0021-972X/9l/7301-0079$03.00/0 Journal of Clinical Endocrinology and Metabolism Copyright © 1991 by The Endocrine Society
Vol. 73, No. 1 Printed in U.S.A.
Hypothalamic-Pituitary Dysfunction in Growth Hormone-Deficient Patients with Pituitary Abnormalities* MOHAMAD MAGHNIE, FABIO TRIULZI, DANIELA LARIZZA, PAOLA PRETI, CINZIA PRIORA, GIUSEPPE SCOTTI, AND FRANCESCA SEVERI Departments of Pediatrics, University of Pavia, IRCCS Policlinico S. Matteo, Pavia, and Neuroradiology (F.T., G.S.), University of Milan, IRCCS H. S. Raffaele, Milan, Italy
ABSTRACT. Hypothalamic-pituitary function was studied in 45 patients with idiopathic GH deficiency (GHD), 33 of whom had pituitary abnormalities on magnetic resonance imaging: pituitary hypoplasia, undescended stalk and ectopia of the posterior lobe in 8 patients with isolated GHD (IGHD) (group I) and in 12 patients with multiple pituitary hormone deficiency (MPHD) (group II); isolated pituitary hypoplasia in 13 patients with IGHD (group III); no evidence of pituitary abnormalities in the remaining 12 patients with IGHD (group IV). Sellar and pituitary volumes were significantly lower in groups I, II, and III than in group IV (P < 0.001). No significant differences were observed between group I and group II in the GH response to GHRHl-44 expressed both as peak serum GH and area under the curve. Mean GH peak in group III and IV was significantly higher than that in group I (P < 0.005) and II (P < 0.001), as were the mean AUC (P < 0.005), suggesting hypothalamic defect. Delayed peak serum TSH after TRH was found in all patients of group II, and overt hypothyroidism in 11 of them. Furthermore, basal hyperprolactinemia was present in 6 patients and
adrenal insufficiency in 7 cases of group II. Finally, a reduced response of FSH to GnRH was observed in all these patients (P < 0.005 vs. each of the other groups), and clinical hypogonadism was present in all of them. We suggest that: 1) A high incidence of pituitary abnormalities seems to be present in idiopathic GHD patients; 2) Pituitary hormone deficiencies are more dependent on the type of the hypothalamic-pituitary abnormality than on the size of the pituitary per se: the association of pituitary hypoplasia, undescended stalk and ectopia of the posterior lobe should possibly be considered a distinct entity reflecting an early abnormality in hypothalamic development; 3) The majority of patients with IGHD or MPHD probably have a primary hypothalamic releasing hormone deficiency even if pituitary hypoplasia is associated; 4) Magnetic resonance imaging may have a role in the diagnosis and prognosis of patients with GHD through differentiation between patients who are at risk for developing MPHD vs. those who are candidates for having a persistently isolated GHD. (J Clin Endocrinol Metab 73: 79-83, 1991)
I
DIOPATHIC hypopituitarism is a heterogeneous group of disorders of unknown etiology (1). Perinatal and postnatal complications are reported to be responsible for reduced sellar and pituitary volumes by computed tomography scan in large numbers of hypopituitaric patients (2-5). Magnetic resonance (MR) imaging offers the advantage of revealing hypothalamic-pituitary abnormalities, such as pituitary hypoplasia, absence of the stalk and posterior lobe ectopia in many GH-deficient (GHD) patients (6-12); the underlying cause of these anatomic defects could be developmental in origin, dating from early intrauterine life (13-17). Whereas relationship of hypopituitarism to reduced sellar and pituitary size shown by computed tomography has already been documented (2-5), little is known about
endocrinological findings in GHD patients investigated by MR imaging. Kikuchi et al. (7) have suggested that the magnitude of hormone responses to stimuli in GHD children with hypothalamic-pituitary abnormalities evidenced by MR imaging is unrelated to pituitary gland height (7). In view of these reports, we studied hypothalamicpituitary function in 45 idiopathic GHD patients evaluated by MR imaging to establish eventual correlations between hormonal and anatomical findings.
Materials and Methods Patients Forty-five patients (30 males, 15 females) aged 6.3-19.8 yr (mean ± SD 10.2 ± 3.4 yr) with idiopathic GHD were studied. At the time of the diagnosis, height was below -2.5 SD and growth velocity was below - 2 SD for the chronological age; bone age, determined by the Greulich and Pyle method, was delayed by more than 2 yr and bone age/chronological age ratio
Received August 9,1990. Address correspondence and reprint requests to: Mohamad Maghnie, M.D., Department of Pediatrics, University of Pavia, IRCCS Policlinico S. Matteo, 27100, Pavia, Italy. * This work was presented at the International Sardinian Congress on Pediatric Endocrinology, Porto Cervo, Sardinia, October 7-10,1990.
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was less than 0.70. GH deficiency was diagnosed on the basis of a GH response of less than 10 ng/L, to insulin, arginine and L-Dopa (18). Pubertal staging was PI at the time of diagnosis and Pl-4 at the time of MR imaging study; at this time the patients aged 6.3-25.3 yr (mean ± SD 13.4 ± 4.2 yr). Diabetes insipidus was not present. Children with acquired GHD such as craniopharyngioma, histiocytosis, cerebral inflammatory diseases, hydrocephalus, and irradiation for tumors were excluded. A complete perinatal history was obtained from the parents. All patients received recombinant GH im or sc, 0.6 IU/kg three to six times weekly. Additional replacement therapy was administered in appropriate dosages in patients with multiple pituitary hormone deficiency (MPHD). MR imaging MR studies were carried out in the Department of Neuroradiology, S. Raffaele Hospital, University of Milan, with a 1.5 T unit by spin-echo Tl-WI technique (TR 600 ms, TE 28 ms, four acquisitions). Sagittal and coronal 3 mm sections, with matrix size of 265 x 256 pixels and field of view of about 20 cm were performed. Sellar and pituitary volumes were evaluated according to Di Chiro and Nelson (19). Endocrinobgical evaluation The GHRH test was performed before GH treatment in 42 patients and 15 days after therapy withdrawal in 3 MPHD patients. GHRH1-44 (Sanofi, Paris, France), 2 Mg/kg, was administered iv and blood samples for GH measurements were obtained at -15, 0, 15, 30, 45, 60, 120 min. The pituitarythyroid axis function was evaluated at the time of diagnosis by determination of serum T4, T3, free T3, free T4, TSH, and by TRH test; TRH test was also repeated before treatment with L-T4 in the patients with low T 3 and T 4 levels. TRH (Reflact, Hoest, Frankfurt, Germany) was given in a dose of 200 fig/m2 iv and blood samples for TSH and PRL determinations were drawn at - 5 , 0, 5, 10, 20, 30, 40, 60, 120 min. The GnRH test was performed at the time of the diagnosis and before the start of CG or estradiol replacement therapy in the hypogonadic patients; GnRH (Relisorm L, Serono, Italy) was given in a dose of 100 MgM2 and blood samples for FSH and LH measurements were drawn at 0, 15, 30, 60, 180 min. Pituitary-adrenal axis function was evaluated by determination of serum cortisol level at 0800 h and during insulin-induced hypoglycemia. In addition, cortisol was determined before and after ACTH1-24 stimulation test (Synacthen, Ciba-Geigy, Basilea) 250 ng im when low morning serum cortisol and symptoms such as weakness and postural hypotension were found. Serum GH (Sorin, Italy), T 3 (DPC, USA), T4 (Diagnostica, Germany), TSH (Cis, France), free T3 and cortisol (Amersham, United Kingdom), free T4 (Clinical Assays, USA), PRL, FSH and LH (Serono), and plasma ACTH (Incstar, USA) were measured using commercial RIA kits. Diabetes insipidus was excluded by the absence of polydipsiapolyuria and by the evaluation of plasma osmolality and specific urine gravity and osmolality. Informed consent was obtained from the parents.
JCE & M • 1991 Vol 73 • No 1
Statistical analysis Data were expressed as mean ± SEM; t test was used for statistical analysis and significance defined as P < 0.05.
Results MR imaging study Pituitary hypoplasia, no evident stalk and posterior lobe ectopia at the infundibular recess were found in 20 patients (44.4%), 8 with isolated GHD (IGHD) (group I) and 12 with MPHD (group II) (Fig. 1A). Associated brain anomalies such as Chiari I malformation in one patient, tentorial anomaly with vermis dysplasia in another, and basilar impression in still another were found. A third group of 13 IGHD patients (group III) (28.9%) presented pituitary hypoplasia and orthotopic posterior lobe (Fig. IB). In a fourth group of 12 IGHD patients (group IV) (26.6%) MR imaging revealed an intact pituitary gland (Fig. 1C). The mean values of sellar and pituitary volumes are shown in Table 1. Gestational and perinatal history In group I, vaginal bleeding occurred during gestation in three; elective cesarean section for podalic presentation was performed in three; in three others, pregnancy was uneventful; neonatal asphyxia was reported in two patients. All the 12 MPHD patients of group II were born by breech delivery and one mother had vaginal bleeding during pregnancy. In group III, vaginal bleeding occurred during gestation in nine of the mothers (69.2%); complications at delivery such as fetal distress and asphyxia were present in seven patients (53.8%), two of whom were born by breech delivery. In group IV, vaginal bleeding was reported in one mother; cesarean sections were performed in three for prolonged labor; neonatal distress was present in two; seven (58.3%) had uncomplicated perinatal courses. Endocrinobgical evaluation In groups I and II, peak serum GH response to GHRH ranging from 4.3-14.8 ng/h was observed between 30 and 90 min. Mean serum GH peak was 9.4 ± 3.3 Mg/L at 45 min in group I and 8.1 ± 2.3 /xg/L at 90 min in group II; mean peak GH and mean area under the curve (AUC) were not significantly different (Table 2). Serum GH peak after GHRH was greater than 20 Mg/L in all patients of groups III and IV and significantly higher than that observed in groups I and II. Mean serum GH peak was observed at 15 min in group III (32.9 ±9.1 Mg/L) and IV (25.2 ± 4.0 Mg/L); mean peak GH values and mean AUC were similar (Table 2). Low serum T 3 and T4 levels were present at diagnosis in five patients and became evident in six of the group II patients during GH treatment. No statistical differences were found between mean serum TSH peak or mean AUC after TRH in all four groups. Peak TSH was observed between 90 and 120
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HYPOTHALAMIC-PITUITARY DYSFUNCTION IN PITUITARY ABNORMALITIES
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TABLE 1. Results of MR image findings of sella and pituitary volumes in 45 hypopituitary patients Group I (n = 8)
Group II (n = 12)
Group III (n == 13)
Group IV (n = 12)
Age (yr) 13.1 ±0.9 18.7:± 1.1 10.4:±0.5 11.4 ±0.3 Sellar volumes 153.5 ±22.0 173.7 :± 19.1 189.6 :±20.5 349.7 ± 21.4° (mm3) 99.7 ±21.0 116.6 :±15.4 138.3 :±13.9 290.1 ± 19.46 Pituitary volumes (mm3) Values are the mean ± SEM. " P < 0.001 group IV vs. group I, vs. group II and vs. group III. b P < 0.001 group IV vs. group I, vs. group II and vs. group III.
regarding mean PRL peak and mean AUC after TRH. Subclinical ACTH deficiency was diagnosed on the basis of morning serum cortisol levels below the normal range in two patients of group II at the time of diagnosis of GHD (96.5 ± 35.8 nmol/L; n.v.:138-635 nmol/L), and in five patients of the same group at different times after diagnosis of GHD. In these patients, the response of cortisol to insulin-induced hypoglycemia was less than 552 nmol/L. Serum LH peaks and mean AUC after GnRH were similar in all patients at PI; mean peak FSH and mean AUC were significantly lower, both at diagnosis (Table 2) and before CG or estradiol treatment (3.1 ± 0.3 IU/L, 508.4 ± 53.2 IU/L, P < 0.005), in group II patients than in the other groups (P < 0.005); in all patients of group II clinical hypogonadotropic hypogonadism was present. Up to now four patients of group I have shown spontaneous puberty.
Discussion
FIG. 1. MR imaging sagittal sections: A, Hypoplasia of both pituitary and sella {arrow) with undescended stalk and ectopic posterior lobe {arrowheads). B, Hypoplasia of anterior lobe {arrow) with evident stalk {arrow) and normal location of posterior pituitary lobe {arrowheads). C, Normal anterior pituitary gland, sella, and stalk {arrow); normal location of posterior pituitary lobe {arrowheads).
min in all group II patients and at 20 min in the others. In six patients of group II the basal PRL level was higher (mean value: 39.4 ± 8.3 Mg/L; n.v. < 20 jig/L) than in the remaining six patients of the same group (14.3 ± 3.7 Mg/L; P < 0.001) and than in the other patient groups (P < 0.001). No significant difference, however, was found in the 4 groups
KiKuchi et al. (7) suggested that the most probable cause of idiopathic hypopituitarism is transection of the pituitary stalk at birth with regeneration of posterior pituitary tissue from the proximal stump (7). Nevertheless the absence of perinatal insults in some of our patients with posterior lobe ectopia and the presence of brain anomalies, which occur during the same embryologic period of pituitary development, are strongly suggestive of a congenital defect (11). Ectopic posterior lobe and brain anomalies have been described in GHD patients by others (12, 15), as well as in GHD patient with congenital malformative syndrome (20), without evidence of birth trauma. Thus, we defined the pituitary stalk as undescended. Association of pituitary abnormalities and IGHD, or MPHD and panhypopituitarism suggests that hypothalamohypophyseal portal circulation may be rescued in some cases. In groups I, II, and III with similar pituitary volumes but stalk abnormality only in groups I and II, GH response to GHRH was different: in the first two groups there was a slight and delayed increase in serum GH after GHRH, which probably denotes a decrease in somatotrope cell number or function. Moreover, delayed serum TSH response to TRH and reduced gonadotropin
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JCE&M-I99I Vol 73 • No 1
TABLE 2. Serum GH {ixg/h) and FSH (IU/L) responses to GHRH and GnRH in 45 hypopituitary patients Mean peak
GH FSH
Area under the curve (area units)
Group I (n = 8)
Group II (n = 12)
Group III (n = 13)
Group IV
Group I (n = 12)
Group II (n = 12)
Group HI (n = 13)
Group IV (n = 12)
10.9 ± 2.1° 6.8 ± 0.5
6.3 ± 1.5* 3.4 ± 0.6°
38.3 ± 7.0 7.2 ± 1.1
33.7 ± 5.7 7.8 ± 0.5
700.7 ± 107.2° 992.0 ± 105.5
516.1 ± 104.2° 579.5 ± 76.2"
2395.9 ± 577.1 976.0 ± 109.5
2314.2 ± 447.3 1138.8 ± 114.6
Values are the mean ± SEM. Mean peak P < 0.005: GH I vs. Ill and IV; FSH II vs. I, III and IV. 6 P < 0.001: GH II vs. Ill and IV. 0
response to GnRH in the MPHD patients suggests both hypothalamic and pituitary disorders. The reduced GH response to GHRH and FSH/LH response to GnRH in these patients does not rule out GHRH and GnRH deficiency; such decreased response could possibly be secondary to early severe chronic GHRH and GnRH deficiency (21). On the other hand, transient deprivation of endogenous GHRH with anti-GHRH-serum in newborn rats, permanently impairs growth rate, somatotropic function and pituitary morphology, weight and GH content (22). Higher GH peak obtained in group III children after GHRH suggests that these patients have functioning pituitary somatotrophs but impaired hypothalamic GHRH synthesis and/or release. Progressive hypoperfusion of the hypothalamus with late GHRH deficiency (after development of somatotrope cells) and secondarily reduced pituitary volume could explain better response of GH to GHRH. In group IV with an intact hypophysis, mean GH level and mean AUC did not significantly differ from group III suggesting that hormone response is unrelated to pituitary size. In these patients GH deficiency could result from a functional hypothalamic impairment. Delayed TSH response to TRH in group II is typical of hypothalamic hypothyroidism. Six of these patients developed hypothyroidism several years after, indicating that delayed TSH response to TRH is an early marker for subclinical hypothyroidism in such patients. In 6/20 cases with hyperprolactinemia, elevated basal PRL levels could be related to primary hypothalamic PRL-inhibiting factor deficiency, or to a disturbance of PRL secretion, which is also under the control of the posterior pituitary lobe and stalk, through PRL-inhibiting factor and PRL-stimulating factors (23). Whereas LH response to GnRH was similar in all prepubertal patients, low FSH response was observed in the patients of group II since prepubertal age and confirmed before substitutive treatment. Such patients should be carefully monitored for a possible development of hypogonadism. It was suggested that perinatal insults may lead to
AUC GH I vs. Ill and IV, and II vs. Ill and IV; FSH II vs. I, III and IV.
hypopituitarism. Adverse events such as early vaginal bleeding, prolonged labor, and breech delivery have been documented in 50-60% of idiopathic GHD (1, 2, 24, 25). Since the fetal endocrine system has a participatory role in the induction of labor, possible disturbance of this system (26) arising from congenital hypothalamic-pituitary abnormalities could contribute to labor complications and particularly to breech presentation, the most frequent birth complication reported in MPHD (1, 2, 2426). In our study, breech delivery characterized all the patients with MPHD and undescended stalk, suggesting that such patients are prone to develop MPHD. It is unlikely that MPHD result from chronic administration of GH per se (27-30) as MPHD was present at diagnosis of GHD in some patients, but did not develop in all patients with the same abnormalities, during chronic GH treatment. We conclude that pituitary function is related to specific anatomical pituitary abnormalities rather than to gland size. Pituitary hypoplasia, undescended stalk and ectopia of the posterior pituitary lobe should be considered as a distinct congenital anatomic and endocrinological entity probably of hypothalamic origin. Our data suggest that patients with MPHD and the majority of those with IGHD have a primary deficiency of hypothalamic releasing hormones, even if pituitary hypoplasia is associated. MR imaging may help in distinguishing two groups of patients with GHD: one characterized by pituitary hypoplasia, undescended stalk and posterior pituitary ectopia, at risk for developing MPHD; the other with normal or hypoplastic pituitary gland with IGHD as the only hormonal defect. MR demonstration of pituitary abnormalities may be suggestive for endocrine deficiency in first-line evaluation of short stature children. Acknowledgment We thank Prof. E. E. Miiller for critical review of the paper.
References 1. Rona RJ, Tanner JM. Aetiology of idiopathic growth hormone deficiency in England and Wales. Arch Dis Child. 1977;52:197-
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HYPOTHALAMIC-PITUITARY DYSFUNCTION IN PITUITARY ABNORMALITIES 208. 2. Stanhope R, Hindmarsh P, Kendall B, Brook CGD. High resolution CT scanning of the pituitary gland in growth disorders. Acta Paediatr Scand. 1986;75:779-86. 3. Inoue Y, Nemoto Y, Fujita K, et al. Pituitary dwarfism: CT evaluation of the pituitary gland. Radiology. 1986;159:171-5. 4. Surtees R, Adams J, Price D, Clayton P, Shalet S. Association of adverse perinatal events with an empty sella turcica in children with growth hormone deficiency. Horm Res. 1987;28:5-12. 5. Huot C, Dube J, Ducharme JR, Collu R. Reduced pituitary volume in children with short stature: clinical and radiological correlates. Horm Res. 1989;32:113-8. 6. Fujisawa I, Kikuchi K, Nishimura K, et al. Transection of the pituitary stalk: development of an ectopic posterior lobe assessed with MR imaging. Radiology. 1987;165:487-9. 7. Kikuchi K, Fujisawa I, Momoi T, et al. Hypothalamic-pituitary function in growth hormone-deficient patients with pituitary stalk transection. J Clin Endocrinol Metab. 1988;67:817-23. 8. Kelly WM, Kucharczyk W, Kucharczyk Y, et al. Posterior pituitary ectopia: an MR feature of pituitary dwarfism. AJNR. 1988;9:45360. 9. Scotti G, Triulzi F, Chiumello G, Di Natale B. New imaging techniques in endocrinology: magnetic resonance of the pituitary gland and sella turcica. Acta Paediatr Scand [Suppl]. 1989;356:514. 10. Werder EA, Zachmann M, Wichmann W, Valavanis A. Neurohypophyseal ectopy in growth hormone insufficiency. Horm Res. 1989;31:210-2. 11. Maghnie M, Triulzi F, Larizza D, et al. Hypothalamic pituitary dwarfism: comparison between MR imaging and CT findings. Pediatr Radiol. 1990;20:229-35. 12. Pellini C, Di Natale B, De Angelis R, et al. Growth hormone deficiency in children: role of magnetic resonance imaging in assessing aetiopathogenesis and prognosis in idiopathic hypopituitarism. Eur J Pediatr. 1990; 149:536-41. 13. Brewer DB. Congenital absence of the pituitary gland and its consequences. J Pathol Bacteriol. 1957;73:59-67. 14. Reid JD. Congenital absence of the pituitary gland. J Pediatr. 1960;56:658-64. 15. Johnson JD, Hansen RC, Albritton WL, Werthemann U, Christiansen RO. Hypoplasia of the anterior pituitary and neonatal hypoglycemia. J Pediatr. 1973;82:634-41. 16. Gluckman PD, Grumbach MM, Kaplan SL. The human fetal hypothalamus and pituitary gland: the maturation of neuroendocrine peptides. In: Tulchinsky R, ed. Maternal fetal endocrinology. Philadelphia: Saunders;1980:321-4.
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17. Kaufman BA, Kaufman B, Mapstone TB. Pituitary stalk agenesis: magnetic resonance imaging of "ectopic posterior lobe" with surgical correlation. Pediatr Neurosci. 1988;14:140-4. 18. Spiliotis BE, August GP, Hung W, Sonis W, Mendelson W, Bercu BB. Growth hormone neurosecretory dysfunction: a treatable cause of short stature. JAMA. 1984;251:2223-30. 19. Di Chiro G, Nelson KB. Volume of the sella turcica. AJR. 1962;87:989-1008. 20. Larizza D, Maghnie M. Poland's syndrome associated with growth hormone deficiency. J Med Genet. 1990;27:53-5. 21. Schriock EA, Lustig R, Rosenthal SM, Kaplan SL, Grumbach MM. Effect of growth hormone (GH)-releasing hormone (GRH) on plasma GH in relation to magnitude and duration of GH deficiency in 26 children and adults with isolated GH deficiency or multiple pituitary hormone deficiencies: evidence for hypothalamic GRH deficiency. J Clin Endocrinol Metab. 1984;58:1043-9. 22. Cella SG, Locatelli V, Mennini T, et al. Deprivation of growth hormone-releasing hormone early in the rat's neonatal life permanently affects somatotropic function. Endocrinology. 1990;127:1625-34. 23. Hyde JF, Ben-Jonathan N. The posterior pituitary contains a potent prolactin-releasing factor: in vivo studies. Endocrinology. 1989;125:736-41. 24. Hugh Craft W, Underwood LE, Van Wyk JJ. High incidence of perinatal insult in children with idiopathic hypopituitarism. J Pediatr. 1980;96:397-402. 25. Steendijk R. Diagnostic and aetiologic features of idiopathic and symptomatic growth hormone deficiency in the Netherlands. Helv Paediat Acta. 1980;35:129-39. 26. Kaplan SA. Growth and growth hormone disorders of the anterior pituitary. In: Kaplan SA, ed. Clinical pediatric endocrinology. Philadelphia: Saunders;1990:l-62. 27. Falconer DS. The inheritance of liability to certain diseases, estimated from the incidence among relatives. Ann Hum Genet. 1965;29:51-76. 28. Goodman HG, Grumbach MM, Kaplan SC. Growth and growth hormone. II. A comparative of isolated growth hormone deficiency and multiple pituitary hormone deficiencies in 35 patients with idiopathic hypopituitary dwarfism. N Engl J Med. 1968;278:57-68. 29. Root AW, Bongiovanni AM, Eberlein WR. Diagnosis and management of growth retardation with special reference to the problem of hypopituitarism. J Pediatr. 1971;78:737-53. 30. Lippe BM, Van Herle AJ, La Franchi SH, Uller RP, Lavin N, Kaplan SA. Reversible hypothyroidism in growth hormone deficient children treated with human growth hormone. J Clin Endocrinol Metab. 1975;40:612-8.
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Vol. 73, No. 1 Printed in U.S.A.
Hypothalamic-Pituitary Dysfunction in Growth Hormone-Deficient Patients with Pituitary Abnormalities* MOHAMAD MAGHNIE, FABIO TRIULZI, DANIELA LARIZZA, PAOLA PRETI, CINZIA PRIORA, GIUSEPPE SCOTTI, AND FRANCESCA SEVERI Departments of Pediatrics, University of Pavia, IRCCS Policlinico S. Matteo, Pavia, and Neuroradiology (F.T., G.S.), University of Milan, IRCCS H. S. Raffaele, Milan, Italy
ABSTRACT. Hypothalamic-pituitary function was studied in 45 patients with idiopathic GH deficiency (GHD), 33 of whom had pituitary abnormalities on magnetic resonance imaging: pituitary hypoplasia, undescended stalk and ectopia of the posterior lobe in 8 patients with isolated GHD (IGHD) (group I) and in 12 patients with multiple pituitary hormone deficiency (MPHD) (group II); isolated pituitary hypoplasia in 13 patients with IGHD (group III); no evidence of pituitary abnormalities in the remaining 12 patients with IGHD (group IV). Sellar and pituitary volumes were significantly lower in groups I, II, and III than in group IV (P < 0.001). No significant differences were observed between group I and group II in the GH response to GHRHl-44 expressed both as peak serum GH and area under the curve. Mean GH peak in group III and IV was significantly higher than that in group I (P < 0.005) and II (P < 0.001), as were the mean AUC (P < 0.005), suggesting hypothalamic defect. Delayed peak serum TSH after TRH was found in all patients of group II, and overt hypothyroidism in 11 of them. Furthermore, basal hyperprolactinemia was present in 6 patients and
adrenal insufficiency in 7 cases of group II. Finally, a reduced response of FSH to GnRH was observed in all these patients (P < 0.005 vs. each of the other groups), and clinical hypogonadism was present in all of them. We suggest that: 1) A high incidence of pituitary abnormalities seems to be present in idiopathic GHD patients; 2) Pituitary hormone deficiencies are more dependent on the type of the hypothalamic-pituitary abnormality than on the size of the pituitary per se: the association of pituitary hypoplasia, undescended stalk and ectopia of the posterior lobe should possibly be considered a distinct entity reflecting an early abnormality in hypothalamic development; 3) The majority of patients with IGHD or MPHD probably have a primary hypothalamic releasing hormone deficiency even if pituitary hypoplasia is associated; 4) Magnetic resonance imaging may have a role in the diagnosis and prognosis of patients with GHD through differentiation between patients who are at risk for developing MPHD vs. those who are candidates for having a persistently isolated GHD. (J Clin Endocrinol Metab 73: 79-83, 1991)
I
DIOPATHIC hypopituitarism is a heterogeneous group of disorders of unknown etiology (1). Perinatal and postnatal complications are reported to be responsible for reduced sellar and pituitary volumes by computed tomography scan in large numbers of hypopituitaric patients (2-5). Magnetic resonance (MR) imaging offers the advantage of revealing hypothalamic-pituitary abnormalities, such as pituitary hypoplasia, absence of the stalk and posterior lobe ectopia in many GH-deficient (GHD) patients (6-12); the underlying cause of these anatomic defects could be developmental in origin, dating from early intrauterine life (13-17). Whereas relationship of hypopituitarism to reduced sellar and pituitary size shown by computed tomography has already been documented (2-5), little is known about
endocrinological findings in GHD patients investigated by MR imaging. Kikuchi et al. (7) have suggested that the magnitude of hormone responses to stimuli in GHD children with hypothalamic-pituitary abnormalities evidenced by MR imaging is unrelated to pituitary gland height (7). In view of these reports, we studied hypothalamicpituitary function in 45 idiopathic GHD patients evaluated by MR imaging to establish eventual correlations between hormonal and anatomical findings.
Materials and Methods Patients Forty-five patients (30 males, 15 females) aged 6.3-19.8 yr (mean ± SD 10.2 ± 3.4 yr) with idiopathic GHD were studied. At the time of the diagnosis, height was below -2.5 SD and growth velocity was below - 2 SD for the chronological age; bone age, determined by the Greulich and Pyle method, was delayed by more than 2 yr and bone age/chronological age ratio
Received August 9,1990. Address correspondence and reprint requests to: Mohamad Maghnie, M.D., Department of Pediatrics, University of Pavia, IRCCS Policlinico S. Matteo, 27100, Pavia, Italy. * This work was presented at the International Sardinian Congress on Pediatric Endocrinology, Porto Cervo, Sardinia, October 7-10,1990.
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was less than 0.70. GH deficiency was diagnosed on the basis of a GH response of less than 10 ng/L, to insulin, arginine and L-Dopa (18). Pubertal staging was PI at the time of diagnosis and Pl-4 at the time of MR imaging study; at this time the patients aged 6.3-25.3 yr (mean ± SD 13.4 ± 4.2 yr). Diabetes insipidus was not present. Children with acquired GHD such as craniopharyngioma, histiocytosis, cerebral inflammatory diseases, hydrocephalus, and irradiation for tumors were excluded. A complete perinatal history was obtained from the parents. All patients received recombinant GH im or sc, 0.6 IU/kg three to six times weekly. Additional replacement therapy was administered in appropriate dosages in patients with multiple pituitary hormone deficiency (MPHD). MR imaging MR studies were carried out in the Department of Neuroradiology, S. Raffaele Hospital, University of Milan, with a 1.5 T unit by spin-echo Tl-WI technique (TR 600 ms, TE 28 ms, four acquisitions). Sagittal and coronal 3 mm sections, with matrix size of 265 x 256 pixels and field of view of about 20 cm were performed. Sellar and pituitary volumes were evaluated according to Di Chiro and Nelson (19). Endocrinobgical evaluation The GHRH test was performed before GH treatment in 42 patients and 15 days after therapy withdrawal in 3 MPHD patients. GHRH1-44 (Sanofi, Paris, France), 2 Mg/kg, was administered iv and blood samples for GH measurements were obtained at -15, 0, 15, 30, 45, 60, 120 min. The pituitarythyroid axis function was evaluated at the time of diagnosis by determination of serum T4, T3, free T3, free T4, TSH, and by TRH test; TRH test was also repeated before treatment with L-T4 in the patients with low T 3 and T 4 levels. TRH (Reflact, Hoest, Frankfurt, Germany) was given in a dose of 200 fig/m2 iv and blood samples for TSH and PRL determinations were drawn at - 5 , 0, 5, 10, 20, 30, 40, 60, 120 min. The GnRH test was performed at the time of the diagnosis and before the start of CG or estradiol replacement therapy in the hypogonadic patients; GnRH (Relisorm L, Serono, Italy) was given in a dose of 100 MgM2 and blood samples for FSH and LH measurements were drawn at 0, 15, 30, 60, 180 min. Pituitary-adrenal axis function was evaluated by determination of serum cortisol level at 0800 h and during insulin-induced hypoglycemia. In addition, cortisol was determined before and after ACTH1-24 stimulation test (Synacthen, Ciba-Geigy, Basilea) 250 ng im when low morning serum cortisol and symptoms such as weakness and postural hypotension were found. Serum GH (Sorin, Italy), T 3 (DPC, USA), T4 (Diagnostica, Germany), TSH (Cis, France), free T3 and cortisol (Amersham, United Kingdom), free T4 (Clinical Assays, USA), PRL, FSH and LH (Serono), and plasma ACTH (Incstar, USA) were measured using commercial RIA kits. Diabetes insipidus was excluded by the absence of polydipsiapolyuria and by the evaluation of plasma osmolality and specific urine gravity and osmolality. Informed consent was obtained from the parents.
JCE & M • 1991 Vol 73 • No 1
Statistical analysis Data were expressed as mean ± SEM; t test was used for statistical analysis and significance defined as P < 0.05.
Results MR imaging study Pituitary hypoplasia, no evident stalk and posterior lobe ectopia at the infundibular recess were found in 20 patients (44.4%), 8 with isolated GHD (IGHD) (group I) and 12 with MPHD (group II) (Fig. 1A). Associated brain anomalies such as Chiari I malformation in one patient, tentorial anomaly with vermis dysplasia in another, and basilar impression in still another were found. A third group of 13 IGHD patients (group III) (28.9%) presented pituitary hypoplasia and orthotopic posterior lobe (Fig. IB). In a fourth group of 12 IGHD patients (group IV) (26.6%) MR imaging revealed an intact pituitary gland (Fig. 1C). The mean values of sellar and pituitary volumes are shown in Table 1. Gestational and perinatal history In group I, vaginal bleeding occurred during gestation in three; elective cesarean section for podalic presentation was performed in three; in three others, pregnancy was uneventful; neonatal asphyxia was reported in two patients. All the 12 MPHD patients of group II were born by breech delivery and one mother had vaginal bleeding during pregnancy. In group III, vaginal bleeding occurred during gestation in nine of the mothers (69.2%); complications at delivery such as fetal distress and asphyxia were present in seven patients (53.8%), two of whom were born by breech delivery. In group IV, vaginal bleeding was reported in one mother; cesarean sections were performed in three for prolonged labor; neonatal distress was present in two; seven (58.3%) had uncomplicated perinatal courses. Endocrinobgical evaluation In groups I and II, peak serum GH response to GHRH ranging from 4.3-14.8 ng/h was observed between 30 and 90 min. Mean serum GH peak was 9.4 ± 3.3 Mg/L at 45 min in group I and 8.1 ± 2.3 /xg/L at 90 min in group II; mean peak GH and mean area under the curve (AUC) were not significantly different (Table 2). Serum GH peak after GHRH was greater than 20 Mg/L in all patients of groups III and IV and significantly higher than that observed in groups I and II. Mean serum GH peak was observed at 15 min in group III (32.9 ±9.1 Mg/L) and IV (25.2 ± 4.0 Mg/L); mean peak GH values and mean AUC were similar (Table 2). Low serum T 3 and T4 levels were present at diagnosis in five patients and became evident in six of the group II patients during GH treatment. No statistical differences were found between mean serum TSH peak or mean AUC after TRH in all four groups. Peak TSH was observed between 90 and 120
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HYPOTHALAMIC-PITUITARY DYSFUNCTION IN PITUITARY ABNORMALITIES
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TABLE 1. Results of MR image findings of sella and pituitary volumes in 45 hypopituitary patients Group I (n = 8)
Group II (n = 12)
Group III (n == 13)
Group IV (n = 12)
Age (yr) 13.1 ±0.9 18.7:± 1.1 10.4:±0.5 11.4 ±0.3 Sellar volumes 153.5 ±22.0 173.7 :± 19.1 189.6 :±20.5 349.7 ± 21.4° (mm3) 99.7 ±21.0 116.6 :±15.4 138.3 :±13.9 290.1 ± 19.46 Pituitary volumes (mm3) Values are the mean ± SEM. " P < 0.001 group IV vs. group I, vs. group II and vs. group III. b P < 0.001 group IV vs. group I, vs. group II and vs. group III.
regarding mean PRL peak and mean AUC after TRH. Subclinical ACTH deficiency was diagnosed on the basis of morning serum cortisol levels below the normal range in two patients of group II at the time of diagnosis of GHD (96.5 ± 35.8 nmol/L; n.v.:138-635 nmol/L), and in five patients of the same group at different times after diagnosis of GHD. In these patients, the response of cortisol to insulin-induced hypoglycemia was less than 552 nmol/L. Serum LH peaks and mean AUC after GnRH were similar in all patients at PI; mean peak FSH and mean AUC were significantly lower, both at diagnosis (Table 2) and before CG or estradiol treatment (3.1 ± 0.3 IU/L, 508.4 ± 53.2 IU/L, P < 0.005), in group II patients than in the other groups (P < 0.005); in all patients of group II clinical hypogonadotropic hypogonadism was present. Up to now four patients of group I have shown spontaneous puberty.
Discussion
FIG. 1. MR imaging sagittal sections: A, Hypoplasia of both pituitary and sella {arrow) with undescended stalk and ectopic posterior lobe {arrowheads). B, Hypoplasia of anterior lobe {arrow) with evident stalk {arrow) and normal location of posterior pituitary lobe {arrowheads). C, Normal anterior pituitary gland, sella, and stalk {arrow); normal location of posterior pituitary lobe {arrowheads).
min in all group II patients and at 20 min in the others. In six patients of group II the basal PRL level was higher (mean value: 39.4 ± 8.3 Mg/L; n.v. < 20 jig/L) than in the remaining six patients of the same group (14.3 ± 3.7 Mg/L; P < 0.001) and than in the other patient groups (P < 0.001). No significant difference, however, was found in the 4 groups
KiKuchi et al. (7) suggested that the most probable cause of idiopathic hypopituitarism is transection of the pituitary stalk at birth with regeneration of posterior pituitary tissue from the proximal stump (7). Nevertheless the absence of perinatal insults in some of our patients with posterior lobe ectopia and the presence of brain anomalies, which occur during the same embryologic period of pituitary development, are strongly suggestive of a congenital defect (11). Ectopic posterior lobe and brain anomalies have been described in GHD patients by others (12, 15), as well as in GHD patient with congenital malformative syndrome (20), without evidence of birth trauma. Thus, we defined the pituitary stalk as undescended. Association of pituitary abnormalities and IGHD, or MPHD and panhypopituitarism suggests that hypothalamohypophyseal portal circulation may be rescued in some cases. In groups I, II, and III with similar pituitary volumes but stalk abnormality only in groups I and II, GH response to GHRH was different: in the first two groups there was a slight and delayed increase in serum GH after GHRH, which probably denotes a decrease in somatotrope cell number or function. Moreover, delayed serum TSH response to TRH and reduced gonadotropin
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JCE&M-I99I Vol 73 • No 1
TABLE 2. Serum GH {ixg/h) and FSH (IU/L) responses to GHRH and GnRH in 45 hypopituitary patients Mean peak
GH FSH
Area under the curve (area units)
Group I (n = 8)
Group II (n = 12)
Group III (n = 13)
Group IV
Group I (n = 12)
Group II (n = 12)
Group HI (n = 13)
Group IV (n = 12)
10.9 ± 2.1° 6.8 ± 0.5
6.3 ± 1.5* 3.4 ± 0.6°
38.3 ± 7.0 7.2 ± 1.1
33.7 ± 5.7 7.8 ± 0.5
700.7 ± 107.2° 992.0 ± 105.5
516.1 ± 104.2° 579.5 ± 76.2"
2395.9 ± 577.1 976.0 ± 109.5
2314.2 ± 447.3 1138.8 ± 114.6
Values are the mean ± SEM. Mean peak P < 0.005: GH I vs. Ill and IV; FSH II vs. I, III and IV. 6 P < 0.001: GH II vs. Ill and IV. 0
response to GnRH in the MPHD patients suggests both hypothalamic and pituitary disorders. The reduced GH response to GHRH and FSH/LH response to GnRH in these patients does not rule out GHRH and GnRH deficiency; such decreased response could possibly be secondary to early severe chronic GHRH and GnRH deficiency (21). On the other hand, transient deprivation of endogenous GHRH with anti-GHRH-serum in newborn rats, permanently impairs growth rate, somatotropic function and pituitary morphology, weight and GH content (22). Higher GH peak obtained in group III children after GHRH suggests that these patients have functioning pituitary somatotrophs but impaired hypothalamic GHRH synthesis and/or release. Progressive hypoperfusion of the hypothalamus with late GHRH deficiency (after development of somatotrope cells) and secondarily reduced pituitary volume could explain better response of GH to GHRH. In group IV with an intact hypophysis, mean GH level and mean AUC did not significantly differ from group III suggesting that hormone response is unrelated to pituitary size. In these patients GH deficiency could result from a functional hypothalamic impairment. Delayed TSH response to TRH in group II is typical of hypothalamic hypothyroidism. Six of these patients developed hypothyroidism several years after, indicating that delayed TSH response to TRH is an early marker for subclinical hypothyroidism in such patients. In 6/20 cases with hyperprolactinemia, elevated basal PRL levels could be related to primary hypothalamic PRL-inhibiting factor deficiency, or to a disturbance of PRL secretion, which is also under the control of the posterior pituitary lobe and stalk, through PRL-inhibiting factor and PRL-stimulating factors (23). Whereas LH response to GnRH was similar in all prepubertal patients, low FSH response was observed in the patients of group II since prepubertal age and confirmed before substitutive treatment. Such patients should be carefully monitored for a possible development of hypogonadism. It was suggested that perinatal insults may lead to
AUC GH I vs. Ill and IV, and II vs. Ill and IV; FSH II vs. I, III and IV.
hypopituitarism. Adverse events such as early vaginal bleeding, prolonged labor, and breech delivery have been documented in 50-60% of idiopathic GHD (1, 2, 24, 25). Since the fetal endocrine system has a participatory role in the induction of labor, possible disturbance of this system (26) arising from congenital hypothalamic-pituitary abnormalities could contribute to labor complications and particularly to breech presentation, the most frequent birth complication reported in MPHD (1, 2, 2426). In our study, breech delivery characterized all the patients with MPHD and undescended stalk, suggesting that such patients are prone to develop MPHD. It is unlikely that MPHD result from chronic administration of GH per se (27-30) as MPHD was present at diagnosis of GHD in some patients, but did not develop in all patients with the same abnormalities, during chronic GH treatment. We conclude that pituitary function is related to specific anatomical pituitary abnormalities rather than to gland size. Pituitary hypoplasia, undescended stalk and ectopia of the posterior pituitary lobe should be considered as a distinct congenital anatomic and endocrinological entity probably of hypothalamic origin. Our data suggest that patients with MPHD and the majority of those with IGHD have a primary deficiency of hypothalamic releasing hormones, even if pituitary hypoplasia is associated. MR imaging may help in distinguishing two groups of patients with GHD: one characterized by pituitary hypoplasia, undescended stalk and posterior pituitary ectopia, at risk for developing MPHD; the other with normal or hypoplastic pituitary gland with IGHD as the only hormonal defect. MR demonstration of pituitary abnormalities may be suggestive for endocrine deficiency in first-line evaluation of short stature children. Acknowledgment We thank Prof. E. E. Miiller for critical review of the paper.
References 1. Rona RJ, Tanner JM. Aetiology of idiopathic growth hormone deficiency in England and Wales. Arch Dis Child. 1977;52:197-
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HYPOTHALAMIC-PITUITARY DYSFUNCTION IN PITUITARY ABNORMALITIES 208. 2. Stanhope R, Hindmarsh P, Kendall B, Brook CGD. High resolution CT scanning of the pituitary gland in growth disorders. Acta Paediatr Scand. 1986;75:779-86. 3. Inoue Y, Nemoto Y, Fujita K, et al. Pituitary dwarfism: CT evaluation of the pituitary gland. Radiology. 1986;159:171-5. 4. Surtees R, Adams J, Price D, Clayton P, Shalet S. Association of adverse perinatal events with an empty sella turcica in children with growth hormone deficiency. Horm Res. 1987;28:5-12. 5. Huot C, Dube J, Ducharme JR, Collu R. Reduced pituitary volume in children with short stature: clinical and radiological correlates. Horm Res. 1989;32:113-8. 6. Fujisawa I, Kikuchi K, Nishimura K, et al. Transection of the pituitary stalk: development of an ectopic posterior lobe assessed with MR imaging. Radiology. 1987;165:487-9. 7. Kikuchi K, Fujisawa I, Momoi T, et al. Hypothalamic-pituitary function in growth hormone-deficient patients with pituitary stalk transection. J Clin Endocrinol Metab. 1988;67:817-23. 8. Kelly WM, Kucharczyk W, Kucharczyk Y, et al. Posterior pituitary ectopia: an MR feature of pituitary dwarfism. AJNR. 1988;9:45360. 9. Scotti G, Triulzi F, Chiumello G, Di Natale B. New imaging techniques in endocrinology: magnetic resonance of the pituitary gland and sella turcica. Acta Paediatr Scand [Suppl]. 1989;356:514. 10. Werder EA, Zachmann M, Wichmann W, Valavanis A. Neurohypophyseal ectopy in growth hormone insufficiency. Horm Res. 1989;31:210-2. 11. Maghnie M, Triulzi F, Larizza D, et al. Hypothalamic pituitary dwarfism: comparison between MR imaging and CT findings. Pediatr Radiol. 1990;20:229-35. 12. Pellini C, Di Natale B, De Angelis R, et al. Growth hormone deficiency in children: role of magnetic resonance imaging in assessing aetiopathogenesis and prognosis in idiopathic hypopituitarism. Eur J Pediatr. 1990; 149:536-41. 13. Brewer DB. Congenital absence of the pituitary gland and its consequences. J Pathol Bacteriol. 1957;73:59-67. 14. Reid JD. Congenital absence of the pituitary gland. J Pediatr. 1960;56:658-64. 15. Johnson JD, Hansen RC, Albritton WL, Werthemann U, Christiansen RO. Hypoplasia of the anterior pituitary and neonatal hypoglycemia. J Pediatr. 1973;82:634-41. 16. Gluckman PD, Grumbach MM, Kaplan SL. The human fetal hypothalamus and pituitary gland: the maturation of neuroendocrine peptides. In: Tulchinsky R, ed. Maternal fetal endocrinology. Philadelphia: Saunders;1980:321-4.
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17. Kaufman BA, Kaufman B, Mapstone TB. Pituitary stalk agenesis: magnetic resonance imaging of "ectopic posterior lobe" with surgical correlation. Pediatr Neurosci. 1988;14:140-4. 18. Spiliotis BE, August GP, Hung W, Sonis W, Mendelson W, Bercu BB. Growth hormone neurosecretory dysfunction: a treatable cause of short stature. JAMA. 1984;251:2223-30. 19. Di Chiro G, Nelson KB. Volume of the sella turcica. AJR. 1962;87:989-1008. 20. Larizza D, Maghnie M. Poland's syndrome associated with growth hormone deficiency. J Med Genet. 1990;27:53-5. 21. Schriock EA, Lustig R, Rosenthal SM, Kaplan SL, Grumbach MM. Effect of growth hormone (GH)-releasing hormone (GRH) on plasma GH in relation to magnitude and duration of GH deficiency in 26 children and adults with isolated GH deficiency or multiple pituitary hormone deficiencies: evidence for hypothalamic GRH deficiency. J Clin Endocrinol Metab. 1984;58:1043-9. 22. Cella SG, Locatelli V, Mennini T, et al. Deprivation of growth hormone-releasing hormone early in the rat's neonatal life permanently affects somatotropic function. Endocrinology. 1990;127:1625-34. 23. Hyde JF, Ben-Jonathan N. The posterior pituitary contains a potent prolactin-releasing factor: in vivo studies. Endocrinology. 1989;125:736-41. 24. Hugh Craft W, Underwood LE, Van Wyk JJ. High incidence of perinatal insult in children with idiopathic hypopituitarism. J Pediatr. 1980;96:397-402. 25. Steendijk R. Diagnostic and aetiologic features of idiopathic and symptomatic growth hormone deficiency in the Netherlands. Helv Paediat Acta. 1980;35:129-39. 26. Kaplan SA. Growth and growth hormone disorders of the anterior pituitary. In: Kaplan SA, ed. Clinical pediatric endocrinology. Philadelphia: Saunders;1990:l-62. 27. Falconer DS. The inheritance of liability to certain diseases, estimated from the incidence among relatives. Ann Hum Genet. 1965;29:51-76. 28. Goodman HG, Grumbach MM, Kaplan SC. Growth and growth hormone. II. A comparative of isolated growth hormone deficiency and multiple pituitary hormone deficiencies in 35 patients with idiopathic hypopituitary dwarfism. N Engl J Med. 1968;278:57-68. 29. Root AW, Bongiovanni AM, Eberlein WR. Diagnosis and management of growth retardation with special reference to the problem of hypopituitarism. J Pediatr. 1971;78:737-53. 30. Lippe BM, Van Herle AJ, La Franchi SH, Uller RP, Lavin N, Kaplan SA. Reversible hypothyroidism in growth hormone deficient children treated with human growth hormone. J Clin Endocrinol Metab. 1975;40:612-8.
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