0163-769X/91/1203-0189$03.00/0 Endocrine Reviews Copyright © 1991 by The Endocrine Society

Vol. 12, No. 3 Printed in U.S.A.

Human Growth Hormone Replacement Therapy: Pharmacological and Clinical Aspects JENS OTTO LUNDE J0RGENSEN Medical Department M, Aarhus Kommunehospital and Institute of Experimental Clinical Research, Aarhus University, Aarhus, Denmark

I. Introduction II. Evaluation of the Response to GH Replacement Therapy A. Linear growth B. Body composition C. Circulating insulin-like growth factors I and II and their binding proteins D. Biochemical growth markers E. Metabolic effects F. Conclusion III. Pharmacokinetic and Biological Effects of Biosynthetic GH as Compared to Pituitary GH A. Pharmacokinetics B. Antibodies to p-hGH and r-hGH during therapy C. Metabolic effects D. Effects on linear growth E. Conclusion IV. Route of GH Administration A. Intramuscular vs. subcutaneous administration B. Absorption kinetics of im and sc GH administration C. Conclusion V. Frequency and Timing of GH Administration A. The normal secretory pattern of GH B. Frequency of GH administration C. Timing of GH administration D. Conclusion VI. Dose of GH A. Production rates of GH in normal subjects B. Dose-response studies with GH C. Conclusion VII. Duration of GH Therapy VIII. Summary and Conclusive Remarks

a number of subsequent case reports (4-8). In 1964, Soyka et al. (9) published results from hGH therapy for up to 2.5 yr in 34 patients with short stature. The treatment schedule was 2 mg (the biopotency of the first pituitary preparations was 1 IU/mg) three times a week by the im route. The growth response was more pronounced in the hypopituitary patients, and it was concluded that treatment should be restricted to this group in view of the scarce supply of the hormone. The introduction of a radioimmunoassay (RIA) for measurements of plasma GH (10) enabled quantitative assessment of GH secretion. The diagnosis of GH deficiency was thereafter corroborated by measuring circulating GH after certain well-defined stimuli or during sleep. It was also revealed that a number of patients apparently had isolated GH deficiency (11). A review on the clinical use of GH after 1968 was presented by Frasier in 1983 (12). He summarized that therapy should be started as early as possible and administered im in a dose of 0.06-0.10 IU/ kg three times a week (the biopotency of highly purified pituitary GH is 2 IU/mg). He also recommended treatment to be continuous and given until closure of the^ epiphyses. Since then several changes have occurred. The most important has been the manufacture of biosynthetic or recombinant hGH (r-hGH) (13, 14). By this method a potentially unlimited supply of the hormone, free of pituitary contaminants, became available. The introduction of biosynthetic GH proved particularly timely as it preceded the reports of several GH-deficient patients who had contracted Creutzfeldt-Jakob disease (CJD). Since it was suspected that the patients had been infected by pituitary GH contaminated with the CJD agent, several countries suspended the use of pituitary GH (15, 16). The research in somatomedins or insulin-like growth factors (IGF) and their binding proteins has developed rapidly and provided new insight into the actions of GH, and the applicability of measuring these substances for clinical purposes is undergoing continuous evaluation (17, 18). Another achievement has been the change in

I. Introduction

A

DMINISTRATION of GH to hypopituitary children . was first reported more than 50 yr ago (1). Initially, GH was prepared from animal sources, but it became evident that nonprimate GH was inactive in man (1). Beck et al. (2) were the first to employ short-term administration of human GH (hGH) in a pituitary dwarf. This was followed by Raben's report in 1958 of an increase in linear height in a pituitary dwarf treated for 10 months with hGH (3). This finding was confirmed in 189

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GH treatment schedule to sc injections given daily at bedtime (19). Among the merits of this new schedule are significant improvements in patient compliance and growth response (20-23). Based on this renewed interest in GH therapy and methods for evaluating its effects, this paper will try to update present knowledge on the clinical pharmacology of GH replacement therapy. Special emphasis will be made on route, frequency, timing, and dosage of GH administration. In addition, the question of therapy duration, in particular the present experience with GH therapy in GH-deficient adults, will be addressed.

II. Evaluation of the Response to GH Replacement Therapy A. Linear growth The objective of GH therapy has traditionally been to increase the growth rate and adult height of short statured GH-deficient children, and the effectiveness of treatment has been evaluated by measuring growth rate and height achieved. The majority of clinical studies mainly comprised data from the initial years of treatment, and a control group of untreated patients has so far never been included. Therefore, information on the growth velocity and adult height in untreated GH-deficient patients is restricted to case reports of familial cases of GH deficiency discovered too late to receive treatment (24, 25), and to Laron type dwarfs, who have GH insensitivity (26). These groups of patients were reported to grow very slowly and experience puberty late, and to reach an adult height of approximately 130-149 cm (24-26). Reports of long-term growth results and adult height after GH treatment are relatively scarce but point to a significant growth response compared to the predicted (untreated) height (27-33) (Table 1). It is understandable that the majority of clinical studies have been relatively short-termed. First, since the treatment is relatively new, many patients have not yet reached adult height. Second, it is difficult in practice to await adult height before drawing conclusions from a particular treatment protocol due to the long duration of therapy. Third, since puberty and adult height are reached late in untreated GH deficiency (24, 25), the ability of GH therapy to induce a catch-up of growth, and in some cases to promote pubertal development (11), is often experienced as a benefit by the patient whatever the adult height may be. The interpretation of short-term growth data may, however, be difficult. One reason for this is the initial catch-up in growth which invariably is followed by a subsequent decline (waning) in growth velocity (12). This waning effect makes it difficult to perform or interpret studies in which a patient receives alternating regimens.

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Another variable that may confound the results is the concurrence of a pubertal growth spurt during a trial. Finally, short-term growth response does not always predict long-term results. Tanner et al. (34) reported that the first-month height gain did not correlate with the first-year response. Furthermore, results after the first year of therapy do not necessarily predict longer term (up to 6 yr) results (35). As regards adult or final height of GH-treated patients, this parameter has been reported to correlate with height velocity during the first year of therapy in one study (29), whereas Burns et al. (27) were unable to reveal such a correlation. B. Body composition The ability of GH to induce protein anabolism and lipid catabolism has been known both from early studies in animals (1), and from the metabolic balance studies in humans (4-7, 36). Tanner et al. (34) observed a rapid increase in muscle mass (MM) and decrease in fat mass after only 1 month of GH therapy in GH-deficient children. This early increment correlated with the first year height gain. Collip et al. (37) reported an increase in lean body mass (LBM) after GH therapy, and when the same patients were studied after 5 months without therapy a significant decrease in LBM was recorded together with an increase in body weight and skinfold thickness. Novak et al. (38) studied four adolescent patients before, during, and after 18 months of GH therapy and reported a GHinduced increase in LBM. Parra et al. (39), who studied eight GH-deficient patients before and after 12 months of therapy, reported a subnormal MM before treatment. After GH therapy a greater increase in MM than expected from the height increments was observed. Apart from the GH-induced increase in LBM and decrease in total adipose tissue content, evidence suggests that exogenous GH promotes a redistribution of adipose tissue from an android (abdominal) to a more gynoid (gluteal) pattern (40). C. Circulating IGF-I and IGF-II and their binding proteins Salmon and Daughaday (41) discovered that the effects of GH on cartilage growth were mediated by, or dependent upon, a substance in serum. This led to the identification of two peptides: IGF-I and IGF-II (17). Only those studies focusing on the clinical feasibility of measuring circulating IGFs and their binding proteins in short stature patients will be recapitulated. Hall and Olin (42) reported a linear relationship between bioassayable IGFI and growth rate before and after long-term GH therapy in 20 GH-deficient patients. A similar positive correlation using a RIA for IGF-I was subsequently reported by others (43-45). These findings have been challenged by

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191

TABLE 1. Long-term growth response to GH therapy End of GH treatment

Start of GH treatment Q

AULnOrS

ratients

Burns et al. (28)

Idiopathic GHD

Burns et al. (27)

GHD secondary to craniopharyngeoma Idiopathic GHD

Joss et al. (29) Bourguignon et al. (30) Hibi and Tonaka (31) Lenko etal. (32)°

Idiopathic GHD Idiopathic GHD Idiopathic GHD Craniopharyngeoma

Dean et al. (33)

Idiopathic GHD (n = 85) and other causes (n = 31)

CA (yr) 14.0 13.2 15.5 13.9

10.6 10.4 11.4 10.1

M (n = 13) F (n = 5) M (n = 22)

11.9

8.2

M (n = 114) F (n = 23) M (n = 12) F (n = 6) M (n = 1) F (n = 3) M (n = 86) F (n = 30)

12.4 11.0 13.5 13.5 16.4 14.2 13.9 12.9

M (n = 41) F (n = 14) M (n = 18) F (n = 12)

BA (yr)

Ht (cm)

Height SDS forCA

140.5 130.5

-4.6 -4.8 -4.0 -3.8

121.5 114.1

10.2

Ht (cm)

Height SDS forCA

(yr) 5.4

167.5 153.5

-1.9 -2.2 -1.1 -1.4

4.5 4.5

-5.5

160.4 148.4 160.8

-2.9

6.2

-4.1 -4.7 -4.3 -6.1 -5.8 -2.7 -4.3 -4.8

157.8 146.2 162.0 142.0 159.3 155.9

-1.9 -2.1 -1.7 -4.3 -2.0 -1.7 -3.1 -2.8

6.6 6.5 5.1 4.6 7.2 2.0 6.0 5.1

13.5 8.0 8.0 8.6 8.5 8.5

Duration of i-l XT , £» Q f

r\

f

GHD, GH-deficient patients; M, males; F, females; n, number of patients; CA, chronological age; BA, bone age; Ht, height; SDS, SD score (mean height for sex and age - actual height)/SD of mean height for sex and age. The population standard for height is used except as noted in footnote. The numbers in parentheses appearing next to the first authors are reference numbers. ° Parent-specific SDS used in this study.

other studies in which no correlation was seen between growth rate (6-10 months) and IGF-I levels (46, 47). It is also important to realize that IGFs are not only produced in the liver but also in peripheral target tissues, suggesting an autocrine/paracrine action (48). The impact of this local production on linear growth and its contribution to or correlation with the circulating level of IGFs is not fully known. A GH dose-dependent increase in serum IGF-I measured every second hour for 15 h has been observed, and it was noted that a daily GH dose of 3 IU (1 mg)/m2 body surface was necessary to maintain serum IGF-I in the normal range, whereas a further dose increase added only a modest increase in IGF-I levels (49). After the development of a specific RIA for IGF-II (50-53), the circulating level of this peptide has also been studied in patients with growth disturbances (50-56). Serum IGF-II seems to be only partly GH dependent since it is low in untreated GH deficiency but not elevated in acromegaly (50, 52). Another distinction is that serum IGF-II remains almost constant with age beyond the first year of life (50, 53). Theoretically, this age independence makes serum IGFII a better predictor of responsiveness to GH therapy. On the other hand, a relatively large proportion of untreated GH-deficient patients have serum IGF-II values within or close to the lower normal range (55-57). After a single im injection of GH, GH-deficient patients experienced a significant increase in serum IGF-I after 8-

24 h, whereas serum IGF-II increased after 24-72 h (54). Ranke et al. (57) reported only a modest increase in serum IGF-II after 5 days of sc GH therapy (0.07 IU/kgday). At present there is no prospective data on the relationship between changes in serum IGF-II and growth rate during long-term GH therapy. Most of the circulating IGF-I and-II are bound to specific binding properties (IGFBP) of which at least four have been identified on the basis of amino acid sequence. According to a recent suggestion (58), these proteins are now designated IGFBP-1, -2, and -3, and an IGFBP isolated from cerebrospinal fluid is termed CSFIGFBP. Quantitatively, the most important is IGFBP-3 which binds approximately 90% of circulating IGF-I and IGF-II (54, 59). In addition, a positive relationship has been shown between serum IGFBP-3 and IGF-I (56, 60). Serum IGFBP-3 is GH dependent with low levels in GH deficiency and high levels in acromegaly (18, 60), and it exhibits only minor circadian fluctuations (56). It has therefore been proposed that single measurements of serum IGFBP-3 may serve as a screening for GH deficiency and perhaps also as a predictor of growth response during treatment (18). D. Biochemical growth markers Several studies have evaluated the usefulness of growth markers other than IGFs as predictors of re-

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sponse to GH therapy. A direct correlation between procollagen III levels and growth velocity during 6-12 months of GH therapy has been documented (61-63). In contrast, Procollagen I measured in serum before and during 12 months of treatment in GH-deficient patients did not correlate with growth velocity (64). While serum levels of procollagen reflect newly synthesized collagen, serum osteocalcin or bone GLA-protein is a specific marker of osteoblast activity. Serum measurements of this protein have been conducted during long-term GH treatment in GH deficiency and appeared to correlate with the length of treatment, but only weakly with the increase in growth velocity (65). E. Metabolic effects Although GH administration is known to influence intermediary metabolism (1, 2, 4-7, 36) only a few attempts have been made to measure these effects as part of the evaluation of GH treatment. Wright et al. (66) claimed that the metabolic response during an initial 39 day administration of GH could not predict the growth response during prolonged treatment, but they observed that GH corrected reactive hypoglycemia (hypoglycemic unresponsiveness) and normalized insulin sensitivity in all patients, of whom some had previously suffered from spontaneous hypoglycemia. These findings were confirmed in a long-term (1 yr) study, which also revealed a normalization in serum patterns of free fatty acids after administration of oral glucose (67). A recent study reported abnormal 24-h patterns of several essential metabolites in untreated GH deficiency and also found that GH replacement therapy normalized these patterns only if GH was administered in the evening (68). The commonly observed decrease in plasma urea after GH administration (1, 4-7, 66) has been reported to be caused by decreased urea synthesis which again reflects nitrogen retention (69). However, no correlation was found between changes in plasma urea and 6 months growth rate in the 10 GH deficient patients studied, perhaps because they all showed a dramatic growth response (69). F. Conclusion Evaluating and predicting the responsiveness of GHdeficient patients to GH therapy regimens are not straightforward. The short-term growth response does not necessarily reflect long-term response or final height, whereas long-term trials may be confounded by concurrent factors such as puberty and a waning growth response. There is at present no data available on the effects of different GH regimens on body composition apart from linear height. There is disagreement about the predictive value of measuring serum IGF-I, although it seems logical to strive for a normalization of serum

Vol. 12, No. 3

IGF-I in the patient, and measurements of serum IGFII and IGFBP are still not standard procedures. Likewise, the experience with other growth markers such as procollagens and osteocalcin is still too limited. Finally, since only little attention has been paid to the metabolic state of GH-deficient patients during treatment it is difficult to ascertain its significance for the overall response to therapy. Since the actions of GH are numerous, it is not surprising that a single predictor is insufficient even if increases in growth rate and final height are the only therapeutical aims. If the aims are widened to include features such as body composition and metabolic homeostasis, it is evident that therapy monitoring will be complex.

III. Pharmacokinetic and Biological Effects of Biosynthetic GH as Compared to Pituitary GH A. Pharmacokinetics Biosynthetic or recombinant hGH (r-hGH) was tested in human subjects for the first time in 1982 (14). Serum GH profiles after im injections of on average 16 IU rhGH (the biopotency of that preparation was 2 IU/mg) and pituitary GH (p-hGH) to healthy adults were almost identical. The initial biosynthetic preparation included an additional methionine residue at the N-terminal end. Subsequently, r-hGH preparations with an amino acid sequence identical to the natural hormone, so-called authentic r-hGH, became available (70, 71). No differences were revealed in a study comparing serum profiles of p-hGH and authentic r-hGH after both sc and im injections to GH-deficient children (72) (Fig. 1). A direct comparison of p-hGH and r-hGH with respect to metabolic clearance rate (MCR), distribution space (DS), and serum half-time (tA) has not been published. Data on the MCR, DS, and th of exogenous and endogenous GH in human subjects are presented in Table 2. The MCR of GH varies between 93.5 to 235 liter/daym2 (73-81). This variability reflects both different experimental procedures and GH sources. As regards the latter, it has been shown that endogenous GH in humans is cleared according to its molecular size (82). This could explain some of the differences, since p-hGH is composed of different mass variants of GH (83), whereas r-hGH consists almost exclusively of the 22K molecule. In general, the elimination is described as following first order kinetics with a serum tA of 15-28 min (77, 79, 80, 82, 8486). However, a slower phase has been reported after the disappearance of serum GH to very low levels (73, 79, 84). In the studies using radiolabeled p-hGH (73, 84), this "slow-component" could represent the disappearance of larger, oligomeric forms or damaged iodinated hormone, whereas in the study which employed unlabeled r-hGH (79), interference of small amounts of en-

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hGH REPLACEMENT THERAPY

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193

100

90

a 80

g 70 O

I « (A

50

40

30

ui O

z X *

o 10

--i-

° t

12

16

20

24

2 lu l.m.

' t

12

16

20

24

8 hours

2 iu ».c.

FlG. 1. Mean ± SE serum profiles of somatomedin-C (IGF-I) (upper panel) and GH (lower panel) in nine GH-deficient children after im and sc administration of p-hGH ( • • ) and biosynthetic hGH ( • • ) . Arrows indicate time of injections. [Data derived from Ref. 72.]

dogenous GH may have occurred. A markedly shorter GH half-time of 8.9 min has been reported in one study (87) after an iv bolus injection of r-hGH in normal subjects before an infusion of somatostatin. The bolus technique is critically dependent on the arbitrary duration of the initial distribution phase, which reflects both a redistribution of GH to peripheral compartments and "true" elimination from the central compartment. In this particular study a very brief distribution phase was defined, which may explain the results. Calculations of the apparent DS varies between 46.7-84.5 ml/kg body weight (77, 79, 86, 87), which is intermediary of plasma volume and total extracellular water (88). Again, the diversities are difficult to scrutinize due to the different experimental procedures and GH sources. When pharmacokinetic data of r-hGH and p-hGH are compared, no gross differences seem to exist.

B. Antibodies top-hGH and r-hGH during therapy The development of antibodies to GH during treatment with p-hGH was early recognized (12). The incidence of antibody formation in the patients ranged between 7-60% and seemed to relate inversely to the purity of preparations. However, antibody development in patients with familial isolated GH deficiency was supposed to be related to decreased immunotolerance to GH, since some of these patients had been shown to exhibit defective or absent GH expression (89). The occurrence of growth attenuating antibodies to p-hGH is low, except in the above mentioned familial cases (89, 90). With the early preparations of methionyl r-hGH, a high incidence of GH antibodies was recorded, which in only one case was associated with growth attenuation (91, 92). It is

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J0RGENSEN

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TABLE 2. Data on pharmacokinetic studies with GH in human subjects Authors

Subjects

GH preparation

Method

MCR (liters/24 h-m2)

Parker et al. (84)

Normal adults (n = 8)

p-hGH

iv bolus

Glick et al. (85)

Normal adults (n = 5)

Endogenous GH

Sequential hypo-/hyperglycemia

Cameron et al. (73)

Normal adults (n = 13 (i) & 7 ii))

125

(i) iv bolus (ii) constant iv infusion

Refetoff and Sonksen (86)

Adult GHD (n = 2)

p-hGH

iv bolus

Taylor et al. (74)

Normal adults (n = 22)

[125I]p-hGH

Constant iv infusion

MacGillivray et al. (75)

(i) Normal adults (n = 17) (ii) GHD (n = 13)

[131I]p-hGH

Constant iv infusion

(i) 163.9 ± 5.6 (ii) 155.7 ± 10.7

Kowarski et al. (76)

Adults females (n = 4)

[131I]p-hGH

Constant iv infusion

235.4 ± 20.0

Owens et al. (77)

Normal adults (n = 11)

p-hGH

Constant iv infusion

Baumann (78)

Normal adults (n = 7)

[125I]p-hGH Isohormones B, C, and D

iv bolus

Hendricks et al. (82)

Adult GHD (n = 5)

p-hGH

iv bolus

J0rgensen et al. (79)

GHD (n = 9)

r-hGH

Constant iv infusion

Faria et al. (80)

Normal adults (n = 7)

Endogenous GH

GHRH stimulation plus somatostatin infusion

Hindmarsh et al. (87)

Normal adult males (n = 6)

r-hGH

iv bolus

Rosenbaum and Gertner (81)

(i) men (n = 13) (ii) women (n = 9) (iii) GHD (n = 5) (iv) children (n = 7)

Methionyl r-hGH

Constant iv infusion

I and 131I-labeled p-hGH

(min)

DS (ml/kg)

27

«ECF

20-28

(i) 196 ± 13 (ii) 203 ± 8 14.9

84.5

19

79.3

180 ± 37

174 B 108.4 ± 8.1 C 67.9 ±12.3 D 55.7 ±4.9

21.5 ± 1.1 124.4 ± 31

21.1 ± 1.7

179 ± 6

20.7 ± 0.7

8.9 ± 0.5

46.7 ± 6.7

(i) 180.3 ± 10.9 (ii) 129.5 ± 11.1 (iii) 98.1 ± 17.9 (iv) 93.5 ± 11.8

n, Number of participants; GHD, GH-deficient patients; ECF, extracellular fluid. The numbers in parentheses are reference numbers.

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August, 1991

hGH REPLACEMENT THERAPY

most likely that the increased antigenicity of early methionyl GH was due to the presence of Escherichia coli protein acting as an adjuvant, since highly purified methionyl preparations are less immunogenic. The problem now seems diminished since the preparations of authentic, so-called "methionine free" r-hGH, which also contains only small quantities of E. coli protein, are not reported to be very immunogenic (93-95). C. Metabolic effects It has been suggested that the metabolic effects of phGH preparations were caused by pituitary contaminants (96, 97). The introduction of biosynthetic GH provided a useful tool for examining this hypothesis. Two studies unequivocally observed identical metabolic effects of p-hGH and r-hGH in terms of insulin resistance (98) and enhanced lipolysis (99). Identical 24-h patterns of blood glucose, serum insulin, and lipid intermediates were also recorded in a double-blind study of p-hGH and r-hGH in GH-deficient children (72). Furthermore, evidence of a dose-dependent increase in insulin resistance in a study of r-hGH in GH-deficient patients has been reported (49). It is likely that the lipolytic and insulin antagonistic effects of GH are intrinsic to the GH molecule. D. Effects on linear growth Analogous to the short-term metabolic effects, the long-term anabolic effects of r-hGH and p-hGH seem to be identical. Although one study has included a control group of patients receiving p-hGH (91), the conclusions drawn from studies with r-hGH of both methionyl (91, 92) and authentic preparations (93-95) for up to 48 months (91) in GH-deficient patients were that r-hGH was equally effective as p-hGH. E. Conclusion There does not seem to be major pharmacokinetic differences between pituitary and recombinant human GH. The increased antigenicity of the early preparations of methionyl r-hGH was presumably caused by E. coli proteins, but this problem is now of minor importance, since the new authentic r-hGH preparations are not very immunogenic. The lipolytic and insulin antagonistic effects of p-hGH have been recorded to the same extent with r-hGH, which implies that these properties are intrinsic to the GH molecule. Finally, longer term effects of r-hGH on linear height in GH-deficient patients are identical to those obtained with p-hGH.

195

IV. Route of GH Administration A. Intramuscular vs. subcutaneous administration Intramuscular injections of GH to GH-deficient patients have been the method of choice since the first pilot studies (2, 3). No explanation for this preference has been given, but it was later reported that sc injections caused local lipoatrophy and were suspected to enhance antibody formation (100). A reevaluation of sc GH injections revealed a very strong preference by the patients for this route without side effects (19-23, 101, 102). Moreover, an increase in growth rate was recorded in those studies, where the patients were shifted from 2- to 3-weekly daytime im injections to daily sc injections given in the evening with the same weekly dose (20-23). B. Absorption kinetics of im and sc GH administration There are relatively few studies on the absorption of exogenous GH. These are summarized in Table 3. Values given for Tmax (the time to reach peak level) and length of disappearance phase in serum are mainly based on visual inspection of the published individual or mean serum GH profiles. A large variation is evident, both among individuals and among the different studies. Still, there appears to be a more rapid absorption from the im bed with a Tmax of 2-3 h and a disappearance phase from serum of 12-20 h, as opposed to sc injections which yield values of 4-6 h (Tmax) and 20-24 h (disappearance), respectively. This difference, which has been confirmed in three out of four studies comparing the two routes (19, 22, 72), is in agreement with studies of insulin absorption in diabetic patients (106). The difference is presumably directly related to the higher im blood flow. Russo and Moore (101) observed no difference between serum GH profiles when comparing the two routes, although the mean curves indicated a slower and biphasic sc absorption. Their findings could partly be due to interindividual variation since this was a comparison between two groups. It could also relate to the injection technique, which was not outlined, since it has been shown that intended im injections often are delivered sc (107), and vice versa (108). This could account for the variation in absorption seen in all the studies, since verification of adequate needle position by means of computed tomography scan or ultrasonography was not carried out. Apart from time course differences in serum profiles after im and sc injections, some evidence suggests a difference in bioavailability between the two routes. In two independent studies, a significantly smaller area under the serum GH curve (AUC) after sc as compared to im injections under the same conditions was recorded (19, 72). The gel chromatographic elution profile of GH in serum has been shown to be unaltered after sc admin-

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Vol. 12, No. 3

J0RGENSEN

TABLE 3. Absorption studies of im and sc administered GH in human subjects

Authors

Subjects

GH preparation

Normal adults (n = 8) GHD (n = 5) Normal adults (n = 10) GHD (n = 13) GHD (n = 7) GHD (n = 16)

p-hGH

Normal adults (n = 10) GHD (n = 9)

im Parker et al. (84) Frasier (103) Hintz et al. (14) Russo et al. (101) Christiansen et al. (19) Albertsson - Wikland et al. (22) Wilton et al. (104) J0rgensen et al. (72) J0rgensen et al. (49) Ho et al. (105) J0rgensen et al. (68)

GHD (n = 7) Normal adults (n = 6) GHD (n = 8)

10 IU

Disappearance phase (h)

T-1 max (h)

Dose (IU)

sc

im

2-5

24 12-24 13 12

3-5 4-6 4-8

12 14 16-20

12 24 >20

>9 4

17

23

n, Number of participants; Tmax, estimated time to achieve maximal serum level after injection. Disappearance phase is the estimated duration of elevated (above baseline) GH levels after Tmai.

istration (19), which suggests that the difference is not caused by major conformational changes of the GH molecule. A reduced MCR of im injected GH due to higher serum levels is also an unlikely explanation, since the MCR of GH is independent of concentration (77). However, the apparent difference in AUC could be an artefact due to a continued small and unmeasurable release of GH from the sc tissue. In a subsequent study, a comparison of steady state serum GH levels after iv and sc infusion of the same amount of GH in GH-deficient patients showed significantly lower GH levels after sc infusion (109). This suggests a true reduced bioavailability of sc administered GH, and similar findings have been reported after iv and sc bolus injections of GH (110). These data suggest a sc degradation of GH although the exact mechanisms remain to be investigated. Another variable that could influence sc absorption is the volume in which GH is dissolved for injection. Data from sc absorption studies of insulin indicate a positive correlation between injection volume and both absorption rate (111, 112), peak value (Cmax), and bioavailability (111). A study on normal subjects who were injected sc with 6 IU (2 mg) of GH in three different volumes on separate occasions revealed that the larger volume (2 ml) yielded a higher Cmax and a larger AUC (113). From these data it was speculated that a large injection volume widens the exposure of the hormone to the sc capillary bed, which then causes a more rapid absorption and a larger AUC due to less exposure to sc degradation. Whether this bears any clinical significance is doubtful, but it suggests that injection volume should be considered when designing or evaluating sc absorption studies.

As previously noted, the implementation of daily sc injections given in the evening was shown to increase height velocity in several studies (20-23). In this respect it is possible that the absorption kinetics of sc GH might contribute to the improved growth response by ensuring a Cmax in a more physiological range and by extending the periods of elevated GH levels. That the sc route should be of significance has been questioned in one study (102), which recorded no difference in growth response after 6 months when two groups of patients treated with either im or sc injections thrice weekly were compared. However, the growth rate at the onset of the study was different in the two groups and a higher proportion of the sc treated patients were withdrawn during the trial, due to a shortage of GH. It is also possible that the advantage of sc administration was unable to overcome the drawback of the infrequent injection schedule. Improved patient compliance with sc injections has been reported in all studies. This is undoubtedly attributable to the sc route, which is less uncomfortable and allows self-administration. Whether the increased compliance contributed to the improved growth response is difficult to evaluate, but injection pain and difficulties with the treatment as such have been shown to be the major negative aspects of GH therapy in a larger retrospective survey (114). Patient compliance might also be improved with the use of injection pens, which have proven successful for frequent sc insulin administration in diabetic patients (115, 116). Similar devices are being introduced for GH administration. One study evaluated the sc absorption

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August, 1991

hGH REPLACEMENT THERAPY

kinetics and long-term patient tolerability using conventional syringe and vial vs. an injection pen (117). The pen was basically a needle, syringe, and GH container in one piece, which was mounted with reconstituted cartridged GH of high concentration (12.5 IU/ml). The postinjectional serum GH profiles did not differ significantly between the two systems, and the biological potency and content of oligomeric GH forms in the cartridged GH in use were comparable to those of the conventional vial. The pen was preferred by all patients because it simplified self-administration. Similar experiences have been made with other GH pen devices (Albertsson-Wikland, K., unpublished data). C. Conclusion

GH was traditionally administered by the im route. This is now obsolete since sc injections are strongly preferred by patients and do not seem to induce local side effects or increased GH antibody formation. Furthermore, increased linear growth response has been documented with daily sc GH injections given in the evening. The absorption kinetic of sc and im injected GH is different in that the former is characterized by a slower appearance (Tmax) and disappearance phase in serum, a lower, more physiological peak value (Cmax), and perhaps also by a smaller bioavailability due to local degradation. The extent to which the sc route contributes to the improved growth response with the new regimen is unresolved, but the increased patient compliance is explained by less discomfort and easier self-administration. A further improvement in compliance might be achieved by the use of injection pen devices. V. Frequency and Timing of GH Administration A. The normal secretory pattern of GH After the introduction of a RIA for GH (10), it became evident that GH is secreted in a pulsatile and episodic manner. This pattern is influenced by several fundamental physiological variables such as age (118-120), sex (120, 121), food intake, nutritional state (122, 123), and physical activity (124). In an unfasted child during normal circadian activities the serum GH pattern is characterized by high nocturnal levels, starting 1-2 h after onset of sleep, with each surge often composed by several secretory episodes. Daytime secretion is less predictable with smaller bursts, which most often appear 2-4 h after meals. In addition, there is evidence that even during periods with low or "basal" GH levels some secretion is still present (125,126). B. Frequency of GH administration The previous GH treatment schedule with 2 or 3 daytime injections per week was not intended to simulate

197

the endogenous serum GH pattern. More likely, it was based on the empiric observations of successful results from the earliest studies, which used this regimen. As also explicitly stated in the studies from that period, the inclination for the im route and the scarce supply of the hormone confined the therapeutical aim to achievement of adequate growth with as few injections and the smallest amount of GH as possible (8, 9, 127, 128). Although these studies are difficult to compare, the data suggest that three injections/week rather than twice weekly injections yielded a better growth response (12). In one study, however, daily administration did not seem superior to thrice weekly schedules (127), and others reported successful results with weekly injections (129, 130) and intermittent therapy (131). However, neither of these latter studies were controlled, and both weekly and intermittent treatment schedules have been shown to be inferior when compared to standard regimens (127, 132, 133). Whether the increased growth rate after the change to daily sc GH injections is due to the increased injection frequency is difficult to assess, since the route, the amount of GH injected on each occasion, and the time of the day of administration were changed simultaneously in these studies (20-23). Therefore, it is not fully documented whether a closer imitation of the endogenous GH pattern in terms of more frequent injections is advantageous. Experimental data on this issue are mainly derived from studies in hypophysectomized (hypox) rats. Thorngren and Jansson and co-workers (134136) performed several studies with hypox rats comparing different frequencies of sc GH injections and reported that two to four injections/day were superior to less frequent administration in promoting longitudinal bone growth, whereas more frequent regimens added no further effect (134-136). In another study of sc administration in hypox rats, continuous infusion induced a greater increase in body weight compared to daily injections. It was also reported that GH dissolved in gelatin to obtain a more protracted absorption induced better growth compared to a conventional preparation, in spite of an apparent reduced bioavailability of the gelatin preparation (137). The configuration of serum GH profile after sc injections makes it impossible to establish whether any given effect after frequent sc injections is due to pulsatility or to prolonged elevations of serum GH, or both (19, 22, 47, 68, 72). To study the isolated effects of pulsatile delivery it is therefore necessary to employ iv administration. This has been done in two experiments (138, 139), which compared pulsatile and continuous iv GH administration in hypox rats. Both reported that pulsatile delivery was superior in terms of weight gain (138) or increase in IGF-I mRNA in rib growth plate and skeletal muscle (139). However, when extrapolating these findings to humans it must be recalled that species-

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specific differences exist as regards both the secretory pattern and actions of GH (121, 140, 141). One study employing iv GH administration has been performed in GH-deficient patients (142). The patients underwent three iv GH administration schedules in random order, separated by 4 weeks. During each study a total GH dose of 2 IU (0.66 mg) was administered as either 2 or 8 boluses, or as a continuous infusion (24 h) followed by an observation period of at least 16 h. The eight bolus regimen and the continuous infusion yielded identical increments in serum IGF-I with time and in terms of total AUC, whereas serum IGF-I during the two bolus regimen displayed a significantly lower peak level and total AUC (Fig. 2). The data seem to indicate that small but frequent iv boluses and continuous infusion of GH possess equal growth-promoting effects. However, this was a short-term study based on circulating IGF-I as a growth predictor. Still, with these experimental data it could be speculated that the benefit of daily sc administration is not solely the increased frequency but may also be a result of the more prolonged serum GH profile after a sc injection. Evidently, controlled long-term trials involving either iv administration as outlined above, or comparing daily im and sc injections, or even continuous infusion vs. injections, would be informative but difficult to carry out.

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FIG. 2. Mean ± SE serum IGF-I profiles in six GH-deficient patients after iv administration of 2 IU GH as either two boluses (O O), eight boluses (D • ) , or a constant infusion ( • • ) . Arrows and bar indicate time of GH administration. [Data derived from Ref. 142.]

Vol. 12, No. 3

C. Timing of GH administration The major proportion of GH secretion in normal subjects occurs at night (118, 125, 143), the most reproducible peak being observed shortly after the onset of sleep (144). In several studies this has been causally linked to stages III-IV of sleep (slow wave sleep) (144, 145). Whether this inherent GH pattern is of significance for the growth promoting and metabolic effects of the hormone has received little attention. Rudman et al. (146) evaluated the effects of morning us. evening GH administration on the anabolic response in a 7 day metabolic balance study in seven GH-deficient children, and three adults with muscular dystrophy. With a daily replacement dose of 0.064 U/kg • day a significantly larger increase in nitrogen balance was obtained when GH was administered in the evening. Since this effect could be reversed in three children with concomitant ACTH deficiency if cortisol was administered in the evening, instead of following the usual procedure of administering it in the morning, it was further speculated that the benefit of evening GH injections could partly be that they ensured peak GH levels during a period when cortisol is normally low. On the other hand, a subsequent paper (147) observed no difference in serum IGF-I pattern or 4 months' growth response when morning and evening GH injections were compared in a cross-over study including nine GH-deficient children. In that study, however, injections were given thrice weekly, which do not in either situation mimic the endogenous pattern, as also reflected in highly fluctuating IGF-I levels. Furthermore, the GH dose varied substantially among the patients, ranging from 0.21-0.63 IU/kg- week. Finally, the study periods comprised only 4 months each and were conducted within the first year after diagnosis in previously untreated patients. This period is usually characterized by an excellent response even to small infrequent GH doses (12). Increased long-term growth velocity has been reported after the therapeutical shift to daily sc injections in the evening. In all instances this increment occurred in patients who had been treated before for an average of 5 yr (range: 0.5-9 yr) (20-23), i.e. at a time point when the waning effect usually prevails (12). It is difficult to assess how evening administration may have contributed to this effect. A recent randomized short-term study (68) compared the effects of morning us. evening administration of GH on 24-h patterns of pertinent circulating hormones and metabolites. Eight GH-deficient patients underwent three 4-week studies in random order receiving either morning (0800 h) or evening (2000 h) sc GH injections (2 IU (0.66 mg)/day), or no therapy. At the end of each period they were hospitalized for 24-h blood sampling. They were also compared with an age- and

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hGH REPLACEMENT THERAPY

August, 1991

sex-matched group of healthy untreated subjects. Evening GH administration resulted in a mean overnight serum GH level similar to that in normal subjects. The AUC of serum IGF-I did not differ between the two treatments, but a significant fluctuation with time of serum IGF-I was observed only after morning injection indicating a non-steady state situation. In addition, morning GH injections were accompanied by significant daytime hyperinsulinemia. Moreover, the normal 24-h pattern of lipid intermediates, characterized by high values preprandially, low levels postprandially and constantly raised levels at night, was only obtained with evening GH injections, whereas morning injections resulted in low night levels. Finally, a distinct diurnal pattern in the circulating gluconeogenic precursors alanine and lactate, which correlated inversely with the pattern of lipid intermediates, was recorded in the control subjects and in the patients when treated with evening GH, but not when GH was administered in the morning (Fig. 3). Although this significant inverse relationship does not imply causality, the existence of a regulatory feedback system involving these two substrates, a so-called alanine-ketone body cycle, based also Reference group r=0.91, p

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Human growth hormone replacement therapy: pharmacological and clinical aspects.

0163-769X/91/1203-0189$03.00/0 Endocrine Reviews Copyright © 1991 by The Endocrine Society Vol. 12, No. 3 Printed in U.S.A. Human Growth Hormone Rep...
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