Acta Psdiatr 81: 698-9. 1992
SHORT COMMUNICATION
Selective growth hormone deficiency of hypothalamic origin following severe head injury A Lopez Guzman, J Salvador, R Albero, J Sastre, P Iglesias, JJ Diez and A Gomez-Pan Department of Endocrinology, Hospital La Paz. Madrid. Spain
The relationship between severe head trauma (SHT) and pituitary hormone deficiencies was first reported by Cyran in 1918 (1). Diabetes insipidus is the endocrino-. pathy most commonly found following head injury (2). Involvement of other pituitary hormones has been described (3) and SHT may result in selective anterior pituitary insufficiency. To date, only one case of selective growth hormone (GH) deficiency of pituitary origin due to SHT has been published (4). We present the case of a boy who developed selective G H failure following closed cranial trauma, which was characterized by a pattern of G H release of hypothalamic growth hormone-releasing hormone (GHRH) deficiency. A four-year-old boy suffered a SHT which resulted in several right-sided parietotemporal fractures. The boy remained in a coma of the third degree for three days. At that time his height was 98.5 cm (25th centile); his preceding growth rate was 6.6 cm/year. Two months later he was discharged complaining of unsteadiness (of vestibular origin) as the only clinical sequela. At the age of six years and four months he was admitted to the endocrinology ward for investigation of shortness of stature. His height was then 104.5 cm (less than third centile) and his bone age (Greulich & Pyle) was delayed by 18 months. Anterior pituitary testing by thyrotrophin-releasing hormone (300 pg. iv), gonadotrophinreleasing hormone (1 00 pg iv) and insulin-induced hypoglycaemia (0.1 units/kg iv) showed adequate TSH, cortisol and gonadotrophin responses. Basal thyroid
50
GH peak
Table I . Results of anterior pituitary function investigation.
Minutes Test Cortisol (nmol/l) IH Glucose (mmol/l) IH FSH (IU/I) LHRH LH (IU/I) LHRH TRH TSH (mu/]) Prolactin (pg/l) Free thyroxine (pmol/l) Total thyroxine (nmol/l)
0
20
40
60
342 3.83
312 2.1 1 4 3 6
703 2.12 3 2 5.5
112 3.33 3 2 6
1 1
3 9.5 24 I10
hormone and prolactin levels were also within the normal range (Table 1). G H response was blunted (0.9 ng/ml) despite effective hypoglycaemia. L-dopa (500 mg orally) and arginine infusion (0.5 g/kg iv) failed to provoke a significant increase in G H levels (1.5 ng/ml and 3.4 ng/ml, respectively, Fig. I ) . However, injection of G H R H (100 pg iv) was followed by a rapid increase in G H levels (44 ng/ml) demonstrating somatotroph cell integrity and indicating hypothalamic GHRH deficiency as the aetiology of growth retardation. G H therapy was started and induced acceleration of growth with an 8-cm increment over the first 12 months of treatment. Anterior pituitary deficiencies due to SHT are probably related to thrombosis or infarction of hypophyseal
-
4o
Pg/L 30
-
20
-
10
, I-Dopa
Arginine
Hypoglycaemia
Fig. I . Maximal G H peaks following different stimuli.
GHRH
Traumaric GHRH deficiency
ACTA PKDIATR 81 (1992)
vessels (3, 5), as suggested by the finding of necrotic changes of the anterior pituitary in patients who died following SHT (6, 7), in contrast to post-traumatic diabetes insipidus which might be due to disruption of axonal connections between the hypothalamus and the posterior pituitary (2). Usually there is a variable period of time ranging from months to years between the occurence of SHT and the diagnosis of hormonal deficiencies (8), with the exception of patients suffering from traumatic diabetes insipidus which usually leads to an extensive investigation of pituitary function. As to hypothalamic-pituitary lesions, no relationship has been found between intensity or location of SHT and hormone deficiencies (9). In accordance with this, our patient had selective G H deficiency with no evidence of other pituitary deficits despite the severity of the injury . Insulin-induced hypoglycaemia, L-dopa and arginine infusion represent strong stimuli for G H secretion. They act at suprapituitary levels by increasing endogenous G H R H or inhibiting somatostatin (10, 11) and, therefore, both hypothalamic and pituitary integrity is needed to trigger G H release. G H R H is adequate for testing pituitary reserve since this peptide induces G H release by direct interaction with somatotroph cells. In this patient, lack of G H response to hypothalamic stimuli together with normal G H response to G H R H injection was characteristic of hypothalamic G H R H deficiency. In contrast, a blunted response to this peptide is found in cases of pituitary failure (4).The good response obtained with G H therapy is in accord with the diagnosis. This case indicates that SHT can be followed by selective G H deficiency and stresses the need for adequate follow-up of patients suffering from SHT, especially those in growth age, to rule out endocrine disturbances as early as possible. The possibility of
699
selective or multiple involvement of hypothalamic releasing hormones emphasizes the convenience of testing anterior pituitary hormones with suprapituitary stimuli, since using hypothalamic releasing factors such as GHRH, although useful to identify the levef of endocrine damage, may be a source of potential errors when used as unique diagnostic tools.
References 1. Cyran E. Hypophysenchadigung durch schadelbasisfraktur.
Dtsch Med Wochenschr 1918;44:1261 2. Notmann DD, Mortex MA, Moses AM. Permanent diabetes
3. 4. 5.
6. 7. 8. 9. 10.
11.
insupidus following head trauma: observations on ten patients and an approach to diagnosis. J Trauma 1980;20:599-602 Fernandez-Castaner M, Martinez de Osaba MJ, Vilardell E. Insuffisance hypohysaire post-traumatique. Ann Endocrinol (Paris) 1982;43:213-18 Eichler I, Frisch H, Eichler HG, Soukop W. Isolated growth hormone deficiency after severe head trauma. J Endocrinol Invest 1988;11:409-1 I Dzur J, Winternitz W. Post-traumatic hypopituitarism: anterior pituitary insufficiency secondary to head trauma. South Med J 1976;69:1377-7 Kornblum RN, Fisher RS. Pituitary lesions in craniocerebral injuries. Arch Pathol 1969;88:242-8 Ceballos R. Pituitary changes in head trauma (analysis of 102 consecutive cases of head injury). Ala J Med Sci 1966;3:185-98 Edwards OM, Clark, JDA. Post-traumatic hypopituitarism. Six cases and review of the literature. Medicine 1986;65:281-90 Valenta LJ, De Feo DR. Post-traumatic hypopituitarism due to a hypothalamic lesion. Am J Med 1980;68:614-17 Page MD. Koppeschaar HPF, Edwards CA, Dieguez C, Scanlon MF. Additive effects of growth hormone releasing factor and insulin hypoglycaemia on growth hormone release in man. Clin Endocrinol(0xfj 1987;26:589-95 Alba-Roth J, Muller OA, Schopohl J, Von Werder K. Arginine stimulates growth hormone secretion by suppressing endogenous somatostatin secretion. J Clin Endocrinol Metab 1988;67:1186-9
Received Aug. 23, 1991. Accepted March 2, 1992
SHORT COMMUNICATION
Selective growth hormone deficiency of hypothalamic origin following severe head injury A Lopez Guzman, J Salvador, R Albero, J Sastre, P Iglesias, JJ Diez and A Gomez-Pan Department of Endocrinology, Hospital La Paz. Madrid. Spain
The relationship between severe head trauma (SHT) and pituitary hormone deficiencies was first reported by Cyran in 1918 (1). Diabetes insipidus is the endocrino-. pathy most commonly found following head injury (2). Involvement of other pituitary hormones has been described (3) and SHT may result in selective anterior pituitary insufficiency. To date, only one case of selective growth hormone (GH) deficiency of pituitary origin due to SHT has been published (4). We present the case of a boy who developed selective G H failure following closed cranial trauma, which was characterized by a pattern of G H release of hypothalamic growth hormone-releasing hormone (GHRH) deficiency. A four-year-old boy suffered a SHT which resulted in several right-sided parietotemporal fractures. The boy remained in a coma of the third degree for three days. At that time his height was 98.5 cm (25th centile); his preceding growth rate was 6.6 cm/year. Two months later he was discharged complaining of unsteadiness (of vestibular origin) as the only clinical sequela. At the age of six years and four months he was admitted to the endocrinology ward for investigation of shortness of stature. His height was then 104.5 cm (less than third centile) and his bone age (Greulich & Pyle) was delayed by 18 months. Anterior pituitary testing by thyrotrophin-releasing hormone (300 pg. iv), gonadotrophinreleasing hormone (1 00 pg iv) and insulin-induced hypoglycaemia (0.1 units/kg iv) showed adequate TSH, cortisol and gonadotrophin responses. Basal thyroid
50
GH peak
Table I . Results of anterior pituitary function investigation.
Minutes Test Cortisol (nmol/l) IH Glucose (mmol/l) IH FSH (IU/I) LHRH LH (IU/I) LHRH TRH TSH (mu/]) Prolactin (pg/l) Free thyroxine (pmol/l) Total thyroxine (nmol/l)
0
20
40
60
342 3.83
312 2.1 1 4 3 6
703 2.12 3 2 5.5
112 3.33 3 2 6
1 1
3 9.5 24 I10
hormone and prolactin levels were also within the normal range (Table 1). G H response was blunted (0.9 ng/ml) despite effective hypoglycaemia. L-dopa (500 mg orally) and arginine infusion (0.5 g/kg iv) failed to provoke a significant increase in G H levels (1.5 ng/ml and 3.4 ng/ml, respectively, Fig. I ) . However, injection of G H R H (100 pg iv) was followed by a rapid increase in G H levels (44 ng/ml) demonstrating somatotroph cell integrity and indicating hypothalamic GHRH deficiency as the aetiology of growth retardation. G H therapy was started and induced acceleration of growth with an 8-cm increment over the first 12 months of treatment. Anterior pituitary deficiencies due to SHT are probably related to thrombosis or infarction of hypophyseal
-
4o
Pg/L 30
-
20
-
10
, I-Dopa
Arginine
Hypoglycaemia
Fig. I . Maximal G H peaks following different stimuli.
GHRH
Traumaric GHRH deficiency
ACTA PKDIATR 81 (1992)
vessels (3, 5), as suggested by the finding of necrotic changes of the anterior pituitary in patients who died following SHT (6, 7), in contrast to post-traumatic diabetes insipidus which might be due to disruption of axonal connections between the hypothalamus and the posterior pituitary (2). Usually there is a variable period of time ranging from months to years between the occurence of SHT and the diagnosis of hormonal deficiencies (8), with the exception of patients suffering from traumatic diabetes insipidus which usually leads to an extensive investigation of pituitary function. As to hypothalamic-pituitary lesions, no relationship has been found between intensity or location of SHT and hormone deficiencies (9). In accordance with this, our patient had selective G H deficiency with no evidence of other pituitary deficits despite the severity of the injury . Insulin-induced hypoglycaemia, L-dopa and arginine infusion represent strong stimuli for G H secretion. They act at suprapituitary levels by increasing endogenous G H R H or inhibiting somatostatin (10, 11) and, therefore, both hypothalamic and pituitary integrity is needed to trigger G H release. G H R H is adequate for testing pituitary reserve since this peptide induces G H release by direct interaction with somatotroph cells. In this patient, lack of G H response to hypothalamic stimuli together with normal G H response to G H R H injection was characteristic of hypothalamic G H R H deficiency. In contrast, a blunted response to this peptide is found in cases of pituitary failure (4).The good response obtained with G H therapy is in accord with the diagnosis. This case indicates that SHT can be followed by selective G H deficiency and stresses the need for adequate follow-up of patients suffering from SHT, especially those in growth age, to rule out endocrine disturbances as early as possible. The possibility of
699
selective or multiple involvement of hypothalamic releasing hormones emphasizes the convenience of testing anterior pituitary hormones with suprapituitary stimuli, since using hypothalamic releasing factors such as GHRH, although useful to identify the levef of endocrine damage, may be a source of potential errors when used as unique diagnostic tools.
References 1. Cyran E. Hypophysenchadigung durch schadelbasisfraktur.
Dtsch Med Wochenschr 1918;44:1261 2. Notmann DD, Mortex MA, Moses AM. Permanent diabetes
3. 4. 5.
6. 7. 8. 9. 10.
11.
insupidus following head trauma: observations on ten patients and an approach to diagnosis. J Trauma 1980;20:599-602 Fernandez-Castaner M, Martinez de Osaba MJ, Vilardell E. Insuffisance hypohysaire post-traumatique. Ann Endocrinol (Paris) 1982;43:213-18 Eichler I, Frisch H, Eichler HG, Soukop W. Isolated growth hormone deficiency after severe head trauma. J Endocrinol Invest 1988;11:409-1 I Dzur J, Winternitz W. Post-traumatic hypopituitarism: anterior pituitary insufficiency secondary to head trauma. South Med J 1976;69:1377-7 Kornblum RN, Fisher RS. Pituitary lesions in craniocerebral injuries. Arch Pathol 1969;88:242-8 Ceballos R. Pituitary changes in head trauma (analysis of 102 consecutive cases of head injury). Ala J Med Sci 1966;3:185-98 Edwards OM, Clark, JDA. Post-traumatic hypopituitarism. Six cases and review of the literature. Medicine 1986;65:281-90 Valenta LJ, De Feo DR. Post-traumatic hypopituitarism due to a hypothalamic lesion. Am J Med 1980;68:614-17 Page MD. Koppeschaar HPF, Edwards CA, Dieguez C, Scanlon MF. Additive effects of growth hormone releasing factor and insulin hypoglycaemia on growth hormone release in man. Clin Endocrinol(0xfj 1987;26:589-95 Alba-Roth J, Muller OA, Schopohl J, Von Werder K. Arginine stimulates growth hormone secretion by suppressing endogenous somatostatin secretion. J Clin Endocrinol Metab 1988;67:1186-9
Received Aug. 23, 1991. Accepted March 2, 1992
