============================================================================= Based on the known trophic effects of growth hormone (GH) on nerve and muscle 75 patients with ALS were treated for up to 18 months with synthetic human growth hormone (Protropin) or a placebo. The course of ALS was assessed serially using a quantitative (TQNE) neuromuscu- lar and manual exam (MRC) and laboratory chemistries. Average insu- lin-related growth factor (IGF-1) values increased from 1.2 to 2.3 U/mL in the treated group. Surprisingly, serum insulin levels did not increase. Hyperglycemia was noted in only 2 patients of the 38 patients receiving hGH, and this resolved with cessation of treatment. Over the 12 months of treatment there were 1 1 deaths (6 controls, 5 treated). Survival anal- ysis, performed approximately 12 months following cessation of treat- ment, did not reveal a difference between the treatment and placebo group. The TQNE scores declined inexorably in both the control and treated group. Retrospective analysis of the TQNE data indicated a poor prognosis for patients who lost arm strength early. A correlation between the TQNE and MRC scores was evident at early stages of motor unit loss, less so when muscle weakness was advanced. 0 1993 John Wiley & Sons, Inc. Key words: ALS (amyotrophic lateral sclerosis) - human growth hor- mone - IGF-1 (insulin-related growth factor) MUSCLE & NERVE 16:624-633 1993 =============================================================================== RECOMBINANT GROWTH HORMONE TREATMENT OF AMYOTROPHIC LATERAL SCLEROSIS R.A. SMITH, MD, S. MELMED, MD, B. SHERMAN, MD, J. FRANE, PhD, T.L. MUNSAT, MD, and B.W. FESTOFF, MD ============================================================================== From the Center for Neurologic Study, San Diego, California (Dr. Smith), Division of Endocrinology, Department of Medicine, Cedar Sinai/UCLA Medical Centers, Los Angeles, California (Dr. Maimed); Genentech, Inc,, S, San Francisco, California (Drs. Sherman and Frane); Neuromuscular Research Unit, Department of Neurology, Tufts-New England Medical Center, Boston, Massachusetts (Dr. Munsat); and Neurobiology Research Laboratory, Department of Neurology, Veteran Affairs, and University of Kansas Medical Centers, Kansas City, Missouri and Kansas City, Kansas (Dr. Festoff) Acknowledgments: Support for these studies was provided by the Mus- cular Dystrophy Association; Genentech, Inc,; the Joseph Drown Foun- dation; and the Medical Research Service of the Department of Veterans Affairs. The authors gratefully acknowledge the participation of our pa- tients and their families, and Drs. Neal Lewis and David Cooper, both formerly associated with the Muscular Dystrophy Association. Clinical co- ordination and oversight was adeptly provided by Sheri Jacoby, RN. (Har- bor View Hospital, San Diego); Gabriela Molnar, PhD (Cedars Sinai Med- ical Center, Los Angeles); Mary Brown, RN (University of Kansas Medical Center, Kansas City, KS); Lori Peterson, BA (Kansas City Veterans Affairs Medical Center, Kansas City, MO); and Joyce Kuntze, RN (Genentech, Inc., San Francisco). This manuscript is dedicated to the memory of Ar- thur Levien and Warren Irwin and to Arlene and William Doro, Milton Fillius, Sheila Irwin, Curtis Robert Jr. and Sr., Wendy Wachtel-Schine, and Joan and George Thagard. Further, we are in debt to Shyla Hernandez, who nurtured this manuscript through its numerous incarnations. Address reprint requests to Barry W. Festoff, MD, Neurobiology Research Laboratory (151), Veterans Affairs Medical Center, 4801 Linwood Boule- vard, Kansas City, MO 64128. Accepted for publication November 25, 1992. CCC 0148-639X/93/060624-10 @ 1993 John Wiley & Sons, Inc =============================================================================== Amyotrophic lateral sclerosis (ALS) is a fatal dis- order of man characterized by muscular weakness and fasciculations, progressive atrophy, and ab- normal muscle stretch reflexes. (12,41.13) As the dis- ease inexorably progresses, there is an effort at regeneration and reinnervation manifested by col- lateral sprouting of still intact peripheral axons which reinnervate muscle fibers whose own neural connection have been lost.(55) This process may be under humoral control.(9) The idea that an abnormality, or deficiency, of a putative motoneuron growth/trophic factor (MNGF) might underlie the cause(s) of ALS, or relate to its pathogenesis, has been inferred from the example of nerve growth factor (NGF).(3) NGF exerts its trophic functions principally on auto- nomic and primary sensory neurons, but is also implicated in CNS cortical and subcortical cholin- ergic systems. 32 58 Although a MNGF has not been definitely identified, a number of candidates have been suggested.(25,34,311) Other factors, among them insulin-like growth factors I and II (IGF-1, IGF-11) and epidermal growth factor (EGF), have all been demonstrated to exert trophic influences on CNS METHODS neurons. (43) Inclusion and Exclusion Criteria. Ambulatory pa- IGF-1, also known as somatomedin C, if of par- tients with mild-moderate "classical ALS," as de- ticular interest, since it is a growth factor which fined by clinical and electromyographic criteria as shares structural and receptor similarities with in- previously established, (19,31,44) were entered into the sulin and is the principal mediator for growth hor- trial in four cohorts at the three centers (Table 1). mone (GH). (16,31,37) Along with insulin, IGF-I and We excluded all "pure" syndromes such as pro- IGF-11 specifically bind throughout mammalian gressive muscular atrophy (PMA), progressive bul- brain. 55 The greatest amount of specific binding is bar palsy (PBP), and primary lateral sclerosis found in cortical grey areas, in particular, the ol- (PLS). factory lobe, whereas binding is lowest in white matter fiber tracts. This topography suggests that Drug and Placebo. Human recombinant, methio- IGF-I may primarily influence neuronal subsets. nyl growth hormone (5 mg) formulated with 40 In cell culture it is also a potent inducer of oligo- mg mannitol, 0.54 mg sodium, and 1. 16 mg phos- dendrocyte development.@9 In the spinal cord, cer- phate was reconstituted in bacteriostatic water and vical-thoracic ventral horns show maximum IGF-I administered intramuscularly at a dose of 0. I mg/ binding. In the periphery, there is evidence to sup- kg, three times a week. Placebo consisted of the port roles for IGF-I in both muscle and same formulation without recombinant human nerve. (21,22,27,50) Relevant to the reinnervation ca- growth hormone (rhGH). No change in dose was pacity in ALS muscle, IGF-I MRNA increases in made regardless of weight loss or gain. All drugs muscle after denervation or paralysis, and direct were refrigerated upon arrival at each center's injection of IGF-I into adult muscle induces intra- pharmacy and at each patient's residence. The muscular nerve sprouting.(11) Further, GH appears manner of administration of rhGH or placebo was to regulate IGF-I MRNA in muscle.(26) carefully reviewed at the outset of the study. Com- Growth hormone has also been shown to have pliance with the treatment regimen was recorded effects on myelination. Newborn rats rendered monthly, at which time used vials were returned to GH-deficient exhibit marked reduction of myeli- the trial coordinator. nation, while mice that are genetically deficient in This was a double-blind, placebo-controlled, GH myelinate poorly. With exogenous administra- parallel therapeutic trial which did not call for tion of GH, these myelination deficits are re- crossover during the study. Randomization was versed. (30,47) performed by use of computer-based tables of ran- Although GH release in ALS patients is appar- dom numbers and was balanced for each site. This ently normal, the above studies suggested the ra- was done to ensure that an approximately equal tionale that the pathophysiologic events which number of treated and placebo patients were en- characterize ALS might respond to growth hor- rolled at each center. Chronological entry into the mone. We considered it likely that, at the mini- study determined the patient's identification num- mum, exogenous administration of human growth ber which was already predetermined by the ran- hormone (hGH) in ALS patients would affect ni- domization procedure. trogen balance as it does in fasting, producing a 11 protein sparing effect."(6,15,40)In subjects adminis- Tufts Quantitative Nouromuscular Examination tered a hypocaloric diet, GH has the effect of in- (TQNE). A modification of the TQNE (Tufts New creasing protein synthesis and attenuating the ef- England Medical Center, Boston, MA) as reported flux of amino acid nitrogen which follows by Andres et al(2). was used for this trial. The iso carbohydrate loading.(35) metric force measurements and manual dexterity More importantly, hGH might influence or (speed) elements were employed as described', but prevent the loss of alpha motoneurons, secondary a hand-held microprocessor controlled spirometer demyelination, or promote reinnervation of mus- (Respiradyne, Pulmonary Function Monitor Man- cle. These hypothetical benefits might result from ufacturer, Chesebrough-Pond Inc., Hospital Prod- direct or indirect influences of hGH, or IGF-1, on ucts Division, Greenwich, CT 06830) was utilized one or more components of the motor system. for pulmonary function parameters. A single, This report summarizes the results of a double- trained registered physical therapist made all blind, placebo-controlled treatment trial. An ac- TQNE measurements at the three centers. This count of our research methodology and treatment individual was trained at Tufts by Dr. T. Munsat strategy has been reported."(3) and P. Andres, RPT. Identical equipment was ----------------------------------------------------------------------------------------------------------------------------------------------------- Table 1. Demographic characteristics of patients enrolled in the protropin treatment trial, Center 1 Center 2 Center 3 Duration Duration Duration Patient Age Sex of Rx* Pat ent Age Sex of Rx Patient Age Sex of Rx A-01 P 57 m 32 B-01 P 55 m 66 C-01 T 74 m 4 A-03P 46 m 57 B-02T 51 m 53 C-02P 43 m 28 A-04T 42 m 56 B-03P 51 m 25 C-03T 65 m 36 A-05P 71 m 63 B-04T 35 m 52 C-04P 68 F 48 A-06T 62 m 1 4 B-05T 67 F 7 C-05T 51 m 8 A-07P 55 m 31 B-06P 51 F 36 C-06P 65 F 36 A-08T 43 F 117 B-07P 64 F 56 C-07P 70 F 40 A-09P 55 m 85 B-08T 44 m 51 C-08T 64 F 4 A-10T 56 m 37 B-09T 73 F 53 C-09T 67 F 40 A-1 1 P 65 F 31 B-1 OP 65 F 34 C-1 OP 65 m 36 A-1 2T 20 m 82 B-11T 45 m 26 C-lip 72 m 56 A-13P 38 m 61 B-1 2P 54 m 52 C-1 2T 62 F 60 A-14T 65 F 67 B-13T 52 m 52 C-13P 64 F 28 A-16T 57 m 24 B-14P 69 m 1 6 C-14T 72 F 1 6 A-17T 56 F 32 B-15T 64 F 1 7 C-1 5P 43 m 28 A-18P 59 F 77 B-1 6P 50 m 40 C-1 6T 58 F 58 A-19T 49 F 24 B-1 7P 57 m 36 C-17T 67 F 1 6 A-20P 66 F 30 C-1 8p 64 m 8 A-21T 54 m 43 C-19P 67 m 32 A-22P 62 F 76 C-20T 51 m 40 A-23T 50 m 1 8 C-22T 67 m 48 A-24P 43 m 67 C-23P 30 m 40 A-25T 60 F 70 C-24T 64 F 4 A-26P 43 F 25 C-25T 57 F 48 A-27P 67 m 70 C-26P 62 F 48 A-28T 67 F 71 C-27P 73 F 32 A-29T 64 F 56 C-28T 50 m 1 6 A-30P 51 m 63 A-31T 59 m 41 A-32P 65 F 53 A-33T 45 F 53 ----------------------------------------------------------------------------------------------------------------------------------------------------- Average patient age 57.49 10.86 years. T = treatment group, P = placebo group, boidface positive family history. *Duration of Rx in weeks. ----------------------------------------------------------------------------------------------------------------------------------------------------- placed at each center and calibrated by the RPT TQNE has been presented previously (20) (presented prior to each measurement. A TQNE was per- at the II 3th annual meeting of the American Neu- formed on entry and every 2 months during the rological Association, Philadelphia, PA, October study. 2-5, 1988). The TQNE raw data was converted to z-scores for standardization and grouped into five mega- Hourologist's Nouromuscular Exams. A modified scores as outlined previously.(45) Mega I represents Medical Research Council (MRC) scoring system pulmonary function; Mega 2, bulbal function; was used. These measurements were performed Mega 3, timed hand activities; Mega 4, isometric every 2-3 months during the course of study. Us- arm strength; and Mega 5, isometric leg strength. ing MRC scoring, muscle strength was graded on The TQNE has been used recently to document an ordinal scale of 1-4 for the following muscle the "natural history" of motoneuron loss in 50 ALS groups: neck flexors and extensors, deltoids, bi- patients followed for as long as 67 months (8,45). In ceps, brachioradialis, triceps, wrist extensors, ilio general, deterioration of motor neuron function is psoas, quadriceps, hamstrings, and anterior tibia- linear in ALS when considering the combined lis. Mega score, although some muscle groups, for ex- ample, knee and elbow flexors, demonstrate a Laboratory Tests. Routine chemistries, coagula- more linear change than others.8 A preliminary tion assays, and fasting blood sugar (FBS) were ob- report validating the test/retest confidence of tained at entry and every month during the study and performed in a central laboratory (SK Beck- man, Los Angeles, CA). Whole blood was collected in EDTA-treated tubes, the plasma separated from cells, aliquoted, and frozen at -20'C within 4 hours of collection. Total somatomedin C (IGF-1), insulin, and anti-hGH antibody levels were ob- tained at entry and every 2 months. These were determined using commercial kits as described (Nicholls Institute, San Juan Capistrano, CA). Sim- ilarly, 24-hour urine creatinine and 3-methylhisti- dine (3-MH) levels, obtained on the same schedule, were measured from 30-mL frozen aliquots using previously reported methods 57 in a central labora- tory (Calcium Research Lab, KCVAMC, Kansas City, MO). Statistics. A double-blind placebo controlled trial was undertaken to minimize bias. Seventy-five patients were recruited so as to insure a power of at least 95% for a single one-sided test at the 0.05 level when the difference of the means of the treated and placebo groups was equal to I stan- dard deviation for any variable. RESULTS Patient Entry. Four cohorts (total of 75 patients) were entered into the trial relatively evenly amongst the three centers (Table 1), beginning in March 1987. The oldest patient was 74, the young- est 20. The mean age was 57.18 - 10.68 (SD). A positive family history for ALS was elicited in 6 patients (8.0%). Two patients knew nothing about their families. Considering those who commenced treatment, there were 41 men and 34 women, ap- proaching the expected sex ratio as reported for ALS in the literature. 28 Forty-one patients com- pleted the 1 -year study, II died, and the remain- der (n - 23) withdrew for a variety of reasons. It was agreed at the outset that preliminary analysis of the data would be undertaken midway in the study to determine if a positive trend existed. If such a trend was found, then the study would have been declared open and all patients would have been provided growth hormone for an additional 12 months. Unfortunately, such a trend was not found at the 6-month point. Accordingly, the study was con- tinued as planned. The last cohort finished the study in late September 1988. Patients in the first three cohorts were offered the opportunity to take hGH or placebo until the last cohort completed their 12 months of therapy. Consequently, some patients received therapy for as long as 18 months. TQNE Reliability Analysis. Reliability data, using a single rater at all three centers, was strikingly good at 0.97-0.98 for all megascores using the TQNE. These results (Fig. 1), using identical equipment all calibrated by the same RPT, were equal to or better than those previously reported at a single cen- ter 1,45 and have been communicated in prelimi- nary form. 20 Factor analysis of individual items demonstrated clustering of specific megascores to related neuraxis regions (i.e., bulbar and arm strength). Nutritional Data. Since growth hormone might conceivably affect the nutritional status of ALS pa- tients, we reviewed the amount of weight loss that occurred over time in the control and treatment groups. In the control group, the mean weight was approximately 155 lbs. at entry versus 152 lbs. for the treatment group. At 24 weeks, chosen to attain a larger sample size, mean weight dropped 5.8 lbs. in the control group compared with the treatment group which lost 4.7 lbs. This difference did not reach significance (Table 2). However, analysis was confounded by the fact that some patients devel- oped edema. This prompted the use of antidi- uretic therapy in several instances. A total of 33 of the combined group of patients lost weight, several losing 15% of their initial weight, and I almost 22% over a 6-month period. ----------------------------------------------------------------------- Table 2. The effect of rhGH on weight loss in ALS. Placebo Protropin N 33 22 Baseline 155.0 #s 151.8 #s Week 24 149.3 147.1 Change - 5.8 -4.7 P-value 0.0069 0.0675 ----------------------------------------------------------------------- Rate of Disease Progression. As an estimate of dis- ease progression we utilized a modified TQNE consisting of 28 components.(45) This allowed for interval data on functional motor units to be quan- titatively compared between the two treatment arms. Test/retest data for all patients at entry indi- cated a high degree of reliability for all megascores (r = 0.96-0.98). For all megascores (hand, arm, leg, and speech) there was a downward trend be- tween the placebo and hGH-treated groups (Fig. 2). The decrease from visit to visit averaged 0. 122 for the placebo patients and 0. 149 for the protro- pin group. This difference was not significant. Be- cause of the fact that losses occurred as the trial proceeded, some caution is warranted in interpret- ing the data. The implication is that patients who died or dropped out would have demonstrated similar decreases in their TQNE scores had they remained in the study. Survival Analysis. At the completion of the 48- week study, 6 placebo and 5 rhGH-treated patients had died. Follow-up data was obtained on as many patients as possible approximately 12 months after termination of treatment in order to maximize the statistical power for the survival analysis. At this juncture, 19 of 38 growth hormone-treated pa- tients had died as had 16 of 36 placebo-treated patients. The difference in the proportion dying in the two groups was not statistically significant (P 0.65 using Fisher's Exact Test). A Cox-model survival regression analysis 1 3 was performed to evaluate the effects of growth hor- mone treatment and prognostic baseline variables including age, and TQNE megascores for arm strength, leg strength, hand strength, and speech on survival time. There were 62 patients with data available for this analysis. In this analysis, only leg strength was found to be statistically significant (P = 0.044), with poorer prognosis for patients with less strength on entry into the study. A separate Cox-model survival regression anal- ysis was performed, including all of the above vari- ables plus the rates of decline in the TQNE mega- scores. Data from 56 patients were available for this analysis. In this analysis, each of the rates of decline in the TQNE megascores were individually statistically significant: ----------------------------------------------------------------------- Rate of decline P-value Hand 0.0047 Speech 0.0046 Leg strength 0.0002 Arm strength <0.0001 ----------------------------------------------------------------------- Using all of the above variablesjointly (baseline values and rates of decline) in Cox multiple regres- sion, only age (P = 0.0062) and the rate of decline in arm strength were statistically significant (P < 0.0001). In this last analysis, older patients and pa- tients experiencing the most rapid decline in arm strength had the worst prognosis. The relationship of decline in arm strength to survival is illustrated in Figure 3. Comparison of MRC with TQNE. Comparing the av- erage MRC scores with the average arm and leg megascores from the TQNE a strong correlation was noted. However, at the lowest MRC values, the variability in the TQNE limb megascores was greater than at higher MRC values (Fig. 4). Chemistries and Coagulation Profile. No signifi- cant abnormalities were detected in routine blood chemistries or hemograms. There was a slight pro- longation of prothrombin time with a mean of ap- proximately 2 seconds. This was statistically signif- icant and merits further evaluation. Bleeding and/ or clotting disorders have not been described as being overrepresented in the ALS patient popula- tion, however, a recent report suggested an inverse association between ALS and atherosclerosis. 4 Hormonal Data. It has been reported (after the initiation of this study) that total plasma IGF-I lev- els in ALS patients are normal.(7) We analyzed total IGF-I in most patients entered into the trial along with fasting blood sugars and insulin levels. The minimal total somatomedin C (IGF-1) detectable level was 2.3 mU/mL. After correction for dilution (1:20) the results were reported in units/mL. Nor- mal values for controls, obtained by sampling a population of 220 adults (Nichols Institute normal data) were 0.89 U/mL (range 0.34-2.2). Approxi- mately 25% (18 of 69) of ALS patients' baseline values were abnormal- 1 0 being lower and 8 being higher than expected. The lowest values were not restricted to older males. At baseline, 8 of the pla- cebo-treated patients were abnormal. On serial sampling over months two of these values re- mained lower than our normal and the value re- cently reported b4,, Braunstein and Reviczky for ALS patients. 7 More striking are the results of the treated ALS patients' responses to rhGH. Over the course of the study, total average IGF- I serum lev- els almost doubled. In the control group IGF-I went from 0.9 U/mL to 0.7 U/mL, whereas in the protropin group the mean went from 1.2 U/mL to 2.3 U/mL. This is the first study demonstrating the intactness of the IGF-I response to exogenous rhGH response in ALS patients (Fig. 5), and, in fact, in an adult population. Shown in Table 4 are the blood glucose and insulin values. We had anticipated that most pa- tients would develop elevated blood glucose, and this was found, but only two developed frank hy- perglycemia (over 149 mg/dL). In contrast to the IGF-I response, and unexpectedly, no change was found in insulin levels after prolonged administra- tion of rhGH. This was paradoxical given the glu- cose and IGF-I responses, and clearly different from non-ALS adult subjects administered protro- pin. 42 3.MH Excretion. Analysis of the excretion of 3-MH and the creatinine: 3-MH ratios failed to show a difference between rhGH- and placebo- treated ALS patients. DISCUSSION This trial sought to determine whether exogenous administration of recombinant human growth hor- mone could modify or arrest the course of amyo- trophic lateral sclerosis or provide ancillary bene- fits in the form of improved nutrition. At the completion of the trial an almost equal number of placebo and treated patients had succumbed to their disease. This suggests that rhGH did not ap- pear to influence the course of ALS as judged by careful measurement of disease progression using the TQNE. More treated versus control patients dropped from the study. This did not appear to be related to side effects which were not noteworthy except in two instances when blood sugar was affected. Withdrawal from ALS trials is commonplace. Olarte et al. reported that 24 of 55 patients left a 1-year trial.(48) Accordingly, our experience is not unique, suggesting between both studies that with- drawal rates of 30-40% are to be expected in ALS trials. This may be an indictment of the trial pro- cess, but most likely represents the fact that ALS patients become discouraged when their disease progresses inexorably in spite of treatment. There are other reasons as well. A few patients switched to other treatments based on sensational reports in the "ALS media." At least one patient was told she did not have ALS and would benefit from immu- nosuppressive therapy. The basis for these conclu- sions was not apparent, but does illustrate the in- fluences that nonparticipating physicians can exert upon subject participation. Since abnormalities of carbohydrate metabo- lism have previously been described in ALS pa- tients, (23,24,46,49,51) it was expected that administra- tion of rhGH might trigger chemical diabetes in the majority of patients. This was not the case, al- though two patients developed hyperglycemia. Prior studies have demonstrated insulin insensitiv- ity5 1 and reduction in monocyte insulin receptors in ALS49 without hyperinsulinism. Although mean insulin levels were generally higher in the treated group, these values were not statistically signifi- cant. In a small number of control patients, IGF-I values remained abnormal throughout the study. With administration of growth hormone there was a marked rise in IGF-I levels in most patients. In at least one of the several growth hormone-treated patients, in whom IGF-I levels did not change with treatment, noncompliance was suspected since the patient soon dropped from the study. As judged by the response of IGF-I to administration of growth hormone it appears that the peripheral, principally hepatic, effects of growth hormone are normal in ALS patients. Earlier workers have re- ported flattening of the circadian pattern for hu- man growth hormone secretion and impairment of 7 the stimulated release of hGh in ALS. In males (ages 35-63) with postpolio syndrome, a neuro- muscular condition sharing some clinical similarity with ALS, serum IGF-I values have been reported been seen to have a pronounced effect on muscle to be below normal. This finding has led to the mass. 29 '36 Along with a direct trophic effect on speculation that denervation of muscle in postpolio muscle, there is reason to believe that growth hor- patients may be influenced by the loss of pulsatile mone might effect neuronal sprouting which ac- GH release that occurs in some older males. 52 Our companies ALS. Although completely denervated data would not support a similar hypothesis for muscle would be unlikely to respond to treatment ALS. it was hoped that remaining motor units might With the recognition that treatment trials in have benefited from hormonal stimulation. 54 ALS have often been faulty in design, considerable While muscle mass and nerve sprouting were not emphasis was placed on trial methodology. Intro- quantified, it is apparent that growth hormone had duction of the TQNE has provided a new standard minimal therapeutic value as judged by the steady for evaluation of ALS patients in clinical trials. decline of strength in the treated group, suggest- This measurement proved to be highly reproduc- ing that any salutary effects of treatment were ible and appeared to quantitatively describe the overwhelmed by the extent of the degenerative course of the disease. This result, previously re- process which characterizes ALS. ported by others, was expected. (8,45) Comparing the It is now known that most, if not all, GH effects TQNE to manual testing, it was found that the are mediated by IGF-1. It has also been shown that TQNE more accurately chronicles deterioration of GH regulates gene expression of IGF-I in the liver. strength that characterizes ALS, especially when Although hepatic synthesis appears to be the major weakness is advanced. Serial clinical assessment led source of serum IGF-1, evidence exists for the local to the interesting observation that deterioration of production by various tissues that also respond to arm strength was a predictor of early death or GH, including muscle. 1 7Although we have dem- withdrawal from the study, independent of the onstrated that administration of exogenous growth mode of therapy. Since diaphragmatic failure is hormone results in an almost twofold increase in the most common cause of death in ALS it is not total serum IGF-1, we did not determine whether surprising that loss of arm strength is an ominous IGF-I was increased in muscle of treated patients. sign. The diaphragm and upper extremity muscles Furthermore, we measured only total, rather than both receive innervation from the midcervical re- free and bound IGF-I in our study. Recently, cir- gion, which is preferentially effected in ALS.(59) culating binding proteins for the IGFs have been Unfortunately, measurement of 3-methylhisti- demonstrated.(5) Of the six IGF -binding proteins dine in the urine, a chemical marker for muscle (IGFBPS) which have been sequenced and cloned, degeneration, 35,57 did not correlate with the IGFBP- I and IGFBP-3 are the most abundant. It is course of ALS. Excretion of this amino acid did not now known that IGFBP-3 is induced by GH ad- change appreciably over time and differences be- ministration,'o whereas direct administration of tween placebo and rhgh-treated ALS patients rhlGF-I does not induce this GH-regulated were not evident. This is consistent with results in IGFBP. Accordingly, one explanation for the lack normal sub .ects in whom exogenous administra- of therapeutic effect of exogenous rhGH could be tion of GH did not effect 3-methylhistidine excre- that much of the IGF-I that was induced was in the 35 tion, which is thought to be a marker of myo bound form. Further, the lack of effect could be fibrillar protein breakdown. 57 This data further accounted for on the basis of IGF-I inhibitors or suggests that GH cannot moderate muscle break- antagonists, faulty interaction with muscle IGF-I down in normal subjects or patients with ALS. receptors or a postreceptor defect in neuron and/ There were a number of reasons we had been or muscle which may characterize this system in optimistic about the treatment of ALS with growth ALS patients. These defects might not be cor- hormone. Exogenous administration of protropin rected through administration of parenteral exerts a profound effect on muscle mass and rhGH. It remains to be determined if delivery of strength in adults with growth hormone defi- pharmacologic doses of rhlGF-I would result in a ciency. 14 This effect is predominantly observed in different therapeutic outcome. limb girdle muscles, probably due to the presence This trial is, to our knowledge, the first to use a of a proximal myopathy associated with growth recombinant molecule as a potential therapy for hormone deficiency. Somewhat similar results amyotrophic lateral sclerosis. Although it is not have been observed in malnourished elderly males unique in reporting the lack of a therapeutic ef- in whom administration of growth hormone has fect, it is novel in that the answer was forthcoming in a relatively short time.19 The history of ALS research is replete with therapeutic claims which have often taken years to resolve. 18 In this respect, it is hoped that the current study offers an exam- ple in which putative therapies may be rapidly tested for efficacy. 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