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Original Studies |
Departments of Endocrinology (G.A.K., T.B.P., P.J.J., J.P.M., G.M.B., A.B.G.), Neuroradiology (J.E.), Radiotherapy (P.N.P.), and Psychological Medicine (J.E.D.), St. Bartholomew’s Hospital, London, United Kingdom EC1A 7BE
Address all correspondence and requests for reprints to: Prof. A. B. Grossman, Department of Endocrinology, St. Bartholomew’s Hospital, London, United Kingdom ECIA 7BE. E-mail: a.b.grossman{at}mds.qmw.ac.uk
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Abstract |
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The median age at diagnosis of DI was 34 yr (range, 2–47 yr); DI was the presenting symptom in four patients, whereas the remaining eight each developed DI 1–20 yr (median, 2 yr) after the diagnosis of LCH. Eight patients developed one or more anterior pituitary hormonal deficiencies at a median of 4.5 yr (range, 2–22 yr) after the diagnosis of DI: GH deficiency developed in eight patients (median, 2 yr; range, 2–22 yr), FSH-LH deficiency in 7 patients (median, 7 yr; range, 2–22 yr), and TSH and ACTH deficiency in five patients (median, 10 yr; range, 3–16 and 3–19 yr), respectively; five patients developed panhypopituitarism. In addition, seven patients with anterior pituitary dysfunction also developed symptoms of other NEH dysfunctions at a median of 10 yr (range, 1–23 yr): five morbid obesity (body mass index, >35), five short term memory deficits, four sleeping disorders, two disorders of thermoregulation, and one adipsia. All patients developed disease outside of the hypothalamus during the course of the study, and no fluctuation of disease activity in the HPA region was noted. Radiological examination of the HPA was abnormal in each of the eight patients with anterior pituitary involvement and in the seven patients with NEH dysfunction (one or more abnormalities): seven had thickening of the infundibulum, and one had hypothalamic and thalamic signal changes. All patients who had a magnetic resonance imaging scan had absence of the bright spot of the posterior pituitary on the T1-weighted sequences, and in four patients with DI and normal anterior pituitary function this was the only abnormality. The five patients who received radiotherapy to the HPA achieved a partial or complete radiological response, and there was no evidence of tumor progression in this region. No form of therapy, including chemotherapy, improved any established hormonal deficiencies or symptoms of NEH.
In summary, in our adult patients with hypothalamic LCH and DI, anterior pituitary hormonal deficiencies developed in 8 of 12 patients; these occurred over the course of 20 yr. They were frequently accompanied by structural changes of the HPA, although these were often subtle in nature. In addition, symptoms of NEH dysfunction developed in up to 90% of such patients and complicated management. Radiotherapy may be useful in achieving local control of tumor, but established anterior, posterior pituitary, and other NEH dysfunctions do not improve in response to current treatment protocols. Patients with LCH and DI, particularly those with multisystem disease and a structural lesion on radiology, should undergo regular and prolonged endocrine assessment to establish anterior pituitary deficiency and provide appropriate hormonal replacement.
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Introduction |
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Because the disease is rare in adults, leading to a paucity of long term follow-up studies, the prevalence and biological predictors of the specific deficits of anterior pituitary function have not been well defined (4, 7, 13, 14). In addition, although symptoms of generalized hypothalamic dysfunction have been described in patients with LCH and central nervous system (CNS) involvement, the prevalence, severity, and clinical implications of such involvement are unknown (13). Disease activity in some sites, such as skin and bone, is known to fluctuate spontaneously, but whether this is so in other sites in adults is less certain. Further, responses to treatment have not been clearly delineated in adults (2, 7, 13).
This study was undertaken to determine the frequency of defects in anterior pituitary function in adult patients with DI and LCH followed for a prolonged period. We have attempted to identify whether there is any particular pattern of evolution of pituitary dysfunction, to detemine the presence of biological predictors with relation to structural changes observed on computed tomography (CT) or magnetic resonance imaging (MRI) scanning, and to monitor the progress of the disease and its response to treatment. Furthermore, we have investigated the development of generalized nonendocrine hypothalamic (NEH) dysfunction and its implications for the management of these complex cases.
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Subjects and Methods |
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Symptoms/signs suggestive of 1) mass effects specific to the HPA either at presentation and/or at regular follow-up, 2) anterior and posterior pituitary hormone deficiencies, and 3) other NEH involvement (appetite, thirst, sleep disturbances, memory deficit, temperature, and food intake dysregulation) were particularly recorded. Complete endocrine evaluation consisted of baseline serum hormonal measurements (serum cortisol, T4, T3, TSH, PRL, LH, FSH, estradiol, progesterone, testosterone, and GH/insulin-like growth factor I levels), early morning plasma and urinary osmolality measurement, and, when appropriate, dynamic endocrine tests: the insulin tolerance test for assessment of GH and/or ACTH/cortisol reserve, TRH and GnRH stimulation tests, and a water deprivation test for assessment of partial states of vasopressin deficiency (18). Neuroendocrine assessment was performed at the time of diagnosis of DI in nine patients, 1 yr after the diagnosis in two patients, and 11 yr after the diagnosis in one patient. Five patients received treatment before the first neuroendocrine assessment; two patients had been given chemotherapy 1 and 15 yr previously, two had been given systemic corticosteroids, and two had been given localized radiotherapy (one of whom was also given corticosteroids). Whenever there was clinical suspicion of NEH involvement, formal neuropsychological- psychometric evaluation was performed. The assessment included tests of general intellectual functioning, memory, attention, and concentration and in some cases the Halstead-Reitan battery. Assessments were carried out at intervals over a period of more than 20 yr, and the tests used have varied as test revisions and innovations have appeared; the tests used were therefore not necessarily the same for each patient. Five patients in total had formal psychometric assessment; two were assessed before any form of radiotherapy was applied to the HPA, whereas two were assessed 2 yr or more after radiotherapy was given.
Radiological assessment included conventional radiology of the localized and/or generalized disease and enhanced CT and/or, since 1993, MRI of the HPA at the time of initial assessment and before and after each therapeutic session in 11 patients; in the other patient HPA involvement was noted at autopsy.
Treatment modalities were categorized as local (radiotherapy) or systemic (glucocorticoid and/or cytotoxic drugs) therapy (see Table 4). Radiotherapy was applied to localized lesions and in five patients with disease confined to the HPA (median dose, 2000 cGy; range, 1000–2500 cGy). All patients received radiotherapy to the HPA region after all their endocrine deficiencies had developed. Response criteria were considered according to disease activity: no response, indicating progressive disease or no improvement or system dysfunction, and local recurrence, vs. complete or partial remission, were differentiated (17). During the assessment of evolving hypothalamo-pituitary dysfunction, particular attention was paid to the effect of possible confounding factors on the development of the dysfunction after treatment with local radiotherapy (19).
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Results |
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Extent of disease (Table 1
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All patients developed multisystemic disease; 7 patients presented with bone involvement, whereas 11 of 12 subsequently developed bone lesions. Five patients presented with soft tissue involvement, besides DI, but eventually all patients developed some form of other soft tissue infiltration. Eleven patients developed both soft tissue and bone disease, 7 multifocal soft tissue, whereas 6 had evidence of multifocal bone disease. There was persistent disease activity despite different treatment modalities, and no patient obtained complete remission. In addition, none of the patients showed spontaneous improvement in disease activity before any form of treatment was applied, and no remission of established endocrine deficiencies was noted. Two of the patients died during the period of the follow-up. One patient died from Creutzfeldt-Jacob disease as a consequence of treatment with cadaveric GH for growth retardation. The other patient died after a severe gastrointestinal bleed secondary to esophageal varices (the patient also suffered from micronodular cirrhosis of the liver, probably alcohol related).
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)Four patients initially presented with DI (defined as raised plasma osmolality, >295 mosmol/kg, in the presence of inappropriate low urine osmolality), but subsequently all patients developed DI during the course of the disease (median, 2 yr; range, 0–20 yr). DI was the earliest hormonal deficiency noted and predated the development of any other endocrine deficiency in all patients with anterior pituitary involvement by a median of 2 yr (range, 1–16 yr). Eight patients with DI developed at least one other anterior pituitary hormone deficiency; DI remained the only endocrine abnormality in the other four patients. All patients with DI eventually developed multisystem disease; no spontaneous improvement in posterior pituitary function was noted.
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)Three patients had pituitary assessment at initial presentation (1 patient with DI). Eight patients in total developed 1 or more anterior pituitary hormonal deficiencies; 6 of 12 patients showed more than 1 hormonal deficiency, whereas 5 patients developed panhypopituitarism.
GH deficiency (GHD). GHD (defined as a peak serum GH <9 mU/L during insulin-induced hypoglycemia or a glucagon test) developed in eight patients (median, 8 yr after diagnosis of DI; range, 2–20 yr). GHD preceded the development of all other endocrine deficiencies in four patients, whereas two patients (cases 5 and 11) developed LH-FSH deficiency at an earlier stage, and one patient (case 8) developed concomitant ACTH deficiency. One patient with GHD and short stature was treated with cadaveric GH, but eventually developed terminal Creutzfeldt-Jacob disease. Two adult patients have received synthetic GH replacement therapy.
FSH-LH deficiency. Gonadotropin deficiency (defined as low basal gonadal steroids with concomitant inappropriately low gonadotropins) developed in six patients at a median of 7 yr after the diagnosis of DI (range, 2–22 yr). Gonadotropin deficiency was the second most common evolving anterior pituitary hormone deficiency, but in two patients (cases 5 and 11) it preceded GHD. One male patient with infertility was successfully treated with gonadotropin treatment.
TSH deficiency. Thyroid hormone deficiency (defined as a lack
of elevation of TSH in the presence of low levels of thyroid hormones)
developed in five patients (median, 10 yr; range, 3–16 yr) and
preceded the development of ACTH deficiency in all except one patient
(Table 2). TSH deficiency developed only in the context of
panhypopituitarism. One patient developed primary hypothyroidism, which
resulted from histologically proven LCH of the thyroid, whereas another
with primary hypothyroidism had positive thyroid antibodies; although
no biopsy was performed to exclude thyroidal infiltration with LCH, a
presumptive diagnosis of autoimmune hypothyroidism was made.
ACTH deficiency. ACTH deficiency [defined as either a 0900 h cortisol level of <100 nmol/L or an impaired cortisol rise (<550 nmol/L) during insulin-induced hypoglycemia or a glucagon test] developed in five patients (median, 10 yr; range, 3–19 yr). ACTH deficiency, similar to TSH deficiency, only developed in the context of panhypopituitarism (cases 6–9 and 11) and was the latest evolving deficiency; no patient presented in adrenal crisis.
PRL levels. PRL levels in excess of the upper extent of the normal range (360 mU/L) were found in two patients (1600 and 1800 mU/L) during the course of the disease (cases 1 and 8). One of these two patients (case 1) had normal anterior pituitary function and no abnormality on imaging, whereas the other was panhypopituitary.
NEH dysfunction (Table 3)
Symptoms of NEH dysfunction, although not noted at initial
presentation, developed in seven patients at a median of 10 yr (range,
1–23 yr) after the diagnosis of DI was made. Each of the seven
patients developed an abnormal eating pattern (hyperphagia) at a median
of 10 yr (range, 1–28 yr); five had morbid obesity, defined as a body
mass index (BMI) greater than 35 (median BMI, 40; range, 35–44), and
required pharmacological intervention with dexamphetamine; although
this treatment may have halted the progression of further weight gain
and helped overcome somnolence, it did not improve obesity overall.
However, minor abnormalities not requiring treatment were observed in
the majority of patients (median BMI, 31; range, 20–44). Four patients
developed worsening short term memory formally assessed with
neuropsychological tests at a median of 10 yr (range, 2–24 yr). Two
patients developed problems with thermoregulation, one of them
requiring recurrent admissions for life-threatening hypothermia.
Another patient developed adipsia, making the management of DI
extremely difficult; this patient was treated with a fixed volume of
fluid intake, and the dose of desmopressin was then adjusted to
requirements according to body weight, fluid balance, and osmolality
measurement. Symptoms of NEH dysfunction developed only in patients
with anterior pituitary dysfunction (seven patients) accompanied by
structural lesions on pituitary imaging (see below). There was one
patient with panhypopituitarism in whom the only evidence of NEH was
severe obesity (BMI, 41; case 8; Table 3). Of the five patients who
underwent formal psychometric assessment, four (two preirradiation, two
postirradiation) had evidence of varying degrees of memory
impairment involving recall and/or recognition of verbal material
(designs, faces, pictures of common objects, and spatial position of
pictures and objects). The fifth patient, and the only one of the five
to show no HPA abnormality on imaging, had no evidence of memory
impairment or neuropsychological impairment generally (Halstead-Reitan
impairment index, 0.14; normal, 0.00–0.30).
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)In total, 11 patients had imaging of the HPA (the other patient had anterior pituitary and NEH involvement demonstrated at autopsy). The most commonly encountered abnormalities were infundibular thickening (7 patients) and hypothalamic and thalamic signal changes (1 patient). Four patients had apparently normal imaging of the HPA; all of these had intact anterior pituitary function, and 1 of these patients had extensive cerebellar involvement without any obvious hypothalamic involvement. However, all patients who had imaging with MRI scanning showed a lack of the bright spot of the posterior pituitary on T1-weighted sequences. Radiological abnormalities always predated the development of anterior pituitary dysfunction.
Patients with panhypopituitarism
Five patients progressed to panhypopituitarism (cases 6–9 and 11); two of these initially presented with DI. The median age at the development of DI was 30 yr (range, 2–45 yr); PRL levels were elevated in only one (case 8). Radiology revealed infundibular thickening in all four patients who were imaged, whereas one patient who did not have pituitary imaging was found to have mamillary body involvement on autopsy; all patients had NEH involvement. However, no particular pattern of clinical presentation, disease extension, evolving endocrine deficiency, or radiological appearance was found that could predict more severe impairment of pituitary function.
Response to treatment (Table 4)
Treatment regimens included a wide range of therapeutic modalities. Radiotherapy was given to six patients with bone and bone/soft tissue lesions; partial responses were initially obtained in all six in terms of tumor mass regression, and during the period of follow-up no irradiated lesion showed progression. However, five of six patients eventually developed additional lesions elsewhere. Five patients with HPA involvement on imaging received treatment with local radiotherapy either alone (median dose, 2000 cGy; range, 1000–2500 cGy) or in combination with other chemotherapeutic agents at a median of 11 yr (range, 2–30 yr) after the diagnosis of DI. All five patients showed evidence of partial or temporary radiological improvement, although the hormonal deficiencies remained. Eleven patients received some form of systemic treatment, which included chemotherapy (etoposide, vinblastine, and/or cyclosporin) and high dose corticosteroids. Although partial responses were obtained, all patients finally relapsed or had progression of the disease. No established endocrine or NEH deficiency responded to treatment.
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Discussion |
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In our subgroup of adult patients with LCH involving the HPA and DI, anterior pituitary dysfunction developed in two thirds of patients followed for a median of 11.5 yr after the diagnosis of DI, unrelated to radiotherapy, but with a wide dispersion of the time to onset. This prevalence is much higher than that previously noted (4, 5, 9, 10, 23), but might be explained by the fact that we studied a particular group, patients with LCH and DI, who are at higher risk for developing anterior pituitary deficiency for a prolonged period (13). However, careful analysis of other studies with prolonged follow-up and more detailed investigation of pituitary involvement in patients with DI demonstrates a similar high incidence (1, 4, 5, 8, 17, 23, 24). As particular attention was paid to eliminate the confounding effects of treatment, particularly radiotherapy, that have previously been implicated in the development of pituitary dysfunction in patients with LCH (4, 13), it seems very likely that anterior pituitary dysfunction develops as a consequence of the disease.
Anterior pituitary deficiency in LCH has almost always been associated with DI (4, 5, 17, 23); only a few cases have been noted in the literature of pituitary hormone insufficiency without DI (25). Although DI may predate the diagnosis of LCH, it develops most commonly at about 12 months, with a range that can extend to many years from diagnosis (2, 4, 26). Associated features are multisystem disease with skull vault defects, but particularly temporal bone or orbital lesions with intracranial tumor extension (5). Similarly, Baumgartner et al. in another recent study found a 21% prevalence of DI in their adult patients with LCH; half of these had concomitant panhypopituitarism, which appeared sporadically and always in combination with DI (17). These researchers concluded that although the frequency of isolated involvement of the pituitary gland is unknown, this should be considered in all patients with DI (6, 17, 27). Kilpatrik et al. (23) found a 15.5% prevalence of DI in adults with LCH; 15% of patients with DI had anterior pituitary involvement. However, as partial forms of DI may also occur and remit spontaneously, this figure may well be an underestimate (4, 17).
GHD occurs in approximately 40% of affected children, and it has been related to histiocytic infiltration of the hypothalamus (14, 22). GHD has frequently been observed as the first endocrine defect in addition to DI, with a median latency of about 1 yr from diagnosis (4, 10, 14, 26, 27). Others have found it only in relation to treatment with radiotherapy (22); however, none of our patients who developed GHD had received any previous radiotherapy to the HPA. Growth retardation, although previously described (21, 22), is thought to be an infrequent presentation of LCH (6, 22). However, it was a common finding in a recent study (14), and GHD should therefore always be considered in children with LCH and DI. As adults with GHD may show an increase in well-being and a favorable metabolic profile in response to GH therapy, assessment of GHD may be an important part of the evaluation of adult patients with LCH (28).
There are only a few reports on gonadal function in patients with LCH, as most studies have been of prepubertal children (14). Although the early studies in adults with LCH and DI failed to demonstrate abnormalities of gonadotropin secretion (8), a few cases of amenorrhea in adults have been described (6, 13). We found a high incidence of gonadotropin deficiency (50% of our patients with DI), which is also apparent in other detailed studies in adults (1, 4, 5, 8, 17, 23, 24). Similarly, thyroid hormone deficiency can be a major component of anterior pituitary dysfunction in patients with LCH (1, 4, 5, 6, 7, 8, 17, 23, 24). One of our patients also developed primary hypothyroidism due to LCH infiltration of the thyroid gland, an involvement that has only rarely been previously described (29). ACTH deficiency mostly presented in the context of generalized pituitary involvement; however, a case of isolated ACTH deficiency has also been described (4). PRL levels were elevated in 2 patients, with only 1 showing HPA involvement, and is therefore unlikely to be a significant factor in the pathogenesis of gonadotropin deficiency. Similarly, Maghnie et al. (26) reported that basal and TRH-stimulated PRL levels were normal in 17 children with LCH.
Imaging studies of patients with LCH and CNS involvement have shown that more than one type of lesion was present in 87% of individual patients, including patients with DI (5, 30). In addition, abnormalities of the HPA were observed in 68% of patients with CNS lesions and in 81.5% of patients with DI (infundibular thickening, partial or complete empty sella with a lack of posterior pituitary bright spot on T1-weighted MRI sequences, or a pituitary mass lesion) (5, 24, 26, 30). Morphological changes in the HPA are currently optimally demonstrated by MR imaging with administration of gadolinium-dimeglumine gadopentetate (26, 31). A small pituitary or empty sella has also been described in cases of combined anterior and posterior pituitary insufficiency (4). However, anterior pituitary dysfunction may also occur in the absence of structural changes on imaging and has been attributed to microinjury leading to vascular impairment and scarring (24). Other possible mechanisms include cytokine modulation from adjacent osseous lesions or an autoimmune effect (32). We noted that all of our patients who developed anterior pituitary deficiency had a form of abnormal HPA imaging other than loss of the bright spot of the posterior pituitary on MRI imaging. Similarly, Broadbent et al. (4), studying children with DI, demonstrated that a mass lesion with an empty sella or pituitary stalk thickening was present when multiple hormonal deficiencies were identified; in addition, when DI occurred either alone or with GHD, the findings were more variable, although the majority of patients had similar abnormalities.
Maghnie et al. attempted to identify predictors of late endocrine sequelae in children with LCH and concluded that dynamic endocrine pituitary testing was not a useful predictor (14). Neither the site of involvement nor the extent of the disease was associated with further endocrine deterioration. Therefore, it seems that only DI in association with markedly abnormal HPA imaging indicates patients with LCH at higher risk for anterior pituitary dysfunction. As DI is associated with multisystem disease in the majority of studies (4, 5, 8, 14), and progression may be greatly delayed (23), such patients should be receiving regular and prolonged follow-up to identify such dysfunction and provide adequate replacement.
DI with structural changes in the HPA often heralds the involvement of other parts of the brain with more global neurological or neuropsychological sequelae, depending on the location of the involvement (5, 30). The signs and symptoms of NEH involvement range from disturbances in social behavior, appetite, and temperature regulation to abnormal sleeping patterns (5). Surprisingly, research is limited on neuropsychological manifestations of the disease, but early findings suggest that these may be relevant in a significant proportion of patients. We found a high prevalence of NEH abnormalities in patients with DI and LCH; all were associated with anterior pituitary deficiency and structural lesions on imaging. The most prominent abnormality was an abnormal eating pattern and obesity; five patients developed morbid obesity, which was difficult to control. Further abnormalities, such as disturbances in thermoregulation and adipsia, can make DI difficult to treat and complicate the overall management of these problematic cases (33, 34). This is particularly significant when there is also memory impairment and problems with compliance (34). Our neuropsychological and radiological findings flag up a link between memory impairment in LCH and structural changes in the HPA, which is consistent with some of the recent work on diencephalic amnesia (35).
It has been suggested that none of the treatments currently available is able to alter the course of LCH or to prevent its progression (23), whereas established endocrine abnormalities do not respond to treatment (8, 23). Although Rosenzweig et al. renewed suggestions that radiotherapy to the HPA when applied early for incipient DI may be effective with partial or even complete remission (27), this has not been found to be the case in other studies (10, 23, 30). In our patients there was clear evidence that localized HPA radiotherapy was associated with tumor regression and stabilization, and none of these patients showed subsequent tumor progression at this site. However, some patients showed little in the way of abnormal imaging of the HPA. Recent advances in MRI imaging have shown absence of the bright spot of the posterior pituitary at the onset or soon after of the development of LCH (5, 26, 30) as well as other HPA abnormalities that may revert to normal at follow-up (5). LCH in adults may run a relatively indolent course (20, 23), and a more conservative approach, especially in elderly or debilitated patients, has been proposed (30). Thus, long term follow-up with proper replacement of hormonal deficiencies may be as important in improving quality of life as other more aggressive interventions.
In summary, adult patients with LCH presenting with DI are at high risk for the development of anterior pituitary deficiency, especially when associated with abnormal HPA imaging. Generalized hypothalamic involvement is also a prominent feature of this disease, and the progressive hypopituitarism appears to be poorly responsive to current modalities of treatment, although localized disease at the HPA responded well to radiotherapy in that region. On the basis of our experience and a review of the literature, systemic chemotherapy appears to be of little benefit in controlling the progression of the disease over the long term, although focal radiotherapy may halt local disease progression in terms of mass effects. We suggest that such endocrine abnormalities should be actively sought in patients with LCH, as their recognition and management play important parts in the treatment of this difficult condition.
Received October 4, 1999.
Revised December 1, 1999.
Accepted December 9, 1999.
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