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Can growth hormone treatment in boys without growth hormone deficiency impair testicular function?
CLINCIAL AND LABORATORY OBSERVATIONS
C
Can growth hormone treatment in boys without
growth hormone deficiency impair testicular function? Silvano Bertelloni, MD, Giampiero I. Baroncelli, MD, Paolo Viacava, MD, Mauro Massimetti, MD, Paolo Simi, PhD, and Giuseppe Saggese, MD
Four young male subjects (age range, 17 ⁄12 to 25 ⁄12 years), previously treated with human growth hormone for non-growth hormone–dependent short stature, showed reduced testicular volume and hypergonadotropic hypogonadism. They also showed impaired spermatogenesis and altered testicular texture as determined by ultrasonography. No clinical or laboratory finding showed disease associated with testicular dysfunction. An unfavorable gonadal outcome could occur in boys without growth hormone deficiency treated with human growth hormone. (J Pediatr 1999;135:367-70) 4
With the unlimited supply of human growth hormone made available by recombinant DNA techniques, the use of growth hormone is expanding not only to children with GH deficiency
From the Adolescent and Pediatric Endocrine Units, II Pediatric Division, Department of Reproductive Medicine and Pediatrics; Pathology Laboratory, Department of Oncology; and Cytogenetic and Molecular Biology Laboratory, University of Pisa, “Santa Chiara” Hospital, Pisa, Italy.
Submitted for publication Nov 9, 1998; revision received Feb 23, 1999; accepted Apr 16, 1999. Reprint requests: Silvano Bertelloni, MD, Department of Reproductive Medicine and Pediatrics, II Pediatric Division, “Santa Chiara” Hospital, Via Roma 67, I-56125 Pisa, Italy. Copyright © 1999 by Mosby, Inc. 0022-3476/99/$8.00 + 0 9/22/99338
5
but also to those with non-GH-deficient short stature.1,2 Although replacement GH therapy in patients with GH deficiency is extremely safe,1 safety data for long-term administration of GH in subjects without GH deficiency are largely not available.
ed with hGH (0.6-1.0 IU/kg/wk, given subcutaneously, subdivided in 6 weekly injections) for non-GH-deficient short stature (Tables I and II) were referred to us because of low testicular volume (Table II). In patient 4 the diagnosis was presumptive and based on family history and auxological findings. Patients 1, 2, and 3 had received recombinant hGH; patient 4 had been enrolled in a trial with pituitary derived hGH from the ages of 67⁄12 years to 89⁄12 years; subsequently, he stopped the treatment for 1.5 years and was then treated with recombinant hGH. FSH GH hGH LH SDS
Follicle-stimulating hormone Growth hormone Human growth hormone Luteinizing hormone Standard deviation score
See editorial, p. 278. Here, we report 4 patients with nonGH-deficient short stature who received long-term hGH therapy and showed impaired testicular function in late adolescence or young adulthood.
METHODS Patients Four male subjects from 2 regions of middle Italy who were previously treat-
The onset of puberty was appropriate (patients 2 and 3) or delayed (patients 1 and 4, confirming the presumptive diagnosis) for male subjects.3 No patient had a history of low birth weight. All patients were ambulatory, had normal physical activity, and were non-drinkers and non-smokers; none had a history of diseases or were taking drugs known to affect gonadal function. Ultrasound scanning of the testes ruled out subclinical varicocele. 367
BERTELLONI ET AL
THE JOURNAL OF PEDIATRICS SEPTEMBER 1999
Table I. Clinical data at the start of hGH treatment
Patient No. 1 2 3 4 Median
Age (y)
Bone age (y)
Height SDS
PAH SDS
MPH SDS
14 ⁄12 106⁄12 84⁄12 67⁄12 95⁄12
13.0 77⁄12 — 5.0 76⁄12
–1.55 –2.48 –2.72 –2.25 –2.36
–0.55 –1.11 — — —
0.87 –1.46 –0.22 –0.90 –0.56
8
LH (IU/L)
FSH (IU/L)
Basal
Peak
Basal
Peak
Diagnosis
1.2 0.6* 0.6 —
4.2 — 5.5* —
1.4 1.9* 0.9 —
5.7 — 6.4* —
CDP ISS ISS CDP
PAH, Predicted adult height; MPH, mid-parental height; CDP, constitutional delay of puberty; ISS, idiopathic short stature. *Determined by radioimmunoassay method.
Table II. Clinical data from this study
Patient No. 1 2 3 4 Median
Age (y)
Height SDS
194⁄12 183⁄12 174⁄12 255⁄12 189⁄12
0.31 –1.43 –2.21 –1.06 –1.24
Mean testicular volume mL SDS 11 11 9 14 11
–4.88 –4.88 –5.65 –3.72 –4.88
Penis SDS
Pubic hair stage
0.75 –0.37 1.50 –0.69 0.19
5 5 5 5
Duration of hGH therapy (y) 4.3 7.5 8.2 12.4 7.8
Table III. Laboratory findings of the patients at time of this study
Patient No. 1 2 3 4 NV
LH (IU/L)
FSH (IU/L)
Basal
Peak
Basal
9.6 2.6 14.6 6.8 0.5-5.0†
100.8 52.7 81.4 46.0 6.0-21.0†
20.6 6.3 13.5 6.0 0.8-4.4†
Testosterone Peak (nmol/L)
44.4 31.3 29.0 18.3 1.5-8.0†
17.3 10.0 11.8 6.9 10-35
Semen volume (mL)
Sperm concentration (mL)
Normal motility (%)
Normal morphology (%)
2.2 3.2 3.5* 1.9 ≥2.0‡
12.0 × 106 10.0 × 106 6.2 × 106* 4.5 × 106 ≥20 × 106‡
25 24 27* 33 ≥50‡
14 36 42§ 22 ≥30‡
NV, Normal value. *Normal values: sperm concentration, 42.8 ± 24.5 × 106; motility, 44.1% ± 18.4%; morphology, 41.5% ± 18.8%.8 †Normal values from Roger M, Lahlou N, Lindner D, Chaussain JL. Gonadotropin-releasing hormone testing in pediatrics. In: Ranke MB, editor. Functional endocrinologic diagnostics in children and adolescents. Mannheim: J&J Verlag; 1992. p. 229-47. ‡Normal values from World Health Organization.7
Measurements Height was expressed as standard deviation score in comparison with published tables.4 Pubertal development was determined according to Tanner and Whitehouse.3 Mid-parental height was obtained by the measured parental heights [(Father’s height + Mother’s height + 12.5 cm) ÷ 2)]. Final height 368
was defined as a bone age greater than 17 years. Testicular size was measured with a Prader orchidometer (Child Growth Foundation, London, UK). Testicular volume was the real measured value and the SDS in comparison with normative data.5 A standard gonadotropin-releasing hormone test (100 µg, given intravenously) was performed
to assess gonadotropin secretion after basal samples for luteinizing hormone, follicle-stimulating hormone, and testosterone were obtained. LH and FSH were assayed by commercially available immunoradiometric assay kits, and testosterone by standard radioimmunoassay kit. Cytogenetic analysis was performed on peripheral blood
BERTELLONI ET AL
THE JOURNAL OF PEDIATRICS VOLUME 135, NUMBER 3 leukocytes, and karyotypes were determined by examining at least 40 to 50 metaphases from each patient by standard techniques; Yq microdeletions for the sequences of regulatory testis function (Y-specific sequence-tagged sites) were checked in 3 patients (patients 2, 3, and 4).6 Semen analysis was done according to the recommended procedure.7 For the patient with chronological age less than 18 years, the normative values were those obtained in healthy Italian adolescents.8 Testicular structure was analyzed by ultrasound scanning of the testes. Informed consent was obtained from the parents of each patient when the chronological age was lower than 18 years and directly from each subject who was older than 18 years; the ethics committees for human investigation of our departments approved the study.
RESULTS Clinical Findings Final height was smaller than midparental height in all but one patient (Tables I and II). Pubic hair stage and penis length were adequate, but testicular volume was decreased in all patients (Table II). Retrospective analysis of patients’ medical records demonstrated normal testicular volume at the beginning of hGH therapy (Figure). Testicular volume decreased during hGH administration and did not worsen in patients 3 and 4 after the discontinuation of therapy (Figure).
Laboratory Data Baseline LH and FSH levels were above normal in all but one patient; peak LH and FSH values were increased (Table III). Available data showed normal LH and FSH values in patients 1, 2, and 3 before therapy (Table I). Testosterone levels were low or in the low-normal range (Table III). Semen analysis revealed oligo-asthenospermia in all patients (Table III). Karyotype was 46,XY; no Yq microdeletion was identified.
Figure. Individual testicular volume in patients 1 to 4 at beginning of (first time point) and during hGH administration; follow-up after discontinuation of therapy in patients 3 and 4 is also shown. Vertical arrows indicate discontinuation of hGH therapy; horizontal dotted line indicates the –2 SDS.
In all but one patient (patient 1), ultrasound scanning of the testes demonstrated altered echogenic pattern of testicular texture with areas of increased and decreased echogenicity.
DISCUSSION We found reduced testicular volume and both exocrine and endocrine gonadal dysfunction in a heterogeneous group of young male subjects previously treated with hGH for short stature not caused by GH deficiency. Retrospective analysis of patients’ files showed a decrease in testicular volume during therapy. Extensive historical, clinical, and laboratory investigations did not identify other known causes of the gonadal alterations.9 Both experimental and clinical evidences suggest that GH exerts regulatory effects on the male gonads.10 GH acts, likely by enhancing gonadotropin effects on Leydig and Sertoli cells, through local insulin-like growth factor I or other growth factor production.10-12 The shorter duration of the pubertal period that occurs during hGH treatment may represent clinical evidence of the hyperstimulatory effect of GH on gonadal function.13,14
An increase of apoptosis-mediated cell death and intravascular accidents leading to testicular damage has been demonstrated after abnormal gonadal hyperstimulation with gonadotropins.15,16 Recently, experimental investigation in dogs demonstrated that short-term administration of pharmacologic doses of GH caused reduction of testicular volume, degeneration of germ cells, disruption of spermatogenesis, and epithelial atrophy.17 In addition to exocrine gonadal damage, we found increased LH values, suggesting Leydig cell damage as well. Although the experimental data15-17 may explain the exocrine alterations we found, the origin of the endocrine damage requires additional study. It may be supposed that in GHsufficient boys, adjunctive hGH administration may lead to unphysiologic overproduction of intra-testicular regulatory peptides and/or steroids that impair testicular development. This effect could be maximal in critical periods of life, as suggested by the rapid decrease of testicular volume in pubertal years. Although we studied a small group of patients, our data add some concerns about indiscriminate use of GH in GHsufficient boys.18 Careful studies should be programmed in larger series of young men who have received long-term hGH 369
BERTELLONI ET AL
THE JOURNAL OF PEDIATRICS SEPTEMBER 1999
therapy for non-GH-deficient short stature to elucidate potential side effects of the hormone on the testes.
7.
REFERENCES 1. Frish H. Clinical review of pediatric indications for treatment with growth hormone. In: Ranke MB, editor. Growth hormone over the human life span. Heidelberg-Leipzig: J. A. Barth Verlag (Edition J & J); 1998. p. 8-24. 2. Rosenfeld RG. Is growth hormone just a tall story? J Pediatr 1997;130:172-4. 3. Tanner JM, Whitehouse RH. Clinical longitudinal standards for height, weight, height velocity, weight velocity and stages of puberty. Arch Dis Child 1976:51:170-9. 4. Tanner JM, Whitehouse RH, Takaishi M. Standards from birth to maturity for height, weight, height velocity and weight velocity: British children–1965. Arch Dis Child 1966;41:454–71, 613–34. 5. Taranger J, Engstrom I, Lichtenstein H, Svennberg-Redegren I. Somatic pubertal development. Acta Paediatr Scand Suppl 1976;(258):121-35. 6. Foresta C, Ferlin A, Garolla A, Rossato M, Barbaux S, De Bortoli, A.
8.
9.
10.
11.
12.
Y-chromosome deletion in idiopathic severe testiculopathies. J Clin Endocrinol Metab 1997;82:1075-80. World Health Organization. WHO laboratory manual for the examination of human semen and sperm-cervical mucus interaction. 3rd ed. Cambridge (UK): Cambridge University Press; 1992. Paris E, Menchetti A, De Lazzaro E, Marrocco M, Nuzzo C, Radicioni A. The spermiogram in adolescence [abstract]. Minerva Pediatr 1998;50:303. Griffin JE, Wilson JD. Disorders of the testes and the male reproductive tract. In: Wilson JD, Foster DW, editors. Wilsons textbook of endocrinology. Philadelphia: WB Saunders; 1992. p. 799-852. Spiteri-Grech J, Neischlag E. The role of growth hormone and insulin-like growth factor I in the regulation of male reproductive function. Horm Res 1992;38(suppl 1):22-7. Chatelain PG, Avallet MO, Nicolino M, Lejeune H, Clark A, Chuzel F, et al. Insulin-like growth factor I actions on steroidogenesis. Acta Paediatr Suppl 1994;399:176-7. De Boer JAM, Schoemaker J, van der Veen EA. Impaired reproductive function in women treated for growth hormone deficiency. Clin Endocrinol (Oxf) 1997;46:681-9.
13. Kawai M, Momoi T, Yorifuji T, Yamanaka C, Sasaki H, Furusho K. Unfavorable effects of growth hormone therapy on the final height of boys with short stature not caused by growth hormone deficiency. J Pediatr 1997;130:205-9. 14. Darendeliler F, Hindmarsh PC, Preece MA, Cox L, Brook CGD. Growth hormone increases rate of pubertal maturation. Acta Endocrinol (Copenh) 1990;122:416-6. 15. Dunkel L, Taskinen S, Hovatta O, Tilly JL, Wikstrom S. Germ cell apoptosis after treatment of cryptorchidism with human chorionic gonadotropin is associated with impaired reproductive function in the adult. J Clin Invest 1997;100:2341-6. 16. Kaleva M, Arsalo A, Louhimo I, Rapola J, Perheentupa J, Henriksen K, et al. Treatment with human chorionic gonadotrophin for cryptorchidism: clinical and histological effects. Int J Androl 1996;19:293-8. 17. Siogren I, Jonson M, Madej A, Hohansson HE, Ploen L. Effects of very high doses of human growth hormone (hGH) on male reproductive system in the dog. Andrologia 1998;30:37-42. 18. Brook CGD. Views on growth hormone treatment in idiopathic shortness of stature. Acta Paediatr 1998;87: 485-6.
To receive the table of contents by e-mail, send an e-mail message to: [email protected] Leave the subject line blank, and type the following as the body of your message: Subscribe jpeds_toc You can also sign up through our website at: http://www.mosby.com/jpeds You will receive an e-mail to confirm that you have been added to the mailing list. Note that TOC e-mails will be sent out when a new issue is posted to the web site.
370
C
Can growth hormone treatment in boys without
growth hormone deficiency impair testicular function? Silvano Bertelloni, MD, Giampiero I. Baroncelli, MD, Paolo Viacava, MD, Mauro Massimetti, MD, Paolo Simi, PhD, and Giuseppe Saggese, MD
Four young male subjects (age range, 17 ⁄12 to 25 ⁄12 years), previously treated with human growth hormone for non-growth hormone–dependent short stature, showed reduced testicular volume and hypergonadotropic hypogonadism. They also showed impaired spermatogenesis and altered testicular texture as determined by ultrasonography. No clinical or laboratory finding showed disease associated with testicular dysfunction. An unfavorable gonadal outcome could occur in boys without growth hormone deficiency treated with human growth hormone. (J Pediatr 1999;135:367-70) 4
With the unlimited supply of human growth hormone made available by recombinant DNA techniques, the use of growth hormone is expanding not only to children with GH deficiency
From the Adolescent and Pediatric Endocrine Units, II Pediatric Division, Department of Reproductive Medicine and Pediatrics; Pathology Laboratory, Department of Oncology; and Cytogenetic and Molecular Biology Laboratory, University of Pisa, “Santa Chiara” Hospital, Pisa, Italy.
Submitted for publication Nov 9, 1998; revision received Feb 23, 1999; accepted Apr 16, 1999. Reprint requests: Silvano Bertelloni, MD, Department of Reproductive Medicine and Pediatrics, II Pediatric Division, “Santa Chiara” Hospital, Via Roma 67, I-56125 Pisa, Italy. Copyright © 1999 by Mosby, Inc. 0022-3476/99/$8.00 + 0 9/22/99338
5
but also to those with non-GH-deficient short stature.1,2 Although replacement GH therapy in patients with GH deficiency is extremely safe,1 safety data for long-term administration of GH in subjects without GH deficiency are largely not available.
ed with hGH (0.6-1.0 IU/kg/wk, given subcutaneously, subdivided in 6 weekly injections) for non-GH-deficient short stature (Tables I and II) were referred to us because of low testicular volume (Table II). In patient 4 the diagnosis was presumptive and based on family history and auxological findings. Patients 1, 2, and 3 had received recombinant hGH; patient 4 had been enrolled in a trial with pituitary derived hGH from the ages of 67⁄12 years to 89⁄12 years; subsequently, he stopped the treatment for 1.5 years and was then treated with recombinant hGH. FSH GH hGH LH SDS
Follicle-stimulating hormone Growth hormone Human growth hormone Luteinizing hormone Standard deviation score
See editorial, p. 278. Here, we report 4 patients with nonGH-deficient short stature who received long-term hGH therapy and showed impaired testicular function in late adolescence or young adulthood.
METHODS Patients Four male subjects from 2 regions of middle Italy who were previously treat-
The onset of puberty was appropriate (patients 2 and 3) or delayed (patients 1 and 4, confirming the presumptive diagnosis) for male subjects.3 No patient had a history of low birth weight. All patients were ambulatory, had normal physical activity, and were non-drinkers and non-smokers; none had a history of diseases or were taking drugs known to affect gonadal function. Ultrasound scanning of the testes ruled out subclinical varicocele. 367
BERTELLONI ET AL
THE JOURNAL OF PEDIATRICS SEPTEMBER 1999
Table I. Clinical data at the start of hGH treatment
Patient No. 1 2 3 4 Median
Age (y)
Bone age (y)
Height SDS
PAH SDS
MPH SDS
14 ⁄12 106⁄12 84⁄12 67⁄12 95⁄12
13.0 77⁄12 — 5.0 76⁄12
–1.55 –2.48 –2.72 –2.25 –2.36
–0.55 –1.11 — — —
0.87 –1.46 –0.22 –0.90 –0.56
8
LH (IU/L)
FSH (IU/L)
Basal
Peak
Basal
Peak
Diagnosis
1.2 0.6* 0.6 —
4.2 — 5.5* —
1.4 1.9* 0.9 —
5.7 — 6.4* —
CDP ISS ISS CDP
PAH, Predicted adult height; MPH, mid-parental height; CDP, constitutional delay of puberty; ISS, idiopathic short stature. *Determined by radioimmunoassay method.
Table II. Clinical data from this study
Patient No. 1 2 3 4 Median
Age (y)
Height SDS
194⁄12 183⁄12 174⁄12 255⁄12 189⁄12
0.31 –1.43 –2.21 –1.06 –1.24
Mean testicular volume mL SDS 11 11 9 14 11
–4.88 –4.88 –5.65 –3.72 –4.88
Penis SDS
Pubic hair stage
0.75 –0.37 1.50 –0.69 0.19
5 5 5 5
Duration of hGH therapy (y) 4.3 7.5 8.2 12.4 7.8
Table III. Laboratory findings of the patients at time of this study
Patient No. 1 2 3 4 NV
LH (IU/L)
FSH (IU/L)
Basal
Peak
Basal
9.6 2.6 14.6 6.8 0.5-5.0†
100.8 52.7 81.4 46.0 6.0-21.0†
20.6 6.3 13.5 6.0 0.8-4.4†
Testosterone Peak (nmol/L)
44.4 31.3 29.0 18.3 1.5-8.0†
17.3 10.0 11.8 6.9 10-35
Semen volume (mL)
Sperm concentration (mL)
Normal motility (%)
Normal morphology (%)
2.2 3.2 3.5* 1.9 ≥2.0‡
12.0 × 106 10.0 × 106 6.2 × 106* 4.5 × 106 ≥20 × 106‡
25 24 27* 33 ≥50‡
14 36 42§ 22 ≥30‡
NV, Normal value. *Normal values: sperm concentration, 42.8 ± 24.5 × 106; motility, 44.1% ± 18.4%; morphology, 41.5% ± 18.8%.8 †Normal values from Roger M, Lahlou N, Lindner D, Chaussain JL. Gonadotropin-releasing hormone testing in pediatrics. In: Ranke MB, editor. Functional endocrinologic diagnostics in children and adolescents. Mannheim: J&J Verlag; 1992. p. 229-47. ‡Normal values from World Health Organization.7
Measurements Height was expressed as standard deviation score in comparison with published tables.4 Pubertal development was determined according to Tanner and Whitehouse.3 Mid-parental height was obtained by the measured parental heights [(Father’s height + Mother’s height + 12.5 cm) ÷ 2)]. Final height 368
was defined as a bone age greater than 17 years. Testicular size was measured with a Prader orchidometer (Child Growth Foundation, London, UK). Testicular volume was the real measured value and the SDS in comparison with normative data.5 A standard gonadotropin-releasing hormone test (100 µg, given intravenously) was performed
to assess gonadotropin secretion after basal samples for luteinizing hormone, follicle-stimulating hormone, and testosterone were obtained. LH and FSH were assayed by commercially available immunoradiometric assay kits, and testosterone by standard radioimmunoassay kit. Cytogenetic analysis was performed on peripheral blood
BERTELLONI ET AL
THE JOURNAL OF PEDIATRICS VOLUME 135, NUMBER 3 leukocytes, and karyotypes were determined by examining at least 40 to 50 metaphases from each patient by standard techniques; Yq microdeletions for the sequences of regulatory testis function (Y-specific sequence-tagged sites) were checked in 3 patients (patients 2, 3, and 4).6 Semen analysis was done according to the recommended procedure.7 For the patient with chronological age less than 18 years, the normative values were those obtained in healthy Italian adolescents.8 Testicular structure was analyzed by ultrasound scanning of the testes. Informed consent was obtained from the parents of each patient when the chronological age was lower than 18 years and directly from each subject who was older than 18 years; the ethics committees for human investigation of our departments approved the study.
RESULTS Clinical Findings Final height was smaller than midparental height in all but one patient (Tables I and II). Pubic hair stage and penis length were adequate, but testicular volume was decreased in all patients (Table II). Retrospective analysis of patients’ medical records demonstrated normal testicular volume at the beginning of hGH therapy (Figure). Testicular volume decreased during hGH administration and did not worsen in patients 3 and 4 after the discontinuation of therapy (Figure).
Laboratory Data Baseline LH and FSH levels were above normal in all but one patient; peak LH and FSH values were increased (Table III). Available data showed normal LH and FSH values in patients 1, 2, and 3 before therapy (Table I). Testosterone levels were low or in the low-normal range (Table III). Semen analysis revealed oligo-asthenospermia in all patients (Table III). Karyotype was 46,XY; no Yq microdeletion was identified.
Figure. Individual testicular volume in patients 1 to 4 at beginning of (first time point) and during hGH administration; follow-up after discontinuation of therapy in patients 3 and 4 is also shown. Vertical arrows indicate discontinuation of hGH therapy; horizontal dotted line indicates the –2 SDS.
In all but one patient (patient 1), ultrasound scanning of the testes demonstrated altered echogenic pattern of testicular texture with areas of increased and decreased echogenicity.
DISCUSSION We found reduced testicular volume and both exocrine and endocrine gonadal dysfunction in a heterogeneous group of young male subjects previously treated with hGH for short stature not caused by GH deficiency. Retrospective analysis of patients’ files showed a decrease in testicular volume during therapy. Extensive historical, clinical, and laboratory investigations did not identify other known causes of the gonadal alterations.9 Both experimental and clinical evidences suggest that GH exerts regulatory effects on the male gonads.10 GH acts, likely by enhancing gonadotropin effects on Leydig and Sertoli cells, through local insulin-like growth factor I or other growth factor production.10-12 The shorter duration of the pubertal period that occurs during hGH treatment may represent clinical evidence of the hyperstimulatory effect of GH on gonadal function.13,14
An increase of apoptosis-mediated cell death and intravascular accidents leading to testicular damage has been demonstrated after abnormal gonadal hyperstimulation with gonadotropins.15,16 Recently, experimental investigation in dogs demonstrated that short-term administration of pharmacologic doses of GH caused reduction of testicular volume, degeneration of germ cells, disruption of spermatogenesis, and epithelial atrophy.17 In addition to exocrine gonadal damage, we found increased LH values, suggesting Leydig cell damage as well. Although the experimental data15-17 may explain the exocrine alterations we found, the origin of the endocrine damage requires additional study. It may be supposed that in GHsufficient boys, adjunctive hGH administration may lead to unphysiologic overproduction of intra-testicular regulatory peptides and/or steroids that impair testicular development. This effect could be maximal in critical periods of life, as suggested by the rapid decrease of testicular volume in pubertal years. Although we studied a small group of patients, our data add some concerns about indiscriminate use of GH in GHsufficient boys.18 Careful studies should be programmed in larger series of young men who have received long-term hGH 369
BERTELLONI ET AL
THE JOURNAL OF PEDIATRICS SEPTEMBER 1999
therapy for non-GH-deficient short stature to elucidate potential side effects of the hormone on the testes.
7.
REFERENCES 1. Frish H. Clinical review of pediatric indications for treatment with growth hormone. In: Ranke MB, editor. Growth hormone over the human life span. Heidelberg-Leipzig: J. A. Barth Verlag (Edition J & J); 1998. p. 8-24. 2. Rosenfeld RG. Is growth hormone just a tall story? J Pediatr 1997;130:172-4. 3. Tanner JM, Whitehouse RH. Clinical longitudinal standards for height, weight, height velocity, weight velocity and stages of puberty. Arch Dis Child 1976:51:170-9. 4. Tanner JM, Whitehouse RH, Takaishi M. Standards from birth to maturity for height, weight, height velocity and weight velocity: British children–1965. Arch Dis Child 1966;41:454–71, 613–34. 5. Taranger J, Engstrom I, Lichtenstein H, Svennberg-Redegren I. Somatic pubertal development. Acta Paediatr Scand Suppl 1976;(258):121-35. 6. Foresta C, Ferlin A, Garolla A, Rossato M, Barbaux S, De Bortoli, A.
8.
9.
10.
11.
12.
Y-chromosome deletion in idiopathic severe testiculopathies. J Clin Endocrinol Metab 1997;82:1075-80. World Health Organization. WHO laboratory manual for the examination of human semen and sperm-cervical mucus interaction. 3rd ed. Cambridge (UK): Cambridge University Press; 1992. Paris E, Menchetti A, De Lazzaro E, Marrocco M, Nuzzo C, Radicioni A. The spermiogram in adolescence [abstract]. Minerva Pediatr 1998;50:303. Griffin JE, Wilson JD. Disorders of the testes and the male reproductive tract. In: Wilson JD, Foster DW, editors. Wilsons textbook of endocrinology. Philadelphia: WB Saunders; 1992. p. 799-852. Spiteri-Grech J, Neischlag E. The role of growth hormone and insulin-like growth factor I in the regulation of male reproductive function. Horm Res 1992;38(suppl 1):22-7. Chatelain PG, Avallet MO, Nicolino M, Lejeune H, Clark A, Chuzel F, et al. Insulin-like growth factor I actions on steroidogenesis. Acta Paediatr Suppl 1994;399:176-7. De Boer JAM, Schoemaker J, van der Veen EA. Impaired reproductive function in women treated for growth hormone deficiency. Clin Endocrinol (Oxf) 1997;46:681-9.
13. Kawai M, Momoi T, Yorifuji T, Yamanaka C, Sasaki H, Furusho K. Unfavorable effects of growth hormone therapy on the final height of boys with short stature not caused by growth hormone deficiency. J Pediatr 1997;130:205-9. 14. Darendeliler F, Hindmarsh PC, Preece MA, Cox L, Brook CGD. Growth hormone increases rate of pubertal maturation. Acta Endocrinol (Copenh) 1990;122:416-6. 15. Dunkel L, Taskinen S, Hovatta O, Tilly JL, Wikstrom S. Germ cell apoptosis after treatment of cryptorchidism with human chorionic gonadotropin is associated with impaired reproductive function in the adult. J Clin Invest 1997;100:2341-6. 16. Kaleva M, Arsalo A, Louhimo I, Rapola J, Perheentupa J, Henriksen K, et al. Treatment with human chorionic gonadotrophin for cryptorchidism: clinical and histological effects. Int J Androl 1996;19:293-8. 17. Siogren I, Jonson M, Madej A, Hohansson HE, Ploen L. Effects of very high doses of human growth hormone (hGH) on male reproductive system in the dog. Andrologia 1998;30:37-42. 18. Brook CGD. Views on growth hormone treatment in idiopathic shortness of stature. Acta Paediatr 1998;87: 485-6.
To receive the table of contents by e-mail, send an e-mail message to: [email protected] Leave the subject line blank, and type the following as the body of your message: Subscribe jpeds_toc You can also sign up through our website at: http://www.mosby.com/jpeds You will receive an e-mail to confirm that you have been added to the mailing list. Note that TOC e-mails will be sent out when a new issue is posted to the web site.
370