reversible endocrine dysfunction and pituitary stalk enlargement
TRANSCRIPT
J. Endocrinol. Invest. 21: 122-127, 1998
CASE REPORT
Reversible endocrine dysfunction and pituitary stalk enlargement
A. Chico*, M. Puig-Domingo*, P. Martul**, M. De Juan***, J.M. Prats**, D. Mauricio****, and S.M. Webb* Department of Endocrinology and **Radiology, Hospital de la Santa Creu i Sant Pau. Autonomous University of Barcelona, Barcelona *Section of Pediatric Endocrinology and Neurology, Hospital de Cruces. Basque Country University, Bilbao, ***Unit of Endocrinology, Hospital del Pare Taul!, Sabadell, Barcelona, Spain
ABSTRACT. We report 4 patients (3 of which were children) with diabetes insipidus and different degrees of hypopituitarism in whom a pituitary stalk enlargement was disclosed on imaging techniques, and in whom radiological and functional recovery was observed during followup. Pituitary substitution therapy with desmopressin, thyroxine, hydrocortisone, growth hormone and/or oral contraceptives was prescribed. During follow-up, regression of the stalk lesion was seen which was spontaneous in 2 cases, fol-
INTRODUCTION
The introduction of highly sensitive MRI (magnetic resonance imaging) techniques, allows the detection and follow-up of very small structural abnormalities of the hypothalamic-pituitary area (1). Enlargement of the pituitary stalk is one of these entities (2-3). The nature of these lesions is not always evident and therefore, the approach to patients harbouring one of such disorders and their outcome is a challenging situation for the clinician. A potentially aggressive neoplastic nature cannot always be initially ruled out, but close follow-up will usually disclose growth of the lesion in these cases. However, a substantial number of subjects represent non-tumoral lesions and are susceptible of spontaneous reversal. We present 4 such patients who recovered functionally and radiologically over the years; to our knowledge this has only been reported previously with extreme infrequency (4-6), and never in children (3).
Key-words: Pituitary stalk, hypopituitarism, reversible dysfunction.
Correspondence: Dr. S.M. Webb, Servicio de Endocrinologia, Hospital de la Santa Creu i Sant Pau, Av. Pare Claret 167, 08025 Barcelona, Spain.
Accepted October 14, 1997.
122
lowing a short course of corticosteroids in another and an empirical trial of tuberculostatic drugs in the fourth. A partial recovery of pituitary function was also observed. These cases illustrate that pituitary stalk enlargement and associated hypopituitarism may be reversible; however, this morphological and functional recovery has rarely been described in adults and has not been previously reported in children. (J. Endocrinol. Invest. 21: 122-127, 1998) ©1998, Editrice Kurtis
CASE REPORTS CASE 1 After menarche at the age of 13 and regular menses, an 18-year-old female presented with secondary amenorrhoea, thirst and polyuria. After a water deprivation test, central diabetes insipidus was diagnosed and treated with carbamazepine. Free T4, prolactin, TSH response to TRH and cortisol response to hypoglycaemia were normal (Table 1). GH response to insulin hypoglycemia was inadequate but gonadotropin response to GnRH was normal. She had no withdrawal bleed after oral medroxyprogesterone, and did not respond to oral clomiphene 50 mg twice daily for 2 weeks (basal LH 8.9 U/I and FSH 8.5 U/I rising to 9.5 and 8 U/I respectively, while 17-beta-estradiol and progesterone remained undetectable). Pelvic examination and ultrasound were normal, so the patient was given oral contraceptives. A CT-scan demonstrated an enlarged pituitary stalk and a 3x3 mm intrasellar hypodensity which did not enhance after iv contrast (Fig. 1). No cause for this stalk enlargement (i.e. aggressive gliomas, metas·· tasis or systemic diseases with potential effective treatment like tuberculosis, sarcoidosis, histiocytosis X) was evident. Height, weight and phsysical ex-
A. Chico, M. Puig-Domingo, P. Martul, et al.
Fig. 1 - Initial CT performed in 1984 (top left) and latest MRI performed in 1991 (top right) of patient 1. The initial pituitary stalk enlargement had disappeared on the MRI scan; even though the images are difficult to compare, the reduction in pituitary stalk enlargement paralleled clinical recovery of pituitary function. MRI in patient 2 showing a marked reduction in her pituitary stalk lesion (initial scan 1991- bottom left; follow-up scan-1993-bottom right).
amination were normal. A neurosurgical approach was not considered appropriate at that time. Initial workup of this patient was reported previously (2). Three years after developing initial symptoms endocrine function was reassessed without medication: a GHRH stimulation test showed a clear response of GH (from 1.5 to 25.5 mUll at 30 minutes). Together with the results of gonadal function testing, these findings pointed to a hypothalamic deficiency of GHRH and GnRH. A water deprivation test showed a partial ADH response (plasma osmolality varied between 307 and 303 mOsm/1 and urine osmolality rose from 530 to 686 mOsm/l, after ADH administration). L-thyroxine (1 00 ~g/day) was begun due to low free T4 levels (7.5 pmol/l) and normal TSH (1.87 mUI/I). Further endocrine testing remained unchanged. Thirst and polyuria decreased and carbamazepine could be withdrawn, but amenorrhoea persisted. The patient stopped oral contraceptives when she was 23 years old; regular menses resumed spontaneously for the first t ime since the age of 18, and complete recovery of gonadotropin function was evident, since pregnancy and delivery of a normal baby occurred two years later. On both CT-scan and MRI performed when
123
L-thyroxine was indicated and after pregnancy (Fig. 1), no abnormalities were observed. L-thyroxine was stopped 12 months after delivery, and normal free T4 and TSH have been observed since.
CASE 2 An 8-year-old girl was diagnosed with complete central diabetes insipidus after two months of intense thirst and polyuria, and headache. Physical examination showed signs of intracranial hypertension with bilateral papilloedema. Endocrine evaluation was diagnostic of severe hypopituitarism with hyperprolactinemia and a hypothalamic TSH response to TRH (delayed peak 60 min after TRH), reflecting pituitary stalk interruption (Table 1). An MRI scan showed a small pituitary and an abnormal gadolinium enhanced image at the hypothalamic-chiasmatic level with an enlarged pituitary stalk (8 mm of diameter) and absence of the normal neurohypophyseal hyperintense image on Tl (Fig. 1). The diagnosis of optic glioma was considered and radiotherapy was recommended but not accepted by the family. A trial of dexamethasone treatment was performed (30 mg/day the first week, tapered down and stopped after 3 weeks) with improvement and final regression of the intracranial hypertense image. Tumor markers (betaHCG, enolase and alphafetoprotein) measured in blood and cerebrospinal fluid were normal. Antiinsulin, islet cell, antithyroid and antiadrenal antibodies were negative. The patient was treated with L-thyroxine, desmopressin and hydrocortisone (15 mg/day); GH treatment was withheld since a tumour had not been completely ruled out. Reevaluation after two years, revealed a complete regression of the chiasmatic lesion, with minimal pituitary stalk enlargement at the infundibular level (Fig . 1). Endocrine assessment also indicated normalization of prolactin, a recovery of thyrotropiC function (normal basal free T4 and TSH, and a peak TSH response to TRH of 4.7 mUll at 30 minutes) and a pubertal gonadotropin response to GnRH (peak of FSH and LH at 30 minutes of 3.3 and 4.8 lUll respectively), with no improvement of GH and cortisol responses after insulin-induced hypoglycaemia. Polyuria rapidly reappeared after discontinuation of desmopressin. Screening of potential spontaneous reversible hypothalamic lesions included an ophthalmologic examination, which revealed a macular iritis suggestive of sarcoidosis. These lesions spontaneously disappeared one month later before a planned biopsy could be carried out. No other signs of systemic sarcoidosis were detected, and angiotensin converting enzyme levels were within the normal range. The patient has begun GH treatment after which
Reversible pituitary stalk enlargement
Table 1 - Basal hormone values and stimulation tests at the time of diagnosis in the four patients.
Patient Free T4 TSH TRH test Prolactin GnRH test (peaks) Hypoglycaemia test* (peaks)
TSH (peak) LH FSH Cortisol GH
25 1.6 22 110 43 9.2 914 5.3
2 5.7 1.7 8.1 854 <0.6 <0.5 94 <0.8
3 15 1.5 7.1 140 <0.6 <0.5 875 0.86
4 14 2.5 9.1 174 38 18.4 605 1.6
*Insulin-induced hypoglycaemia. Reference values: Free T4 (12.5-25 pmolll); TSH (0.3-5 mUll); TSH afterTRH (5-22); Pr~lactin (70-530 mUll); LH (>5 U/I) and FSH (>4 U/I) after GnRH in adults; Cortisol (>550 nmolll) and GH (>20 mUll) response to insulin hypoglycaemia.
growth velocity has increased from 2.1 to 5.6 cm/year and continues on hydrocortisone and desmopressin substitution.
CASE 3 A 12 year-old boy was diagnosed after a water deprivation test with complete hypothalamic diabetes insipidus. He complained of thirst and polyuria over the previous month. MRI demonstrated a pituitary stalk enlargement of approximately 4-5 mm, which enhanced after contrast, and an absence of the normal neurohypophyseal hyperintense image on T1 (Fig. 2). Tumor markers (HCG and alpha-fetoprotein) in blood and cerebrospinal fluid were negative. No evidence of systemic granulomatous disease was found, except for a positive intradermal tuberculin test, for which 12 months treatment with isoniazid, rifampin and ethambutol was prescribed. Anterior pituitary function at the time of diagnosis revealed GH deficiency; gonadotropins were undetectable but serum testosterone was 1 .15 nmol/I (demonstrating early puberal development) (Table 1). The patient was treated with desmopressin for 10 months after which G H replacement was started. Two months later, MRI showed a significant decrease in stalk enlargement: testosterone reached 1.27 nmol/I 4 months after starting GH therapy, when LH and FSH became detectable (LH 1.5 UlI, FSH 2.3 U/I respectively) with concomitant increase in testicular volume from 4 ml to 6 ml which demonstrated pubertal progression. Two years after diagnosis, MRI was absolutely normal (Fig. 2) and the patient remains under GH and desmopressin replacement therapy, with a growth velocity of 4.3 cm/year.
CASE 4 A 14-year-old girl presented with a 1 month history of intense polyuria and thirst; complete hypothalamic diabetes insipidus was diagnosed after a water deprivation test. She had presented with irregular menses (every 60 to
124
90 days) after menarche at the age of 13. A subnormal response of GH to insulin-induced hypoglycemia with no other anterior pituitary deficiencies were observed (Table 1). On M RI a hyperintense pituitary stalk enlargement, which enhanced after contrast, and absence of the normal neurohypophyseal hyperintense image on T1 was observed (Fig. 2). Screening for granulomatous and systemic diseases was negative; alpha feto-protein and human chorionic gonadotrophin (hCG) in blood and CSF were negative. There were no skin or bone lesions. At age 15 she became amenorrheic; physical examination was normal with unchanged height (167.5 cm) and weight (60 Kg). A second MRI disclosed the same findings as at initial work up. Two years after diagnosis, anterior pituitary function was reassessed and remained normal except for the persistent GH deficiency. Amenorrhoea persisted despite normal gonadotropin response to GnRH but regular menses resumed after oral contraceptives suggesting hypothalamic amenorrhoea. A further MRI examination revealed absence of the normal neurohypophysal signal but an evident decrease in size of the pituitary stalk enlargement (Fig. 2). She remains asymptomatic with DDAVP (0.1 mg tid) and oral contraceptive treatment, 30 months after initial workup.
METHODS
Serum cortisol concentration was measured by enzyme chemiluminescent immunoassay (Amerlite TM,
Kodak Clinical Diagnostics Ltd, Amersham, UK). Serum prolactin, TSH, LH, FSH, and free T4 were measured using a fully automated chemiluminescent immunoassay system (ACS: 180™, Ciba Corning Diagnostics Corp., Medfield, MA, USA). GH measurements in serum were performed by using an immunochemiluminometric assay (Luma-Tac™, Nichols Institute Diagnostics, San Juan Capistrano, CA, USA). Combined tests for assessment of anterior pituitary consisting of the intravenous administration of solu-
A. Ch ico, M. Puig-Domingo, P. Martu l, et cl.
Fig. 2 - Initial MRI performed in 1993 (left) and 2 years later (right) in patients 3 (top) and 4 (bottom). In both cases, a marked reduction in the pituitary stalk enlargement is observed.
ble insulin (0.1-0.2 Iu/Kg body weight) followed 60 minutes later by thyrotropin-releasing hormone (TRH, 400 ~g, T.R.H. PREMTM, Zyma Farmaceutica, SA, Barcelona, Spain), and gonadotropin-releasing hormone (GnRH, 100 ~g, Luforan 500™, Serono Laboratorios SA, Madrid, Spain) were performed to evaluate GH, cortisol, TSH, FSH and LH responses. Blood samples were taken before and at 30, 45, 60, 90 and 120 min. Cortisol and GH were measured in serum from all blood samples obtained, and TSH, FSH and LH concentrations in serum from basal samples, and 30 and 60 min after GnRH and TRH. The GH response to growth hormone-releasing hormone (GHRH) was evaluated at 0, 15, 30, 45, 60 and 90 min after an intravenous bolus administration of 1 ~g/kg body weight of synthetic G H RH (1-29, GerefTM, Serono Laboratorios, SA, Madrid, Spain).
DISCUSSION
We present four patients with diabetes insipidus and different degrees of anterior pituitary insufficiency who showed pituitary stalk enlargement on imaging techniques. In the follow-up, improvement of radiological (in all patients) and endocrine abnormalities (in three of them) was observed, a finding described only very rarely in adults but not in pediatric patients (3). The initial radiological extension of the lesion var-
125
ied; while in case 1 there were signs of stalk and pituitary involvement, in case 2 the lesion was confined to the infundibular region, and in case 3 and 4 only pituitary stalk enlargement was observed. Loss of the normal neurohypophyseal hyperintense signal on the T1 weighted MRI was present in the 3 more recent cases where it was initially performed; this finding is generally observed when secondary or idiopathic diabetes insipidus is present (7-8) . Anterior pituitary function recovery varied in the 3 patients in whom it was observed. While ADH, TSH and gonadotropin deficency normalized in patient 1, only TSH recovered in patient 2 in whom initial hyperprolactinemia also disappeared. As far as the gonadal axis, initially detectable testosterone with undetectable LH and FSH associated with subsequent increase in gonadotropins and pubertal testicular volume in patient 3 also suggest recovery of the gonadal axis; a similar increase in LH and FSH after GnRH suggested a recovery of the gonadal axis also in patient 2, although a normal evolution of a prepubertal to pubertal response could not be ruled out, since the patient was aged 8 at initial workup. In the fourth patient hypothalamic amenorrhea and diabetes insipidus persist 3 years after initial presentation . Finally, it is worth pointing out that in none of the 4 cases did GH secretion recover. The development of MRI has allowed to disclose abnormalities in situations considered up to now as "idiopathic" syndromes, which affect the hypothalamicpituitary axis. Spontaneous improvement of endocrine dysfunction and/or radiological abnormalities have been described previously in central diabetes insipidus associated or not to hypopituitarism (5-6) and more recently in some cases of lymphocytic infundibuloneurohypophysitis, sometimes associated with anterior pituitary hormone deficiencies, which seems to be a self-limited process (4). Astrocytomas, pineocytomas and other tumors of the central nervous system (CNS) may damage brain structures including the pituitary and the stalk (9-11). Clinical remission or stabilization has been reported in children with optochiasmatic glioma, particularly in young children with neurofibromatosis. Boit and Richardson (12) reported a 4 monthsold child with a biopsy-proven optochiasmatic glioma who died 13 1/2 years later with no evidence of tumor at autopsy. More recently, a 2 year-old child with an optochiasmatic glioma diagnosed by biopsy who experimented spontaneous size reduction has been described (13). No pituitary hormone deficiencies were reported in these cases. In the present report, improvement occurred spontaneously in case 1 and 4; in the other two patients
medical treatment was indicated; thus, the reversal of both the morphologic lesion and the pituitary dysfunction can strictly not be considered spontaneous. In case 3, tuberculosis chemotherapy on clinical grounds was initiated without histological or microbiological proof, despite the fact that tuberculosis of the eNS is very rare. In case 2, the brief glucocorticoid course of therapy given to reduce intracranial hypertension may have contributed to reduce the mass, especially since a diagnosis of sarcoidosis was suggested. Neurological involvement in sarcoidosis occurs in about 5% of cases (14) and diabetes insipidus or hypopituitarism due to infiltration of the hypothalamic-pituitary area is often present (15); however, most of them have evidence of chest disease (80%) or ocular involvement (50%) (16). Nonetheless, a small percentage appears to manifest the disease only in the eNS without extraneural involvement (17). In general, ocular involvement is present in 11% to 32% of patients with sarcoidosis, and anterior segment structures are most often affected. After chronic granulomatous uveitis and acute iritis, iris nodules are the most frequent findings, as found in patient 2, which spontaneously disappeared, as described in the literature (18). Isolated sarcoidosis of the eNS is still less frequent in children (19). In a series of 14 adults with neurosarcoidosis, when the eNS was involved the disease remained active two years later despite glucocorticoid treatment (20). The benign outcome rules out the possibility of histiocytosis-X and metastatic lesions as causes of these patients lesions. Similarly, lymphocytic hypophysitis, an inflammatory process with a striking female predilection often presenting during pregnancy or in the postpartum period, is highly unlikely since it primarily involves the pituitary and rarely is associated with diabetes insipidus (21) as in entities which primarily involve the pituitary stalk, such as lymphocytic infundibuloneurohypophysitis (4). In the absence of any positive diagnostic procedures the cause of pituitary stalk enlargement in patients 1 and 4 remains unproven. However, based on the previous discussion their long, benign course is compatible with self-limited lymphocytic infundibuloneurohypophysitis, or a low grade glioma which spontaneously regressed. In conclusion, we describe four cases of pituitarystalk enlargement in whom all showed a radiological and three a partial endocrine improvement in the course of follow-up. The benign course of these cases did not make the recommendation of a biopsy necessary, which would probably have damaged the nerve fibers and vascular structures of the pituitary stalk to cause irreversible pituitary insufficiency. Nevertheless, other more aggressive lesions such
126
Reversible pituitary stalk enlargement
as high-grade gliomas, dysgerminomas, histiocytosis or metastasis should be kept in mind, if the stalk lesion progresses; thus, when confronted with a patient with a pituitary stalk enlargement, careful endocrine workup and close morphological followup, preferably with MRI, is recommended, in order to identify those cases in which a biopsy is warranted. On the other hand, since hypopituitarism was found to recover in parallel to the decrease in size of the lesion, in the benign cases periodic hormonal reassessment is recommended to confirm the necessity of continued substitution therapy.
ACKNOWLEDG EM ENTS We wish to acknowledge the help of Dr. J. Rodriguez-Espinosa (Department of Biochemistry, Hormone Section, Hospital Santa Creu i Sant Paul in preparing the manuscript.
REFERENCES
1. Webb S.M., Ruscalleda J., Schwarzstein D., Calaf-AIsina J., Rovira A., Matos G., PUig-Domingo M., de Leiva A. Computerized tomography versus magnetic resonance imaging: a comparative study in hypothalamic-pituitary and parasellar pathology. Clin. Endocrino!. (Oxf.) 36: 459, 1992.
2. Puig M.L., Webb S.M., del Pozo c., de Juan M., Serrano S., Vilardell E. Endocrine aspects of pituitary stalk enlargement. Clin. Endocrino!. (Oxf.) 27: 25, 1987.
3. Banerjee A., Leger J., Garel C, Hassan M., Czernichow P. Anomalies morphologiques de la tige pituitaire sans cause reconnue dans quatre cas de diabete insipide de I'enfant. Arch. Pediatr. 1: 223, 1994.
4. Imura H., Nakao K., Shimatsu A., Ogawa Y., Sando T., Fujisawa I., Hirohiko Y. Lymphocytic infundibuloneurohypophysitis as a cause of central diabetes insipidus. N. Engl. J. Med. 329: 683, 1993.
5. Ahmed S.R., Aiello D.P., Page R., Hopper K., Towfighi J., Santen R.J. Necrotizing infundibulo-hypophysitis: a unique syndrome of diabetes insipidus and hypopituitarism. J. Clin. Endocrino!. Metab. 76: 1499, 1993.
6. Teelucksingh S., Sellar R., Seckl J.R. Reversible pituitary stalk enlargement in cranial diabetes insipidus. Lancet ii: 973, 1991.
7. Fujisawa I., Nishimura K., Asato R. Posterior lobe of the pituitary in diabetes insipidus: MR findings. J. Comput. Assist. Tomogr. 11: 221, 1987.
A. Chico, M. Puig-Domingo, P. Martu!, et al.
8. Gudinchet F., Brunelle F., Barth M.O. MR imaging of the posterior hypophysis in children. Am. J. Roentgenol. 10: 511, 1989.
9. Takeuchi J., Kikuchi K., Shibamoto Y., Fujisawa I. Radiation therapy for juvenile pilocytic astrocytoma of the pituitary stalk. J. Neurosurg. 77: 139, 1992.
10. D'Andrea AD., Packer R.J., Rorke L.B., Larissa T., Bilaniuk T., Sutton L.N., Bruce DA, Schut L. Pineocytomas of childhood: a reappraisal of natural history and response to therapy. Cancer 59: 1353, 1987.
11. Alvord E.e., Lofton S. Gliomas of the optic nerve or chiasm. J. Neurosurg. 68: 85, 1991.
12. Boit A, Richardson E.P. The biological and clinical behavior of pilocytic astrocytomas of the optic pathways. Brain 105: 161, 1982.
13. Venes J.L., Latack J., Kandt R.S. Postoperative regression of optochiasmatic astrocytoma: a case for expectant therapy. Neurosurgery 15: 421, 1984.
14. Scott T.F. Neurosarcoidosis: progress and clinical aspects. Neurology 43: 8, 1993.
15. Stuart e.A, Neelon FA Levobitz H.E.
127
Hypothalamic insufficiency: the cause of hypopituitarism in sarcoidosis. Ann. Intern. Med. 88: 589, 1978.
16. Chapelon e., Ziza J.M., Piette J.e., Levy I., Raguin G., Wechsler B., Bitker M.O., Bletry 0., Laplane E., Bousser M.G., Godeau P. Neurosarcoidosis: signs, course and treatment in 35 confirmed cases. Medicine 69: 261, 1990.
17. Cariski A.T. Isolated CNS sarcoidosis. JAMA 245: 62, 1981.
18. Obenauf C.D., Shaw H.E., Syndor e.F., Klintworth G.K. Sarcoidosis and its ophthalmic manifestations. Am. J. Ophthalmo!. 86: 648, 1978.
19. Siltzbach L.E., Greenberg G.M. Childhood sarcoidosis. N. Eng!. J. Med. 279: 1239, 1968.
20. Salazar A, Mana J., Albareda J.M., Badrinas F., Fernandez-Nogues F. Neurosarcoidosis: presentaci6n de 14 cases. Med. Clin. 100: 292, 1990.
21. Thodou E., Asa S.L., Kontogeorgos G., Kovacs K., Horvath E., Ezzat S. Lymphocytic hypophysitis: clinico-pathological findings. J. Clin. Endocrino!. Metab. 80: 2302, 1995.