexually dimorphic. Whether GH
secretion pattern regulates the metabolic effects of GH in humans is
largely unknown. To address this question, we administered the same
daily intravenous dose of GH (0.5 mg · m2 · day
1)
for 8 days in different patterns to nine GH-deficient adults. Each
subject was studied on four occasions: protocol 1 (no
treatment), protocol 2 (80% daily dose at 0100 and 10%
daily dose at 0900 and 1700), protocol 3 (8 equal boluses
every 3 h), and protocol 4 (continuous GH infusion).
The effects of GH pattern on serum IGF-I, IGF-binding protein
(IGFBP)-3, osteocalcin, and urine deoxypyridinoline were measured.
Hepatic CYP1A2 and CYP3A4 activities were assessed by the caffeine and
erythromycin breath tests, respectively. Protocols 3 and
4 were the most effective in increasing serum IGF-I and IGFBP-3, whereas protocols administering pulsatile GH had the greatest
effects on markers of bone formation and resorption. All GH treatments
decreased CYP1A2 activity, and the effect was greatest for pulsatile
GH. Pulsatile GH decreased, whereas continuous GH infusion increased,
CYP3A4 activity. These data demonstrate that GH pulse pattern is an
independent parameter of GH action in humans. Gender differences in
drug metabolism and, potentially, gender differences in growth rate may
be explained by sex-specific GH secretion patterns.
sex characteristics; insulin-like growth factor I; bone; cytochrome P-450
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INTRODUCTION |
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PITUITARY GH SECRETORY PATTERN in humans and other species is highly pulsatile. In rats, this pattern is sexually dimorphic; males have regular high-amplitude pulses and relatively low interpulse growth hormone (GH) levels, and females have lower amplitude pulses and higher interpulse levels (11). These gender-specific patterns of GH secretion in rats are independent regulators of GH bioactivity. For example, pulsatile GH is more effective than continuous GH infusion in stimulating somatic growth (9, 16) and muscle and growth plate insulin-like growth factor (IGF) I mRNA (16, 17). In addition, the expression of some P-450 cytochromes (CYPs) is highly sexually dimorphic in rodents, and a gender-specific GH secretory pattern, not sex steroids, regulates many of these differences (7, 49, 50). For example, the male pattern in rats increases hepatic expression of the male-specific P-450 steroid hydroxylase CYP2C11, whereas the female GH pattern of more continuous GH release stimulates the expression of the female-specific CYP2C12 (50). In rats, GH secretory pattern also controls apolipoprotein levels (34, 41), major urinary proteins (15), and hepatic carbonic anhydrase III (21). Similar gender-dependent effects of GH are found in mice (20, 22, 32) and hamsters (40, 42).
Whether the pattern of GH secretion plays a role in the regulation of human growth and metabolism is unclear. Equal daily doses of GH administered either as continuous infusion or as intravenous boluses every 3 h for 24 h were equipotent in inducing a rise in plasma IGF-I (24). Laursen et al. (29) reported that GH administered as a continuous subcutaneous infusion or intermittently had similar effects on serum concentrations of IGF-I, IGF-binding protein (IGFBP)-3, and lipoproteins and on insulin sensitivity (29). However, once a day, subcutaneous GH administration does not reproduce the highly pulsatile GH profiles found in normal men and women.
Parallels between human and rat physiology suggest that GH pulse pattern could play a role in regulating GH effect in humans. As is true in rats, humans have gender differences in the ability to metabolize drugs. Women metabolize caffeine (3-demethylation by CYP1A2) more slowly than do men (4, 36). The observations that GH deficiency results in a rise in the 3-N-demethylation of caffeine, as measured by the caffeine 13CO2 breath test (CBT), and that GH therapy decreases CBT (30) suggest that GH plays a role in the regulation of CYP1A2. A fall in CBT occurs during puberty (26), a time during which total GH and GH pulse amplitude dramatically increase; this further supports a role for GH in CYP1A2 regulation.
In contrast to the observations with caffeine, women appear to metabolize erythromycin faster than do men, suggesting higher activity of the CYP3A4 (47). GH also plays a role in the regulation of CYP3A4. In vitro, GH increased CYP3A4 expression in primary hepatic cells (31). In vivo, intramuscular or subcutaneous GH treatment increased antipyrine metabolism, which is mediated, in part, through the CYP3A family of enzymes (5, 38). In preliminary studies, we observed that this gender difference was not a function of estrogen, that CYP3A4 activity was high in patients with acromegaly, and that CYP3A4 activity increased in men who were treated with GH-releasing hormone (GHRH) every 2 h for a week (48). However, we were not able to determine whether the increase during GHRH treatment was attributed to GH in general or, as seen in the rat, to a particular component of the GH secretory pattern. We (18) and others (44, 51) have demonstrated that GH secretion in adults is sexually dimorphic. Women have more continuous secretion of GH (18), and this provides a conceptual framework for potential gender-specific effects of GH. Thus, in the present study, we investigated whether the pattern of GH delivery influences metabolic parameters in humans. We evaluated the effects of 1-wk treatment with equivalent doses of pulsatile or continuous GH on IGF-I, IGFBP-3, and markers of bone metabolism and on CYP1A2 and CYP3A4 activities.
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METHODS |
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The study was approved by the University of Michigan Institutional Review Board and the General Clinical Research Center (GCRC) Advisory Committee. All subjects signed informed consent documents before participation. Nine patients (4 men, 5 women) with GH deficiency were recruited from the University of Michigan Endocrinology and Metabolism Clinics. All had onset of GH deficiency during or after puberty, and none had been previously treated with GH. Each subject had documented GH deficiency, with peak GH concentration during an insulin tolerance test of <3 µg/l and had at least one other pituitary hormone deficiency. Seven of nine subjects had a pretreatment serum IGF-I concentration that fell below the lower limit for the age-adjusted normal range, and IGF-I concentration in five subjects was below 80 ng/ml. All subjects with hypothyroidism were on stable doses of levothyroxine and had normal free thyroxine concentrations. Subjects with adrenal insufficiency were on stable physiological replacement doses of hydrocortisone. All subjects were on sex hormone replacement before participation in the study. Gonadal steroid replacement was changed to transdermal sex steroid patches [Androderm (SmithKline Beecham, Philadelphia, PA) 5 mg daily in men, and Vivelle (Novartis, Summit, NJ) 0.05 mg twice weekly in women] at least 2 wk before the first GCRC admission and then continued until the completion of the study. The subjects were given a caffeine-free standardized, weight-maintaining diet that did not alter CYP3A4 levels.
Each subject was admitted for four studies. Protocol 1 was a baseline study during which time no GH treatment was given. Protocols 2-4 were subsequently performed in random order, and there was at least a 1-mo washout period between each study. Protocol 2 consisted of 80% of the daily GH given as an intravenous bolus at 0100 and two 10% boluses at 0900 and 1700 and was designed to mimic "male" pattern GH secretion. Protocol 3 was designed to mimic "female" GH secretion and consisted of eight equal boluses every 3 h. Protocol 4 consisted of continuous intravenous GH infusion with the use of a MiniMed model no. 404-SP infusion pump (MiniMed Technologies, Sylmar, CA). The GH boluses and the GH infusions were administered through an indwelling antecubital cannula. The total daily dose for each study was 0.5 mg/m2 and was based on published estimates of daily GH production rate (51). The stylized patterns of delivery were derived from our previous studies on gender differences in GH secretion (18).
The subjects were admitted on the evening of day 0. At 0800, day 1 and day 7 (day 4 in protocol 1), serum samples for IGF-I, IGFBP-3, and osteocalcin were obtained. A 24-h urine for deoxypyridinoline cross-links (Dpd) and creatinine was collected starting at 0800 on day 7 (day 4 in protocol 1). During this same time period, blood was sampled every 10 min from an indwelling antecubital venous catheter for the assessment of 24-h GH concentration profile. CYP1A2 and CYP3A4 activities were quantified by CBT and erythromycin breath test (ERMBT), respectively, at 0800 on day 8 (day 5). The CBT was performed by measuring 13C in exhaled breath sampled every 20 min for 3 h after administration of oral [13C]caffeine (45). ERMBT was performed by measuring 14C in exhaled breath for 20 min after administration of intravenous [14C]erythromycin (45, 46).
GH was measured by a sandwich chemiluminometric assay with detection limit of 0.01 µg/l, as previously described (19). All samples for a given subject were run in the same assay. Total serum IGF-I, IGFBP-3, and osteocalcin were measured using commercial ELISA kits (Diagnostic Systems Laboratory, Webster, TX). Urine Dpd was measured by a competitive enzyme immunoassay (Pyrilinks-D; Metra Biosystems, Mountain View, CA). All samples for a given subject were run on the same ELISA plate. The intra-assay coefficient of variation (CV) for each analyte was <10% at the measured concentrations.
Analysis of variance (ANOVA) with repeated measures was used to determine the effects of the GH treatment regimens on a measured parameter (SuperAnova; Abacus Concepts, Berkeley, CA). When a treatment effect was found in a primary analysis, post hoc testing was performed by contrasts. P values for all ANOVA and contrasts were corrected for the repeated measures by Huynh-Feldt adjustment factors. Data having unequal variance were logarithmically transformed before analysis. Results are reported as means ± SE, and P < 0.05 was considered statistically significant.
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RESULTS |
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Figure 1 shows the mean 24-h GH
profiles for nine subjects during the four stages of the study.
Daily mean plasma GH concentration was 0.09 ± 0.05, 1.58 ± 0.11, 1.35 + 0.12, and 1.83 ± 0.20 µg/l for
protocols 1-4, respectively (Fig.
2). By ANOVA, all GH treatments increased mean plasma GH above baseline daily GH (P < 0.0001). Mean daily GH during protocol 4 was greater than
during protocol 3.
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The effects of the GH treatments on serum IGF-I and IGFBP-3 are shown
in Figs. 3 and
4,
respectively. By ANOVA, there was a treatment effect for
IGF-I (P < 0.0001), and all GH treatment protocols
significantly increased IGF-I above the baseline concentration (P < 0.005 for each). Moreover, serum IGF-I
concentrations were higher in protocols 3 and 4 than in protocol 2. Similarly, there was a treatment effect
for IGFBP-3 (P = 0.001), and all treatments increased
IGFBP-3 above the baseline concentration. Continuous GH (protocol
4) was significantly more efficacious than protocol 2 in increasing IGFBP-3 (P < 0.05).
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The effects of the GH treatments on bone formation were measured by
serum osteocalcin. Serum osteocalcin on day 1 of each protocol was similar (20.8 ± 4.2, 21.0 ± 3.1, 18.8 ± 3.7, and 22.4 ± 4.5 ng/l for protocols 1-4,
respectively; P = 0.64). There was a treatment effect
(P = 0.015) such that serum osteocalcin concentrations
on day 7 of each GH administration protocol were higher than
serum osteocalcin at the end of the baseline study. Although the order
of the three GH treatment protocols was randomized, and serum
osteocalcin on day 1 of protocols 2-4 was
similar, there was concern for carryover effect from previous GH
treatment (3). To adjust for this potential confounding
factor, an "adjusted osteocalcin" was determined by subtracting
serum osteocalcin concentration on day 1 from the
concentration measured on day 7 of each study (Fig.
5). Repeated-measures ANOVA again
demonstrated a treatment effect (P = 0.016). During the
baseline study, there actually was a decline in serum osteocalcin
between days 1 and 4. In contrast, during the GH
treatment protocols, there was no decrease in osteocalcin during each
study, and the adjusted osteocalcin was significantly greater in
protocols 2 and 3 than at baseline.
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Figure 6 shows the effects of treatment
on Dpd, a marker of bone resorption. Again, there was a
treatment effect (P = 0.05). The urinary
Dpd-to-creatinine ratio was similar in protocols 1 and
3 but increased and decreased by ~25% above and below
baseline in protocols 2 and 4, respectively. The
difference between the Dpd-to-creatinine ratio for protocols
2 and 4 was the driving force for the observed
treatment effect in the ANOVA.
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GH treatment also significantly affected CYP1A2 and CYP3A4 activities.
As shown in Fig. 7, there was a treatment
effect on CBT (P = 0.04), and all GH treatments tended
to decrease CBT below the baseline value. This difference was
significant for protocols 2 and 3, and there was
a trend to lower CBT in protocol 4 (P = 0.10). The effect of GH ERMBT is shown in Fig.
8. There was an overall treatment effect
(P = 0.01), and, again, the effect of GH was dependent
on the pattern of administration. There were trends for lower ERMBT
during protocols 2 and 3 compared with baseline
(P = 0.1 and 0.2, respectively). Continuous GH
(protocol 4) resulted in significantly higher ERMBT than at
baseline (P = 0.03) or during either of the two
protocols in which pulsatile GH was administered (P = 0.002 and 0.006 for protocols 2 and 3, respectively). This corresponded to an average increase in ERMBT of 51 and 35% for protocols 2 and 3, respectively, vs.
protocol 4.
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By unpaired t-tests, there was no gender-related difference in any parameter during protocol 1 (baseline). Repeated-measures ANOVA with one between-group factor (gender) was performed on each of the data sets to determine whether sex steroids made a difference in the treatment group responses. No gender effects were found.
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DISCUSSION |
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Gender-specific GH secretion is an important determinant of the metabolic and somatic actions of GH in rodents. The present study demonstrates for the first time that several GH-sensitive end points in humans are regulated by different components of GH exposure. These observations have important implications with regard to our understanding of human GH physiology and replacement therapy.
After the groundbreaking animal studies demonstrating the importance of GH pulse pattern as a tissue-specific regulator of IGF-I biosynthesis and of hepatic cytochrome P-450 enzymes, several attempts were made to assess whether the same was true in humans. Jorgensen and colleagues (23, 24) could not find a difference between the effects of continuous GH infusion or eight intravenous boluses on IGF-I, IGFBP-3, or serum lipids. More recently, Laursen et al. (29) reported that 6-mo treatment with continuous or daily subcutaneous GH had similar effects on IGF-I and IGFBP-3, bone metabolism, body composition, insulin sensitivity, and lipoproteins. Thus it is currently assumed that the pattern of GH pulsatility, whereas important in rodents, is not important in humans. Our study, however, proves that GH pattern does play a role in determining GH effect in humans.
There are several simple explanations why previous studies failed to detect the differences. The first reason is the duration of some of the previous negative studies. In the studies from Jorgensen and colleagues (23, 24), GH-deficient patients received GH for only 20 h. An increase in serum IGF-I concentration occurred within 6 h of beginning GH treatment, and IGF-I was still increasing when the GH treatments were stopped. The effect on IGFBP-3 was much slower, and a measurable increase in IGFBP-3 did not occur until ~20 h after GH treatment was begun. In contrast, our subjects were treated with GH for 1 wk. We achieved steady-state GH concentrations with the GH infusion, which was not the case in the earlier study. One week of treatment should also have allowed us to achieve IGF-I and IGFBP-3 steady-state concentrations.
Steady-state effects were reached in a recent study that compared the metabolic effects of 6-mo treatment, using continuous GH, with daily subcutaneous GH (29). The authors concluded that GH effects in humans were not dependent on a pulsatile pattern. This conclusion, however, is based on the assumption that daily subcutaneous GH administration is an appropriate way to approximate endogenous GH secretion. The GH concentration profiles obtained with subcutaneous GH are relatively flat and of long duration (25), rather than the normal, highly pulsatile pattern found in normal men and women (18). Moreover, the nadir concentrations of GH in the study by Laursen et al. (29) were not formally reported; they did not appear to reach the very low interpulse GH concentrations obtained with our intravenous boluses. Therefore, although this study was of adequate duration, the protocol used did not truly address the selective effects of GH pulse pattern, since subcutaneous GH injections are a better approximation of continuous GH exposure than of endogenous GH pulses.
A third and most important limitation of the earlier studies was the primary end point measured. In rats, both continuous GH and pulsatile GH are equally efficacious in increasing hepatic IGF-I mRNA and protein (16, 17). Therefore, failure to see an effect on systemic IGF-I in either earlier or the present studies does not indicate that GH pulse pattern plays no role in human physiology. Rather, it suggests that the rat is an appropriate model for humans with regard to GH effects on hepatic IGF-I production. Other GH-sensitive end points could be responsive to pulse pattern.
In contrast to the pulse pattern-independent effect on hepatic IGF-I production, several constitutively activated CYPs in rats are regulated by GH pulse pattern (33). In this study, we examined the role of GH pulse pattern on human CYP1A2 and CYP3A4 activity. These enzymes are central to the metabolism of a large number of xenobiotics and to the bioactivation of procarcinogens (28). Differences in their levels of expression might contribute to gender differences in susceptibility to the toxic effects of many medications (2). As discussed earlier, limited data have implicated a role for GH in the regulation of CYP1A2 and CYP3A4 activity.
All GH treatments decreased CBT, although the effect tended to be greatest with pulsatile GH administration. This fall in CBT during GH treatment is consistent with the decrease in CBT at puberty (26). Whether the small difference in CBT between pulsatile GH (protocols 2 and 3) and continuous GH (protocol 4) is of physiological significance is uncertain. In normal adults, CYP1A2 activity is higher in men than in women (2, 28). As discussed below, protocol 3 is likely to be more representative of normal GH secretion in men, whereas protocol 4 represents GH secretion in normal women. Therefore, CBT might be expected to be higher in protocol 3 than in 4. Although it is clear that GH per se decreases CBT, more studies are needed to determine whether the patterns of either exogenous GH administration or gender-specific GH secretion differentially regulate CYP1A2 levels.
The ERMBT data provide compelling evidence for the importance of GH pulse pattern in the regulation of other important metabolic pathways. Only the continuous GH infusion (protocol 4) increased ERMBT, whereas pulsatile GH in protocol 2 tended to decrease ERMBT. Although changes in ERMBT could reflect an effect on P-glycoprotein (27), we believe that it most likely indicates changes in CYP3A4 regulation (31, 39). Because ERMBT decreases with increasing erythromycin volume of distribution, and GH treatment of GH-deficient adults increases total body water (8), the difference between baseline and protocol 4 ERMBT likely underestimated the magnitude of the GH effect on CYP3A4 activity.
We had previously reported that ERMBT was higher in women than in men (47) and that ERMBT was high in acromegaly patients (48), a state of continuous GH exposure. In addition, we noted that ERMBT increased in middle-aged men treated with GHRH every 2 h for a week (48). Because plasma GH concentrations during GHRH treatment never fell below 0.5 µg/l (19), the subjects effectively had continuous GH exposure. This last explanation fits best with the data from the present study. Similarly, the demonstration that subcutaneous GH treatment increased antipyrine metabolism (5) suggests that subcutaneous GH administration approximates tissue exposure to continuous, not pulsatile, GH.
Presumably, this differential regulation in humans is similar to what occurs in rats. Regulation of constitutively expressed rat CYP by GH pulse pattern has been extensively investigated (33), and GH-mediated control of the signal transducer and transcriptional activator STAT5b is central to many of these gender-specific GH effects (6, 10, 35, 43). Pulsatile or continuous GH increases or decreases STAT5b activation, respectively (12, 13, 50). Whether gender-specific GH patterns are involved in STAT5b regulation of human CYPs has not been studied.
The pattern of GH administration also differentially affected markers of bone metabolism, with parameters of both bone formation and resorption increasing more after pulsatile than after continuous GH infusion. These results agree with data demonstrating that pulsatile GH is more potent than continuous GH in stimulating IGF-I message and growth in cartilage and bone growth in rats (9, 16). The reason for a decrease in serum osteocalcin between the first and last days of protocol 1 is not clear. Potentially, this fall is related to a relative decrease in physical activity, as the subjects were at bed rest for much of the day. It will be important to verify this decrease in subsequent studies and interpret data from periods of GH treatment accordingly.
In clinical practice, subcutaneous GH administration, which does not give a sharp serum GH pulse, accelerates linear growth in GH-deficient children. However, many of these children fail to achieve their target midparental height. This could be due to an irreversible loss of growth potential resulting from late diagnosis of GH deficiency, an inadequate daily GH dose, or non-GH causes, such as sex steroid deficiency. Alternatively, the manner of GH delivery to the tissue might be important. In support of this, positive growth in normal children correlated best with GH peak height (1). Our data suggest that pulsatile pattern of GH treatment might be optimal for bone development and subsequent growth. Therapeutic modalities producing rapid, transient, and high GH pulses might be more efficacious in restoring linear growth in GH-deficient children.
A major aim of the study was to determine whether gender-specific GH secretion patterns resulted in different peripheral effects of GH. Men have small daytime pulses with pronounced nocturnal augmentation of GH, whereas GH pulses in women are more uniform in size, and nocturnal augmentation of GH secretion is less extreme (18). Perhaps most importantly, we (18) and others (14, 51) have shown that tissue exposure to physiologically effective concentrations of GH is more constant in women than in men. GH concentrations in normal women fall below a cutoff of 0.25 µg/l for only 20% of the day, whereas they are below this value for over 50% of the time in men (18). On the basis of data from GH-deficient subjects, GH concentrations below 0.25-0.5 µg/l are likely to be minimally effective (37). Our patterned GH treatments resulted in GH concentrations below this cutoff 89, 78, 54, and 0% of the day for protocols 1-4, respectively. Protocols 2 and 3 were designed to represent the idealized versions of male and female GH patterns, respectively. However, on the basis of the duration of time during which GH concentrations fell below the 0.5-µg/l cutoff, the true male pattern is likely closer to protocol 3, whereas the true female pattern is closer to protocol 4. Moreover, the nocturnal GH pulse in protocol 2 reached peak amplitudes of >80 µg/l, which was clearly beyond peak concentrations in normal adult men (18). In contrast, peak GH concentrations in protocol 3 were more physiological. Again, this supports protocol 3 over protocol 2 as more representative of normal physiology in men.
An alternative explanation for the measured differences in GH effect is gender-specific effects of sex hormones. However, separately analyzing the data in men and women did not change the conclusions. For example, there was a treatment effect (P < 0.05) on ERMBT in men, with the highest ERMBT occurring in protocol 4. In women, there was a strong trend for treatment effect (P = 0.07), and, again, the highest ERMBT was observed in protocol 4. Repeated-measures ANOVA that included gender as a between-groups effect found no differences across gender. Admittedly, after stratification of the data by gender, the numbers of subjects in each group were small, so that it was possible that the study was underpowered to observe sex hormone-mediated differences. However, the fact that we still observed differences across GH treatments suggests that even if sex steroids play a role, their effects are likely of a lesser magnitude than that of GH.
Another potential limitation of this study is that assignment of biological importance to these data is uncertain. Although tissue- and GH pattern-specific effects were found, some of these differences were relatively small. For example, continuous GH (protocol 4) compared with pulsatile GH treatment (protocol 2) resulted in a 51% average increase in ERMBT. This is smaller than many of the GH-regulated effects on hepatic enzyme levels observed in rodents. Yet, changes in ERMBT of a magnitude similar to that observed in our study result in clinically important effects on CYP3A4 (47). Further studies are needed to clearly define the relative biological relevance of each of our observations.
Even with these limitations, our data clearly support our hypothesis that GH delivery pattern results in tissue-specific effects in humans. Although protocol 2 was less effective with regard to IGF-I and IGFBP-3, pulsatile GH was more effective in inducing bone metabolism and tended to be more effective in suppressing CYP1A2. In contrast, only continuous GH exposure increased CYP3A4 activity, which is consistent with GH and CYP3A4 differences in normal men and women.
In conclusion, this study demonstrates for the first time the tissue- and pattern-specific effects of GH secretion in humans. The interpulse GH levels are the primary determinants of hepatic IGF-I, IGFBP-3, and CYP3A4. In contrast, bone effects of GH are pulse amplitude sensitive. CYP1A2 is regulated largely by the prevailing daily GH concentration, although GH pulse amplitude might also play a role. These data shed light on the known gender-specific differences in drug metabolism and linear growth. Pattern-specific delivery protocols for GH treatment might bring about selective effects on linear growth and hepatic CYP expression.
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ACKNOWLEDGEMENTS |
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We thank the General Clinical Research Center staff for excellent nursing support, SmithKline Beecham for providing Androderm patches, Novartis for providing Vivelle patches, and MiniMed for providing infusion pumps.
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FOOTNOTES |
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This work was supported by Department of Veterans Affairs Merit Review Award (C. A. Jaffe); National Institutes of Health Grants MO1-RR0043-34S3 (Clinical Associate Physician Award to C. A. Jaffe), GM-38149 (P. B. Watkins), and MO1-RR0042 (General Clinical Research Center); and the Research Service of the Department of Veterans Affairs.
Address for reprint requests and other correspondence: C. A. Jaffe, Division of Endocrinology and Metabolism, Univ. of Michigan Medical Center, 3920 Taubman Center, 1500 Medical Center Dr., Ann Arbor, MI 48109-0354 (E-mail: cjaffe{at}umich.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.
July 17, 2002;10.1152/ajpendo.00513.2001
Received 13 November 2001; accepted in final form 5 July 2002.
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