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The Journal of Clinical Endocrinology & Metabolism Vol. 85, No. 2 569-573
Copyright © 2000 by The Endocrine Society

Original Studies

Near Final Height in Pubertal Growth Hormone (GH)-Deficient Patients Treated with GH Alone or in Combination with Luteinizing Hormone-Releasing Hormone Analog: Results of a Prospective, Randomized Trial1

M. Veronica Mericq, Martha Eggers, Alejandra Avila, Gordon B. Cutler Jr.2 and Fernando Cassorla

Institute of Maternal and Child Research (M.V.M., M.E., A.A., F.C.), University of Chile, Santiago, Chile; and DEB, NICHD (G.B.C.), National Institutes of Health, Bethesda, Maryland 20892

Address correspondence and requests for reprints to: M. Verónica Mericq, IDIMI, University of Chile, Casilla 226-3, Santiago, Chile.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
To study the effects of delaying puberty in GH-deficient (GHD) children, we studied 21 GHD (9 boys, 14 girls), treatment-naive, pubertal patients in a prospective, randomized trial. Their chronological age was 14.3 ± 1.6 yr, and their bone age was 11.3 ± 1.1 yr (mean ± SD) at the beginning of the study. Four patients who developed hypogonadotropic hypogonadism were subsequently excluded from the study. Patients were randomly assigned to receive GH + LH-releasing hormone analog (LHRH-A) (n = 7), or GH alone (n = 10). GH and LHRH-A treatment started simultaneously in each patient. GH (Nutropin) was administered at a dose of 0.1U/kg·day sc, until patients reached a bone age (BA) of 14 yr in girls and 16 yr in boys, and LHRH-A (Lupron depot) was administered at a dose of 300 µg/kg·every 28 days in during 3 yr. We defined GH deficiency as patients with a growth velocity less than 4 cm/yr, BA delay more than 1 yr in relationship to chronological age, GH response to two stimulation tests less than 7 µg/L, associated with low serum insulin-like growth factor I and insulin-like growth factor binding protein 3 levels. Statistical analysis was performed by ANOVA or Kruskall Wallis when variances were not homogeneous. We observed a significant decrease in the rate of BA maturation in the group treated with GH+LHRH-A (1.5 ± 0.2 yr) compared with the group treated with GH alone (4.2 ± 0.5 yr) during the 3 years of LHRH-A therapy (P < 0.05). This delay in BA maturation produced a significant gain in final height in the group treated with GH+LHRH-A, which reached -1.3 ± 0.5 SD score compared with -2.7 ± 0.3 SD score (P < 0.05) in the group treated with GH alone. These results indicate that delaying puberty with LHRH-A in GHD children during treatment with GH increases final height.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
PATIENTS with GH deficiency treated with the currently accepted doses of GH usually attain a mean adult height that is below their target height (1). Final height correlates significantly with pretreatment chronological age, height SD score (SDS), and age at start of puberty (2, 3). One of the factors that may limit achievement of a better final height is an attenuated pubertal growth spurt during GH therapy and/or a shortening of the pubertal process (2, 4, 5, 6). The onset of pubertal development in children with GH deficiency is a two-edged sword because it increases growth velocity, but initiates the process that leads to epiphyseal fusion and terminates linear growth. This hypothesis is supported by the observation that GH-deficient (GHD) patients with associated hypogonadism achieve a greater final height than children with isolated GH deficiency (4, 7).

One of the strategies to optimize final height in GHD patients has been to increase the dose of GH administered per unit of weight during puberty, in an attempt to mimic the physiological increment in GH concentrations that occurs during adolescence (8, 9). In this study, we explored another strategy to optimize final height in pubertal GHD patients by delaying their epiphyseal fusion with LH-releasing hormone analog (LHRH-A) therapy. Administration of such analogs inhibits secretion of gonadotropins and gonadal sex steroids in children with precocious puberty and improves final height (9, 10, 11). We hypothesized that inhibition of sex steroid secretion by LHRH-A would increase final height in pubertal GHD children treated with GH. To test this hypothesis, we conducted a randomized, controlled clinical trial that compared the effects of GH combined with LHRH-A vs. GH alone in the treatment of adolescents with GH deficiency.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Twenty-one GHD adolescents were initially enrolled in this study (9 boys and 14 girls). Their mean initial height was -4.3 ± 1.3 SDS, and their mean predicted adult height was -3.1 ± 1.2 SDS. Their mean chronological age was 14.3 ± 1.6 yr (range, 12–18.5 yr), and their mean bone age (BA) was 11.3 ± 1.1 yr (range, 8.8–13 yr). Mean height velocity before the study was 3 ± 0.3 cm/yr. GH deficiency was defined by clinical criteria, including auxological data, and a GH response to two GH stimulation tests (insulin and clonidine) below 7 µg/L. Most patients had low serum concentrations of insulin-like growth factor (IGF) I and IGF binding protein 3 (IGFBP-3). The GH stimulation tests were performed during early puberty without sex steroid priming. The diagnosis of GH deficiency was made after excluding other identifiable systemic, genetic, skeletal, nutritional, or psychological causes of short stature. The initial clinical characteristics of the 17 patients who completed the study are shown in Table 1Go.


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  		Table 1. Clinical and laboratory data of patients at the study entry

 
Ten patients had isolated GH deficiency, six had associated TSH deficiency, and one had combined TSH and partial cortisol deficiency. Thyroid and cortisol deficiency were treated with replacement doses of T4 and oral hydrocortisone. The diagnosis of puberty was based on clinical assessment by the method of Tanner and a pubertal response to an LHRH test (12). Testicular volume was assessed by the Prader orchidometer. All patients were in early to midpuberty at the beginning of the study (Tanner II to III), with a maximum testicular volume of 10 mL in the boys, and all girls were premenarchal.

The study was approved by the Institutional Review Boards of the NICHD and the San Borja Arriarán Hospital in Santiago, Chile. Informed consent was obtained from at least one parent of each patient. All patients were naive to GH therapy before starting their participation in this study. Patients were randomly assigned to receive either GH plus LHRH-A (six girls, four boys) or GH alone (six girls, five boys). Treatment with GH and LHRH-A started simultaneously. GH (Nutropin; donated by Genentech, South San Francisco, CA) was administered at a dose of 0.1 U/kg · day until achievement of near final height (NFH) defined as a BA of 14 yr in girls and 16 yr in boys. LHRH-A (depot Lupron; donated by TAP Pharmaceuticals, Deerfield, IL) was administered at a dose of 300 µg/kg every 28 days for a fixed period of 3 yr (13).

Patients were evaluated at the beginning of the study and every 3 months with a complete clinical examination which included height, weight, and body proportions. During each assessment, height was measured 10 times by the same observer (AA) with a Harpenden stadiometer. At baseline and every 6 months we obtained a BA, which was determined by the method of Greulich and Pyle, by a single observer blinded to the patient treatment status. Predicted adult height was determined by the Bayley-Pinneau method. In addition, we obtained an early morning (0800 h) serum sample for determination of CBC and blood chemistries, sex steroids, thyroid function, cortisol, and gonadotropins (LH and FSH). After obtaining this baseline sample, we administered 100 µg native LHRH iv and withdrew serum samples at 15, 30, 45, and 60 min for determination of LH and FSH. The interval between the LHRH bolus test and the previous dose of Lupron was approximately 25 days.

Serum LH, FSH, estradiol, and testosterone were measured by RIA (14, 15). The assay for LH and FSH has a sensitivity of 2 mUI/mL, an interassay coefficient of variation (CV) of 8.5% and 10%, respectively, and a intrassay CV of 7% and 8%, respectively. For estradiol and testosterone the detection limit of the assay was 10 pg/mL and 0.1 ng/mL, respectively, and the interassay and intrassay CV were 8% and 10%, respectively. Serum GH was measured by a double antibody RIA (Diagnostic Products Corp., Los Angeles, CA), with a sensitivity of 0.8 ng/mL and an inter- and intrassay CV of 10% and 6.5%, respectively. Serum IGF-I was measured by RIA acid-ethanol extraction (16), and serum IGFBP-3 was measured by immunoradiometric assay with a commercial kit (DSL, Webster, TX). The IGF-I and IGFBP-3 detection limit was 10 ng/mL and 0.05 mg/L, respectively, with a interassay CV of 10.2% and 1.8% and an intrassay CV of 8.6 and 1.1%, respectively. The statistical analysis of the data was performed by ANOVA. Data are expressed as the mean ± SEM.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
A preliminary report of this study regarding predicted height has been published by our group (17). The clinical characteristics of the patients at the beginning of the study are shown in Table 1Go. The patients’ mean chronological age, BA, height, maximum GH concentrations after GH stimulation tests, and midparental height SDS were similar in both groups of patients.

As expected, mean breast and pubic hair development did not change significantly during the 3 years of combined GH and LHRH-A therapy, whereas for the group treated with GH alone, puberty progressed at a normal rate. The median Tanner stage was II in the group treated with GH+LHRH-A and early Tanner III in the group treated with GH alone. Mean testicular volume at the beginning of the study was 7.5 ± 1 mL in the patients treated with GH plus LHRH-A and 6.5 ± 0.8 mL in the patients treated with GH alone. Mean breast Tanner stage at the beginning of the study was 2.8 ± 0.3 in the girls treated with GH plus LHRH-A and 2.8 ± 0.1 in the girls receiving GH alone. During the study, four patients (two boys and two girls) gradually developed clinical and biochemical evidence of permanent hypogonadism and were excluded from the study (three in the GH+LHRH-A-treated group, and one in the GH-treated group).

Treatment with LHRH-A suppressed gonadotropin secretion at all time points during the study (Fig. 1Go). Serum testosterone concentrations were significantly lower in the boys during GH and LHRH-A therapy compared to pretreatment levels and to the concentrations observed in the group receiving GH alone. A similar effect was observed for estradiol levels (Fig. 2Go).



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  		Figure 1. Peak LHRH stimulated gonadotropin serum levels at baseline and during the first 3 yr of the study. The dashed columns represent the group treated with GH+LHRH-A, and the black columns represent the group treated with GH alone. *, P < 0.001; **, P < 0.05.

 


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  		Figure 2. Serum testosterone and estradiol levels at baseline and during the first 3 yr of the study. The dashed columns represent the group treated with GH+LHRH-A, and the black columns represent the group treated with GH alone. *, P < 0.001; **, P < 0.05.

 
As a consequence of gonadotropin and sex steroid suppression, BA progression was delayed in the group receiving GH plus LHRH-A. After the first year of the study, the patients receiving GH combined with LHRH-A had advanced their BA 0.5 ± 0.1 yr compared with 1.4 ± 0.2 yr in the group treated with GH alone. After the second year, the GH+LHRH-A-treated group had advanced its BA 0.9 ± 0.1 yr compared with 2.7 ± 0.3 yr in the group treated with GH alone. After 3 yr, the patients treated with GH+LHRH-A had advanced their BA 1.5 ± 0.2 yr compared with 4.2 ± 0.5 yr in the group treated with GH alone. BA progression was significantly different between the groups at all times (Fig. 3Go). This BA delay produced a greater cumulative increase in height prediction over baseline, as shown in Fig. 4Go. After the first and second year of the study, there was a gain in predicted height over baseline in the group treated with GH+LHRH-A compared with the group treated with GH alone, but this difference did not reach statistical significance. However, after 3 years of therapy, the increase in height prediction was 12.3 ± 1.8 cm in the group treated with GH+LHRH-A compared with 3.3 ± 2.1 cm in the group treated with GH alone (Fig. 4Go, P < 0.005).



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  		Figure 3. Cumulative change of BA during the study. The dashed columns represent the group treated with GH+LHRH-A, and the black columns represent the group treated with GH alone. *, P < 0.001; **, P < 0.005.

 


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  		Figure 4. Cumulative increase in height prediction over baseline. The dashed columns represent the group treated with GH+LHRH-A, and the black columns represent the group treated with GH alone. *, P < 0.005.

 
Growth velocity increased in the group treated with GH+LHRH-A from a baseline of 2.9 ± 0.3 cm/yr to 7.9 ± 0.3 cm/yr at 1 yr (P < 0.001), 5.3 ± 0.5 cm/yr at 2 yr (P < 0.001), and 4.4 ± 0.5 cm/yr at 3 yr (P < 0.02). Growth velocity in the group treated with GH alone increased from 3.0 ± 0.3 cm/yr before therapy to 11.2 ± 0.7 cm/yr at 1 yr (P < 0.001), 6 ± 1.2 cm/yr at 2 yr (P < 0.02), and 2.7 ± 0.7 cm/yr at 3 yr (not significant). As expected, growth velocities were lower in the GH+LHRH-A treated patients, compared with the growth velocities in the group treated with GH alone. However, this difference reached statistical significance only during the first year of the study (P < 0.02).

At the beginning of the study, both groups had a mean height SDS of -4 ± 0.3 SDS, but after finishing GH therapy the group treated with GH+LHRH-A reached a NFH mean of -1.3 ± 0.5 SDS compared with -2.7 ± 0.3 SDS in the group treated with GH alone (P < 0.02). Thus, the improvement in NFH for the group treated with GH plus LHRH-A was 2.7 ± 0.3 SD, whereas the group treated with GH alone had a gain of 1.3 ± 0.1 SD (Fig. 5Go).



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  		Figure 5. Improvement in NFH in SDS compared to initial height in the group treated with GH+LHRH-A (dashed columns) and in the group treated with GH alone (black columns). *, P < 0.02.

 
We should mention that body proportions at the end of the study were not different between the two groups of patients (data not shown). As expected, menarche was achieved at a significantly older chronological age in the girls treated with GH+LHRH-A (18.2 ± 0.4 yr) compared with the girls treated with GH alone (15.9 ± 0.7 yr). The period elapsed between discontinuation of LHRH-A therapy and menarche was 1.2 ± 0.2 yr, whereas the group treated with GH alone experienced menarche 1.7 ± 0.4 yr after starting GH therapy.


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
We report the results of a randomized, prospective clinical trial in pubertal GHD patients. We observed a significant difference in NFH in the patients treated with GH+LHRH-A compared with the patients treated with GH alone, suggesting that combined treatment with GH and LHRH analog improves final height, particularly in pubertal GHD patients with long-standing untreated GH deficiency.

Several strategies have been used to increase final height in patients with GH deficiency. Starting GH therapy as soon as the diagnosis is made may constitute the best approach, as suggested by Grumbach et al. (3) and Blethen et al. (1). However, an inadequate growth spurt and/or a shorter duration of puberty has been reported in GHD patients treated with GH, which may lead to a final height below target height (2).

Another approach is to increase the dose of GH administered per unit of body weight during puberty in an attempt to mimic the physiological increase in GH secretion that normally occurs during this period. A positive correlation has been found between growth velocity and the dose of GH administered to GHD patients, but a faster rate of pubertal progression has been reported with this approach, suggesting that it may compromise final height (8). In contrast, Mauras et al. (9) have recently shown that treatment with an increased dose of GH (0.7 mg/Kg·week) in pubertal GHD children increases height prediction and does not appear to advance skeletal maturation.

Another strategy to increase final height in pubertal patients with GH deficiency is to delay the progression of puberty and, thus, epiphyseal fusion with an LHRH-A. LHRH-A therapy has been shown to increase final height in children with central precocious puberty (11). Preliminary findings suggest that NFH may also increase in children with short stature and a normally timed puberty when they are treated with LHRH-A for 4 yr (18).

The effects of pubertal delay in GHD patients has been reported by several investigators who compared final height of patients with isolated GH deficiency who underwent spontaneous puberty or had associated hypogonadism (4, 5, 7). These authors reported an increased final height in patients with GH deficiency combined with hypogonadism compared with patients with isolated GH deficiency.

Combined GH and LHRH-A therapy has been used for 1 to 2 yr in pubertal GHD children in several protocols without a placebo-control group. Saggesse et al. (19) studied children with isolated GH deficiency and spontaneous puberty and observed a 4.5-cm increase in predicted adult height after 1–2 yr of combined treatment with GH and LHRH-A. Toublanc et al. (20) showed a similar increase in height prediction after administering LHRH-A to 18 GHD children for 1–2 yr. In addition, Tanaka et al. (21) recently published the results of an uncontrolled study assessing the effects of combined treatment with GH and LHRH-A or GH alone on pubertal height gain in 15 boys and 10 girls with GH deficiency. In the study by Tanaka et al. (21), LHRH-A was administered during a period of 5.1 ± 1.5 yr. The pubertal height gain and final height was significantly greater in the group that received GH combined with LHRH-A.

The results of our prospective, randomized study support the concept that pubertal delay in children with GH deficiency increases NFH. The gain in NHF expressed as SDS was 2.7 ± 0.3 SDS in the group treated with GH combined with LHRH-A, whereas it was 1.3 ± 0.1 SDS in the group treated with GH alone. The attained NFH was approximately 4 cm below the predicted final height after 3 yr of LHRH-A therapy (17). Some of this difference may reflect the remaining growth potential at the BA chosen to define NFH. Alternatively, BA may increase faster than normal after LHRH-A therapy is withdrawn, so that not all the gain in predicted final height during LHRH-A may actually be achieved.

Some potentially adverse events may be observed during prolonged LHRH-A therapy in children. We did not observe, however, any differences in body proportions between the groups of patients during the study. The psychological profiles of the patients who participated in this study showed that their first priority was linear growth, whereas pubertal progression was less important, particularly for boys (22). In addition, an assessment of the effects of LHRH-A treatment on bone mineralization is currently underway in these patients.

In summary, we studied 17 pubertal GHD patients in a prospective, randomized, study that compared the effects of treatment with GH combined with LHRH-A with GH alone on NFH. As expected, we observed a significant decrease in the rate of bone maturation in the group treated with GH combined with LHRH-A compared with the group treated with GH alone. The children treated with GH plus LHRH-A reached a NFH of -1.3 ± 0.5 SDS, whereas the children treated with GH alone reached a NFH of -2.7 ± 0.3 SDS. Our results indicate that the addition of LHRH-A to GH during puberty in pubertal GHD children with long-standing untreated GH deficiency increases NFH.


   Acknowledgments
 
We are very grateful for the support of Kenneth Attie, M.D., and Neil Gesundheit, M.D., from Genentech, C. B. Clarke, R.N., and John Page, M.D., from TAP Pharmaceuticals, Lynnette Nieman, M.D. from NICHD, and for the expert secretarial assistance of Mrs. Nancy Zúñiga.


   Footnotes
 
1 Supported in part by Fondecyt Grant 1940543, NICHD, and Genentech. This paper was presented in part at the 81st Annual Meeting of the The Endocrine Society, San Diego, California, 1999. Back

2 Present address: Eli Lilly and Company, Lilly Research Laboratories, Indianapolis, Indiana 46285. Back

Received August 31, 1999.

Revised October 12, 1999.

Accepted October 25, 1999.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

  1. Blethen SL, Baptista J, Kuntze J, Foley T, LaFranchi S, Johanson A. 1997 Adult height in growth hormone (GH)-deficient children treated with biosynthetic GH. The Genentech Growth Study Group. J Clin Endocrinol Metab. 82:418–420.[Abstract/Free Full Text]
  2. Darendeliler F, Hindmarsh PC, Preece MA, Cox L, Brook CG. 1990 Growth hormone increases rate of pubertal maturation. Acta Endocrinol (Copenh). 122:414–416.[Medline]
  3. Grumbach MM, Bin-Abbas BS, Kaplan SL. 1998 The growth hormone cascade: progress and long-term results of growth hormone treatment in growth hormone deficiency. Horm Res. 49:41–57.
  4. Burns EC, Tanner JM, Preece MA, Cameron N. 1981 Final height and pubertal development in 55 children with idiopathic growth hormone deficiency, treated for between 2 and 15 years with human growth hormone. Eur J Pediatr. 137:155–164.[Medline]
  5. Frisch H, Birnbacher R. 1995 Final height and pubertal development in children with growth hormone deficiency after long-term treatment. Horm Res. 43:132–134.[Medline]
  6. Price DA. 1991 Puberty in children with idiopathic growth hormone deficiency on growth hormone treatment: preliminary analysis of the data from the Kabi Pharmacia International Growth Study. Acta Paediatr Scand Suppl. 379:117–124.[Medline]
  7. Hibi I, Tanaka T, Tanae A, et al. 1989 The influence of gonadal function and the effect of gonadal suppression treatment on final height in growth hormone (GH)-treated GH-deficient children. J Clin Endocrinol Metab. 69:221–226.[Abstract]
  8. Stanhope R, Albanese A, Hindmarsh P, Brook CG. 1992 The effects of growth hormone therapy on spontaneous sexual development. Horm Res. 38:9–13.
  9. Mauras N, Reiter EO, Baptista J, Attie KM, Genentech Collaborative Study Group. 1998 Effects of high dose of rhGH therapy in adolescent children with GH deficiency: a randomized, multicenter study. Pediatr Res. 43:81A.
  10. Crowley Jr WF, Comite F, Vale W, Rivier J, Loriaux DL, Cutler Jr GB. 1981 Therapeutic use of pituitary desensitization with a long-acting LHRH agonist: a potential new treatment for idiopathic precocious puberty. J Clin Endocrinol Metab. 52:370–372.[Abstract]
  11. Oerter KE, Manasco P, Barnes KM, Jones J, Hill S, Cutler Jr GB. 1991 Adult height in precocious puberty after long-term treatment with deslorelin. J Clin Endocrinol Metab. 73:1235–1240.[Abstract]
  12. Oerter KE, Uriarte MM, Rose SR, Barnes KM, Cutler Jr GB. 1990 Gonadotropin secretory dynamics during puberty in normal girls and boys. J Clin Endocrinol Metab. 71:1251–1258.[Abstract]
  13. Parker KL, Baens-Bailon RG, Lee PA. 1991 Depot leuprolide acetate dosage for sexual precocity. J Clin Endocrinol Metab. 73:50–52.[Abstract]
  14. Devoto L, Vega M, Navarro V, Sir T, Alba F, Castro O. 1989 Regulation of steroid hormone synthesis by human corpora lutea: failure of follicle-stimulating hormone to support steroidogenesis in vivo and in vitro. Fertil Steril. 51:628–633.[Medline]
  15. Devoto L, Soto E, Magofke AM, Sierralta W. 1980 Unconjugated steroids in the fallopian tube and peripheral blood during the normal menstrual cycle. Fertil Steril. 33:613–617.[Medline]
  16. Garcia H, Henriquez C, Ugarte F, et al. 1996 GH-IGF axis during catch up growth in small for gestational age (SGA) infants. J Pediatr Endocrinol Metab. 9:561–567.[Medline]
  17. Cassorla F, Mericq V, Eggers M, et al. 1997 Effects of luteinizing hormone-releasing hormone analog-induced pubertal delay in growth hormone (GH)-deficient children treated with GH: preliminary results. J Clin Endocrinol Metab. 82:3989–3992.[Abstract/Free Full Text]
  18. Yanovski JA, Rose SR, Filmer KM, et al. 1996 Deslorelin-induced delay of puberty increases adult height of adolescents with short stature: results of a randomized, placebo-controlled trial. Pediatr Res. 39:592.
  19. Saggese G, Cesaretti G, Andreani G, Carlotti C. 1992 Combined treatment with growth hormone and gonadotropin-releasing hormone analogues in children with isolated growth hormone deficiency. Acta Endocrinol (Copenh). 127:307–312.[Medline]
  20. Toublanc JE, Couprie C, Garnier P, Job JC. 1989 The effects of treatment combining an agonist of gonadotropin-releasing hormone with growth hormone in pubertal patients with isolated growth hormone deficiency. Acta Endocrinol (Copenh). 120:795–799.[Medline]
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M. Tauber, B. Berro, V. Delagnes, N. Lounis, B. Jouret, C. Pienkowski, I. Oliver, and P. Rochiccioli
Can Some Growth Hormone (GH)-Deficient Children Benefit from Combined Therapy with Gonadotropin-Releasing Hormone Analogs and GH? Results of a Retrospective Study
J. Clin. Endocrinol. Metab., March 1, 2003; 88(3): 1179 - 1183.
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 J. Clin. Endocrinol. Metab.Home page
V. Mericq, H. Gajardo, M. Eggers, A. Avila, and F. Cassorla
Effects of Treatment with GH Alone or in Combination with LHRH Analog on Bone Mineral Density in Pubertal GH-Deficient Patients
J. Clin. Endocrinol. Metab., January 1, 2002; 87(1): 84 - 89.
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D. Mul, J .M. Wit, W. Oostdijk, and J. Van den Broeck
The Effect of Pubertal Delay by GnRH Agonist in GH-Deficient Children on Final Height
J. Clin. Endocrinol. Metab., October 1, 2001; 86(10): 4655 - 4656.
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 Endocr. Rev.Home page
W. M. Drake, S. J. Howell, J. P. Monson, and S. M. Shalet
Optimizing GH Therapy in Adults and Children
Endocr. Rev., August 1, 2001; 22(4): 425 - 450.
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G. A. Kamp, D. Mul, J. J. J. Waelkens, M. Jansen, H. A. Delemarre-van de Waal, L. Verhoeven-Wind, M. Frolich, W. Oostdijk, and J. M. Wit
A Randomized Controlled Trial of Three Years Growth Hormone and Gonadotropin-Releasing Hormone Agonist Treatment in Children with Idiopathic Short Stature and Intrauterine Growth Retardation
J. Clin. Endocrinol. Metab., July 1, 2001; 86(7): 2969 - 2975.
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G. Saggese, G. Federico, S. Barsanti, and L. Fiore
The Effect of Administering Gonadotropin-Releasing Hormone Agonist with Recombinant-Human Growth Hormone (GH) on the Final Height of Girls with Isolated GH Deficiency: Results from a Controlled Study
J. Clin. Endocrinol. Metab., May 1, 2001; 86(5): 1900 - 1904.
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