| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Original Article |
Oregon Health Sciences University (D.M.C.), Portland, Oregon 97201; Massachusetts General Hospital (B.M.K.B.), Boston, Massachusetts 02114; University of Virginia (M.L.V.), Charlottesville, Virginia 22901; Veterans Affairs Palo Alto Health Care System and Stanford University School of Medicine (A.R.H.), Palo Alto, California 94304; Emory University (L.S.P.), Atlanta, Georgia 30322; Alkermes, Inc. (K.M.F., D.P.B., A.I.), Cambridge, Massachusetts 02139; and Genentech, Inc. (S.L.B., K.M.A., L.N.D., J.D.R., P.J.F.), South San Francisco, California 94080
Address all correspondence and requests for reprints to: David M. Cook, M.D., Department of Medicine/Division of Endocrinology, Oregon Health Sciences University, 3181 SW Sam Jackson Park Road, M/S L-607, Portland, Oregon 97201. E-mail: cookd{at}ohsu.edu.
Abstract
A pharmacokinetic-pharmacodynamic study of a long-acting GH [Nutropin Depot; somatropin (rDNA origin) for injectable suspension] was performed in 25 patients with adult GH deficiency. Single doses of 0.25 mg/kg and 0.5 mg/kg, based on ideal body weight, were administered sc. After either dose, serum GH concentrations rose rapidly in both sexes. In men, the lower dose maintained serum IGF-I levels within 1 SD of the mean for age and sex for 14–17 d; the higher dose raised IGF-I levels 2 SD above the mean. In most women, all of whom were receiving oral estrogen, the lower dose did not normalize IGF-I levels; the higher dose maintained IGF-I near the mean for approximately 14 d. Increases in IGF binding protein-3 and acid-labile subunit levels were observed in both sexes; however, a sex-related difference was not obvious. Fasting glucose and insulin concentrations were transiently elevated in men receiving the higher dose. Patients tolerated the injections well. We concluded that a single injection of Nutropin Depot at these doses in patients with adult GH deficiency increased serum IGF-I to within normal limits for 14–17 d. Estrogen-treated women required approximately twice the dose needed in men to produce comparable IGF-I concentrations.
IN THE UNITED STATES, recombinant human GH (rhGH) has been available for the treatment of adult GH deficiency (AGHD) since 1996. It has become apparent that adults with GH deficiency (GHD) require lower GH doses than do children, tolerating approximately 10–20% of the doses used in children with GHD (1, 2). Although the benefits of GH replacement therapy are well documented, AGHD continues to be an undertreated disease in the United States. One potential barrier to increasing the use of rhGH in this population has been the reluctance of patients to accept the need for daily injections. Therefore, the delivery of rhGH in a manner that eliminates the requirement for daily injections may increase the ability of physicians to successfully treat these patients.
Recently, a long-acting preparation, in which rhGH is encapsulated in biocompatible, biodegradable, polylactide-coglycolide polymer microspheres (Nutropin Depot), has become available. After sc injection, these microspheres degrade slowly so that rhGH is released into the bloodstream over approximately a 1-month period (3). Studies in children with GHD indicate that this formulation, dosed either once or twice a month, is effective in stimulating linear growth, and that side effects related to rhGH excess are not an issue (4). Currently, Nutropin Depot is approved for use in children with GHD in doses of 1.5 mg/kg monthly or 0.75 mg/kg twice monthly. Due to its success in this population, it was logical to investigate the pharmacokinetic and pharmacodynamic properties of this agent in adults with GHD.
Theoretically, there may be concerns about the safety of continuous release of rhGH from a long-acting preparation, for example, sustained elevations in IGF-I concentrations and glucose intolerance in adults. In the present study, we examine the effects of a single dose of Nutropin Depot in AGHD and the resulting impact on serum concentrations of GH, IGF-I, IGF binding protein-3 (IGFBP-3), acid-labile subunit (ALS), insulin, and glucose over a 56-d study period.
Patients and Methods
Patients
Patients were enrolled at five medical centers that specialize in pituitary disorders. Institutional Review Board approval was obtained separately at each institution and patients signed informed consent forms. Fourteen men and 11 women were recruited for the study. Patients were included for study participation if they were in good general health but had adult-onset GHD as determined by standard pharmacological stimulation testing (using insulin, arginine alone, or combined with GHRH, L-dopa, or clonidine). Peak responses to stimulation tests of 2.5 µg/liter or less for two-site GH assays using monoclonal antibodies or 5.0 µg/liter or less for polyclonal GH assays were considered consistent with GHD. Doses of other replacement hormone therapies were stable for 1 month or longer before study participation. All women were receiving oral estrogen replacement therapy. Patients receiving prior GH replacement therapy were required to discontinue treatment for 4 wk or longer before study entry. Patients were excluded if they had a history of malignancy or diabetes mellitus.
Study treatment
Twenty-five patients with AGHD were randomized to receive one dose of Nutropin Depot, 0.25 mg/kg (7 men and 5 women) or 0.5 mg/kg (7 men and 6 women), based on ideal body weight (IBW), by sc injection. IBW was calculated using calipers to measure the width of the bony prominences at the elbow to determine small, medium, or large frame, and compared with an adapted Metropolitan Life Insurance table (5) using the patient’s measured height. This table yielded the IBW in kilograms, which was used for dose calculation.
Study procedures and assay methods
Patients were admitted to each institution’s Clinical Research Center for the initial 48 h after rhGH administration. Blood was collected every 2 h for the first 24 h, then every 4 h for the second 24-h period. After discharge (d 3–28), blood was collected, after an overnight fast, every 3 d, and then weekly during d 29–56. Results for GH and IGF-I serum concentrations are presented through d 28. Measured endpoints included serum GH, IGF-I, IGFBP-3, ALS, glucose, and insulin concentrations. All samples except ALS were analyzed in a central laboratory [Esoterix Center for Clinical Trials (formerly Endocrine Sciences, Inc.), Calabasas Hills, CA]. Serum GH levels were measured using the Esoterix-validated two-site immunochemiluminescence assay that detects serum GH levels as low as 0.05 µg/liter. Concentrations of IGFBP-3 were determined using the Esoterix RIA with a lower limit of 300 µg/liter. IGF-I was measured after extraction using an immunoradiometric assay (Nichols/Quest, San Juan Capistrano, CA) with a lower limit of detection of 13.5 µg/liter. Selected serum ALS levels were measured using the Genentech, Inc. (South San Francisco, CA) colorimetric sandwich ELISA, which has a detection limit of 0.782 mg/liter, with a range of 0.00313–0.100 mg/liter, using a 1:250 dilution (6). This assay uses a monoclonal antibody specific for ALS in the capture phase of the assay and an enzyme-linked monoclonal antibody specific for ALS as the detection antibody. ALS concentrations were obtained by assaying each sample in singlicate with four dilutions each and reporting the median. Using this method, the intra-assay coefficient of variation ranged from 3–14%, and the inter-assay coefficient of variation ranged from 9–14%. Insulin concentrations were measured using immunochemiluminescence assay, with a lower limit of sensitivity of 1.0 µU/ml. Serum glucose concentrations were measured using the Roche (Basel, Switzerland) glucose hexokinase liquid assay, with a lower limit of detection of 2.0 mg/dl.
Analysis
Pharmacokinetics. Derived pharmacokinetic parameters [peak plasma concentration (Cmax), time to peak plasma concentration (Tmax), and areas under the curve (AUCs)] were calculated using standard noncompartmental methods from the serum concentration vs. time values of each patient. Pharmacokinetic calculations were performed using SAS Version 8 (SAS Institute, Inc., Cary, NC). All values were determined using actual collection timepoints. Cmax and Tmax were determined directly from the data, and AUC values were determined using the linear trapezoidal rule. Baseline values were calculated as the average of samples drawn at 1 h and at 5 min before drug administration. For baseline corrected parameters, the average baseline value was subtracted from each concentration-time point before parameter estimation.
Pharmacodynamics.
For pharmacodynamic parameters IGF-I and IGFBP-3, Cmax, Tmax, and AUC intervals (AUC0–7 d, AUC0–14 d, and AUC0–28 d) were calculated. Baseline corrected IGF-I values were used to determine Cmax and AUC values. IGF-I SD scores were calculated using the standard values of mean and SD of serum IGF-I levels (on log scale) by sex and age provided by the central laboratory (Esoterix). The SD score for each patient was calculated as follows: SD score = (log serum level - µ)/
, where µ and are the mean and SD, respectively, of the log-transformed serum IGF-I levels for the age group and sex of the patient.
Statistical analysis.
Two-sample t tests unadjusted for multiple comparisons were performed on untransformed and log-transformed data, as appropriate, to compare treatment arms for the pharmacokinetic and pharmacodynamic parameters of interest. Results are reported as mean ± SD of all available data. Ninety-five percent confidence intervals were constructed for selected parameters. All test procedures were two-sided, and all tests and confidence intervals used 
= 0.05 as the level of significance. P values for the comparisons between the two dose groups and between male and female patients were derived from exact permutation tests performed with Proc StatXact 4 (Cytel Software Corporation, Cambridge, MA).
Results
Baseline characteristics
Table 1
summarizes selected demographic and baseline characteristics for the 25 adults who received a single dose of Nutropin Depot (0.25 or 0.5 mg/kg IBW). Dose groups were similar in age, weight, sex, and etiology of AGHD. At baseline, mean serum concentrations of GH and IGF-I were low in both groups. Only two patients had IGF-I levels within the normal range for age and sex.
|
Serum GH concentrations
Serum GH concentration vs. time profiles for the 0.25 mg/kg and 0.5 mg/kg dose groups are presented in Fig. 1, A and B. Tmax was approximately 12 h in each dose group and was similar in men and women. In men, mean (±SD) peak serum GH concentrations were 11.0 ± 6.0 µg/liter and 20.1 ± 12.9 µg/liter after 0.25 mg/kg and 0.5 mg/kg doses, respectively (Table 2). Serum GH concentrations were similarly dose-dependent in women, with peak concentrations of 7.5 ± 7.0 µg/liter and 18.0 ± 8.5 µg/liter after 0.25 mg/kg and 0.5 mg/kg doses, respectively (Table 2). A similar dose-related effect was observed for the overall GH exposure as measured by AUC. Both initial exposure (AUC0–7 d) and total exposure (AUC0–28 d) demonstrated a dose-related increase in both sexes.
|
|
, A and B, GH serum concentrations declined slowly over the period of study, reaching baseline values at approximately 2–3 wk after injection. As expected, results from the stratified comparison (when adjusted for sex) indicated a significant effect of dose level on both Cmax (P = 0.011) and AUC (P < 0.001 for AUC0–7 d, AUC0–14 d, and AUC0–28 d). However, AUC is not log-transformed, so the greatest exposure occurs early, when sex differences in serum GH concentration are minimal. When the data were adjusted for dose, no significant effect of sex was observed. Although there was no significant difference in overall GH exposure (Cmax, AUC0–7 d, AUC0–14 d, AUC0–28 d) between men and women during the study period, the GH concentrations (although very low) on d 10 post injection were consistently higher in women than in men. Serum IGF-I concentrations
Serum IGF-I concentration vs. time profiles for the 0.25 mg/kg and 0.5 mg/kg dose groups are presented in Fig. 2, A and B. In both men and women, serum IGF-I concentrations rose rapidly above baseline, reaching peak concentrations at approximately 2–6 d post injection (Table 3). IGF-I levels remained above baseline for approximately 14–17 d, returning to baseline levels at approximately 3–4 wk post dose. Because of the differences in baseline IGF-I levels between the study groups, data were baseline-corrected for statistical analyses. Results from the stratified comparison (when adjusted for sex) indicated a significant effect of dose level on both Cmax and AUC (AUC0–7 d, AUC0–14 d, and AUC0–28 d; P < 0.001 for all comparisons). When the data were adjusted for dose, a significant effect of sex was observed in overall IGF-I response (Cmax, AUC0–7 d, AUC0–14 d, AUC0–28 d; P < 0.001 for all parameters listed). This is consistent with previously published data comparing the effects of rhGH on IGF-I response between men and women receiving oral estrogen replacement therapy (8). If one examines the change in IGF-I SD score, the 0.5 mg/kg dose was associated with levels of approximately 2 SD above the mean for more than 10 d in men, whereas the lower dose maintained serum IGF-I levels within 1 SD of the mean for age and sex for 14–17 d (Fig. 3A). In women, the higher dose produced IGF-I SD scores approximating the mean (0 SD) for 14 d, whereas the 0.25 mg/kg dose did not raise scores above -2 SD throughout the period studied (Fig. 3B). These data indicate that sex-specific dosing of Nutropin Depot will be required to achieve similar target IGF-I levels in adult men and women.
|
|
|
Serum IGFBP-3 and ALS concentrations were measured for the 0.25 mg/kg and 0.5 mg/kg dose groups. Summary data are presented in Table 4. In both men and women, IGFBP-3 concentrations increased above baseline for approximately 7–10 d before returning to baseline at approximately 3–4 wk. After adjusting for sex differences, the dose had a significant effect on total exposure (AUC0–28 d; P < 0.05), but not on Cmax. No significant effect of sex was observed for the IGFBP-3 response (Table 4).
|
). ALS levels remained elevated for approximately 2 wk before returning to baseline by 3 wk. However, results from the stratified comparison (when adjusted for sex) indicated a significant effect of dose level on Cmax, but not on total exposure (AUC0–28 d). Similar to the IGFBP-3 data, no significant effect of sex was observed for the ALS response. Serum glucose and insulin concentrations
Fasting serum glucose levels measured over the 56-d period of study are presented for men (Fig. 4A) and women (Fig. 4B) receiving 0.25 mg/kg or 0.5 mg/kg doses of Nutropin Depot. Mean concentrations were transiently increased over the first 7 d in men who had received 0.5 mg/kg doses. Although not markedly elevated over baseline in either men or women after the first week, serum glucose tended to continue to be higher in men than in women. Serum insulin levels were highly variable at baseline (0.25 mg/kg dose group: men, 7.1 ± 6.0 mU/liter; vs. women, 11.2 ± 10.3 mU/liter; 0.5 mg/kg dose group: men, 23.9 ± 33.6 mU/liter; vs. women, 5.6 ± 4.4 mU/liter) and during therapy in both sexes. Serum insulin levels rose in parallel with serum glucose concentrations. Mean peak insulin levels observed during d 1–5 were higher in men than in women (data not shown). Similar to glucose concentrations, insulin levels returned to baseline by d 17 in both sexes.
|
A summary of all reported side effects occurring after Nutropin Depot administration is presented in Table 5. Overall, similar rates of occurrence were observed between the two doses administered. In addition, no differences in frequencies of side effects were noted between sexes. When side effects were further examined in light of GH and IGF-I exposure, no relationship between the appearance of these events and peak serum concentrations or AUC was noted.
|
Discussion
The AGHD syndrome has been well characterized over the last 10 yr (9, 10). A number of features appear to separate this syndrome from childhood GHD. Adults have a greater tendency to experience symptoms such as decreased energy and social isolation (11, 12) and an increased propensity for developing side effects during GH replacement therapy (13, 14). Early experience using IGF-I levels and symptoms to guide dosage adjustments suggests that adults should receive doses of rhGH that are much lower than those used in children (15, 16). In adults, initial rhGH doses should be low to avoid side effects (2), with dose escalation based upon the goal of achieving an IGF-I level within the normal range for age and sex. Although the definitive dosing interval for long-acting rhGH therapy in adults has not been established, data from the present study do offer some guidance for future studies.
The unique formulation of Nutropin Depot allows rhGH to be released from the surface of the microspheres soon after injection, allowing peak GH levels to be achieved within 24–48 h after dosing. IGF-I generation follows, with peak concentrations occurring approximately 2–6 d after injection. After the first 24–48 h, GH serum concentrations slowly decrease, with the longer half-lived IGF-I being maintained within a stable range during the first 14–17 d after drug administration. Based on these findings, doses (based on ABW) of 0.2 mg/kg for men and 0.4 mg/kg for women taking oral estrogens may be adequate to maintain IGF-I concentrations near the mean of the target range for age and sex for approximately 2 wk. It is, however, unclear if maintaining IGF-I levels within this range is adequate for achieving the desired goals in AGHD therapy. Recent studies of daily rhGH suggest that therapy should be initiated at a low dose and titrated to achieve IGF-I levels that target the mean for age and sex (17, 18). These data suggest that a low daily dose of rhGH (0.002–0.006 mg/kg·d) may be sufficient to achieve efficacy. Although this seems logical and some patients given daily rhGH did reach their IGF-I target levels at these doses, improvements in body composition were not consistently reported. Therefore, it may be necessary to titrate the rhGH dose to maintain IGF-I levels in the upper normal range (+1 to +2 SD) to achieve desired efficacy. A more recent study that titrated IGF-I levels to SD scores between the median and the upper end of the age-related reference range did show decreased fat and increased lean body mass (19). Taken together, these findings suggest that Nutropin Depot doses of 0.2–0.4 mg/kg in older men and 0.4–0.6 mg/kg in women taking oral estrogen or in young men may be more appropriate. In addition, a dosing interval of 14 d should be evaluated in a long-term treatment study to determine its appropriateness for both men and women.
Glucose metabolism has also been well studied in adults with GHD and, unlike pediatric patients, who are insulin sensitive when untreated for GHD, adults frequently demonstrate insulin resistance along with obesity and the lipid abnormalities associated with the insulin resistance syndrome (20). GH replacement therapy may enhance insulin resistance initially, with subsequent improvement in insulin sensitivity after fat loss is achieved with chronic treatment. As expected, we observed an initial rise in serum glucose and insulin levels, which was more pronounced in men, and which returned to baseline well before the end of the study period.
The present study validates our current understanding of sex differences in rhGH dose requirements in adults. We have confirmed that women receiving oral estrogen replacement therapy require approximately twice as much rhGH as do adult men to attain IGF-I concentrations within the same range (8). We have demonstrated that sex-related differences in IGF-I responses during GH replacement therapy are not dependent upon sex differences in serum GH concentrations or metabolism. Presumably, the marked differences in IGF-I concentrations between men and women relate to the concomitant administration of oral estrogen in women. Because all women in this study were taking oral estrogens, it is possible that the first-pass effect of estrogen played a significant role in blunting the effect of rhGH on hepatic IGF-I production. Although some have suggested that a decrease in both IGFBP-3 and ALS occurs in response to rhGH in women taking oral estrogens (21), no clear sex-related effect was observed for IGFBP-3 or ALS in our study. It is unclear why we did not observe a difference in IGFBP-3 or ALS response between men and women, although it could be related to a difference between daily and more continuous rhGH therapy or possibly to differences in the assays used to measure these markers.
Efficacy endpoints in adults receiving GH replacement therapy include improvements in quality of life, body composition, and bone density. We do not know whether the reduced fluctuations in serum GH and IGF-I concentrations associated with this long-acting rhGH formulation may improve these outcomes over traditional daily rhGH therapy; if, indeed, side effects such as arthralgia are less of a problem with the depot formulation, it may be possible to achieve target maintenance IGF-I levels more rapidly with this regimen than with daily administration. Both short- and long-term studies comparing daily rhGH injections to continuous sc infusion in AGHD have been performed (7, 22). Minimal differences in efficacy or safety have been observed between these methods of administration, although patients receiving a continuous sc infusion of rhGH tended to have slightly higher IGF-I levels and slightly lower levels of nonesterified fatty acids. This may suggest a lower lipolytic effect in the patients given the continuous infusion.
What is the need for a new preparation of GH, and for that matter, one in depot form? With the availability of a recombinant GH product that is safe and effective when administered daily by the sc route, this is a good question. Currently, daily GH replacement therapy is well tolerated, and few patients who are truly GH deficient will prematurely discontinue treatment because of improvement in their sense of well-being and physical functional abilities. At minimum, a depot preparation should provide equivalent efficacy and safety when compared with the daily preparations already in use. The study herein reported begins to confirm the safety and efficacy of this long-acting formulation in adults with GHD. Other depot preparations such as depot octreotide for acromegaly and long-acting LH-releasing hormone preparations have received enthusiastic acceptance by the endocrine community. The ability to deliver GH in a depot formulation should be very attractive to patients who do not feel comfortable with daily injections and others who may have mental or physical impairments that preclude daily self-injection. Other patients, reluctant to comply with a daily regimen, may accept a trial of twice-monthly GH administration.
How the unique pharmacokinetic and pharmacodynamic profiles of Nutropin Depot translate into long-term efficacy in AGHD needs to be determined in future clinical trials. A twice-monthly rhGH dosing option may improve patient acceptance and, ultimately, compliance if this schedule is proven to be safe and effective in this population.
Summary
This study supports the feasibility of effectively and safely administering Nutropin Depot in adults with GHD. In this study, two different doses of long-acting rhGH (0.25 and 0.5 mg/kg, based on IBW) were associated with clear sex differences in IGF-I response. In this regard, the higher dose of 0.5 mg/kg was more appropriate for women, whereas a lower dose closer to 0.25 mg/kg may be more appropriate in men, with regard to achieving the most desirable IGF-I concentrations. Erythema and induration (nodules) at the injection site occurred in nearly all patients but were not a limiting factor for patient acceptance. Fasting glucose and insulin concentrations rose transiently, but did not reach levels regarded as clinically significant with rhGH dosages that produced IGF-I levels within 1–2 SD of the mean for age and sex for approximately 2 wk. Because this study observed the effects after only one dose of Nutropin Depot over a 56-d period, further evaluation focusing on repeated doses at 2-wk intervals seems warranted to evaluate more long-term efficacy and safety outcomes.
Acknowledgments
We thank the following persons for their technical and/or administrative assistance: Margaret Jenkins, Sarah Pitts, and Karen Pulaski. D.M.C., B.M.K.B., M.L.V., and L.S.P. acknowledge National Institutes of Health–General Clinical Research Center support of the study described herein.
Footnotes
Genentech, Inc., provided financial support for editorial assistance for this paper. The efforts of L.S.P. were supported in part by Grant HS-07922 (Agency for Healthcare Research and Quality/National Institute of Diabetes and Digestive and Kidney Diseases).
Abbreviations: ABW, Actual body weight; AGHD, adult GH deficiency; ALS, acid-labile subunit; AUC, area under the curve; Cmax, maximum concentration; GHD, GH deficiency; IBW, ideal body weight; IGFBP, IGF binding protein; rhGH, recombinant human GH; Tmax, time to maximum concentration.
Received March 27, 2002.
Accepted July 12, 2002.
References
This article has been cited by other articles:
 |
|
 |
|
  J. F Langenheim and W. Y Chen Improving the pharmacokinetics/pharmacodynamics of prolactin, GH, and their antagonists by fusion to a synthetic albumin-binding peptide J. Endocrinol., December 1, 2009; 203(3): 375 - 387. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. Peter, C. Savoy, H.-J. Ji, M. Juhasz, M. Bidlingmaier, and P. Saenger Pharmacokinetic and pharmacodynamic profile of a new sustained-release GH formulation, LB03002, in children with GH deficiency Eur. J. Endocrinol., March 1, 2009; 160(3): 349 - 355. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. L. M. Oliveira, M. H. Aguiar-Oliveira, A. D'Oliveira Jr, R. M. C. Pereira, C. R. P. Oliveira, C. T. Farias, J. A. Barreto-Filho, F. D. Anjos-Andrade, C. Marques-Santos, A. C. Nascimento-Junior, et al. Congenital Growth Hormone (GH) Deficiency and Atherosclerosis: Effects of GH Replacement in GH-Naive Adults J. Clin. Endocrinol. Metab., December 1, 2007; 92(12): 4664 - 4670. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Bidlingmaier, J. Kim, C. Savoy, M. J. Kim, N. Ebrecht, S. de la Motte, and C. J. Strasburger Comparative Pharmacokinetics and Pharmacodynamics of a New Sustained-Release Growth Hormone (GH), LB03002, Versus Daily GH in Adults with GH Deficiency J. Clin. Endocrinol. Metab., August 1, 2006; 91(8): 2926 - 2930. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. R. Hoffman, B. M. K. Biller, D. Cook, J. Baptista, B. L. Silverman, L. Dao, K. M. Attie, P. Fielder, T. Maneatis, B. Lippe, et al. Efficacy of a Long-Acting Growth Hormone (GH) Preparation in Patients with Adult GH Deficiency J. Clin. Endocrinol. Metab., December 1, 2005; 90(12): 6431 - 6440. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. F. Kemp, P. J. Fielder, K. M. Attie, S. L. Blethen, E. O. Reiter, K. M. Ford, M. Marian, L. N. Dao, H. J. Lee, and P. Saenger Pharmacokinetic and Pharmacodynamic Characteristics of a Long-Acting Growth Hormone (GH) Preparation (Nutropin Depot) in GH-Deficient Children J. Clin. Endocrinol. Metab., July 1, 2004; 89(7): 3234 - 3240. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. R. Hoffman, J. E. Kuntze, J. Baptista, H. B. A. Baum, G. P. Baumann, B. M. K. Biller, R. V. Clark, D. Cook, S. E. Inzucchi, D. Kleinberg, et al. Growth Hormone (GH) Replacement Therapy in Adult-Onset GH Deficiency: Effects on Body Composition in Men and Women in a Double-Blind, Randomized, Placebo-Controlled Trial J. Clin. Endocrinol. Metab., May 1, 2004; 89(5): 2048 - 2056. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Endocrinology | Endocrine Reviews | J. Clin. End. & Metab. |
| Molecular Endocrinology | Recent Prog. Horm. Res. | All Endocrine Journals |
