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Hypothalamo-Pituitary Surveillance Imaging in Hypopituitary Patients Receiving Long-Term GH Replacement Therapy

Departments of Endocrinology (V.F., W.M.D., R.A.L., D.C., D.F.W., A.B.G., G.M.B., J.P.M.) and Diagnostic Imaging (J.E.), St. Bartholomew’s Hospital, London EC1A 7BE, United Kingdom

Address all correspondence and requests for reprints to: Prof. John P. Monson, Department of Endocrinology, St. Bartholomew’s Hospital, West Smithfield, London EC1A 7BE, United Kingdom. E-mail: J.P.Monson{at}mds.qmw.ac.uk

Abstract

Most cases of adult-onset (AO) GH deficiency (GHD) result from the presence of hypothalamo-pituitary tumors or their treatment. GH replacement is now widely used in adults with hypopituitarism, but its effect on hypothalamo-pituitary tumor growth or recurrence is unknown. Anecdotal evidence from early experience of GH replacement in adults documented occasional tumor recurrence, but any relationship of this to the use of GH was unclear. We have now prospectively imaged the pituitary glands of 100 consecutive patients (60 females, 40 males; mean age, 46 yr; range, 18–69 yr) who had AO-GHD after appropriate treatment for a pituitary or peripituitary tumor. External radiotherapy had been given to 91 patients. All patients were treated with a dose titration regimen to maintain serum IGF-I between the median and upper end of the age-related reference range. Pituitary imaging was performed before the commencement of GH and after 6 and 12 months of treatment in all patients, again at 2 yr in 92 patients, at 3 yr in 63 patients, and after 4 yr in 23 patients. In only one patient was there evidence of slight intrasellar tissue enlargement at 6 months; GH replacement was continued, and there was no further change between 6 and 12 months. In all other patients, either the appearances were unchanged or the amount of tissue was reduced during long-term follow-up on GH. We have shown that hypothalamo-pituitary tumor recurrence was thus very rare over this time period in this group of GH-treated patients, and this is reassuring. Similar prospective longitudinal observation of patients who have not received postoperative irradiation and comparison with rates of tumor recurrence in control series are desirable.

SINCE THE PUBLICATION of the early placebo-controlled trials of the use of recombinant human GH (rhGH) for the treatment of GH deficiency (GHD) in hypopituitary adults (1, 2, 3, 4, 5), much attention has been focused on developing treatment protocols by which GH replacement can be most safely and effectively delivered. With time and shared clinical experience, it has become apparent that optimum GH replacement is most appropriately achieved by dose titration, with individual tailoring of GH dose for each patient to achieve a normal serum IGF-I level (6). This strategy is associated with minimal side effects and a reduction in the required maintenance dose compared with previous weight-based and/or surface area-based dosing regimens, but without loss of efficacy (7, 8). In addition to clinical and biochemical monitoring, the practice of GH replacement requires additional, rigorous surveillance protocols because GH and IGF-I are known mitogens. Most cases of adult onset GHD result from hypothalamo-pituitary tumors or their treatment, and the question therefore arises as to whether GH replacement therapy may promote tumor recurrence. In the early trials of GH replacement for adult hypopituitarism, there were anecdotal reports of hypothalamo-pituitary tumor recurrence or enlargement, although the relationship of these events to the use of GH was far from clear. This is because there was often no baseline, pretreatment imaging since this was not a requirement for entry into those studies; furthermore, the doses of GH used were pharmacological rather than physiological such that serum IGF-I levels were frequently elevated (1, 2, 3, 4, 5). To establish whether GH replacement therapy is associated with a risk of pituitary/peripituitary tumor growth, we have prospectively imaged the hypothalamo-pituitary region of 100 consecutive patients with AO hypopituitarism immediately before commencing GH and at regular intervals during clinical follow-up. All patients received GH replacement according to an identical protocol to maintain serum IGF-I between the median and the upper end of the age-related reference range (6).

Subjects and Methods

Patients

One hundred consecutive AO-GHD patients (60 females, 40 males; mean age, 46 yr; range, 18–69 yr) were studied. GHD was diagnosed on the basis of a peak GH response of 3 ng/ml (9 mU/liter) or less during insulin-induced hypoglycemia (81% of patients) or on a glucagon stimulation test, if an insulin tolerance test was contraindicated (19%). GHD was established after appropriate primary treatment in patients with the following diagnoses: 30 clinically functionless pituitary tumors (immunohistochemistry positive for glycoprotein -subunit in 29%, LHß in 24%, and FSHß in 35%), 26 corticotropinomas (81% microadenomas, 19% macroadenomas, at the time of original presentation), 24 prolactinomas (40% microadenomas, 60% macroadenomas), 13 craniopharyngiomas, 2 somatotropinomas, 2 FSHomas, and 2 dysgerminomas. A total of 23% of the corticotropinomas and 8% of the prolactinomas were cured by surgery alone (postoperative serum cortisol <50 nmol/liter, or normal serum PRL). All of the patients except 9 (all corticotropinomas, 83% microadenomas) had received either postoperative or primary external beam pituitary irradiation. The mean time between primary therapy and the commencement of GH treatment was 11 yr, and the median was 9 yr (range 1–32 yr). The relatively high percentage of patients who had been treated with external pituitary irradiation reflects the long mean duration since primary therapy of the pituitary tumor and previous prevailing policies regarding routine external irradiation after surgery for nonfunctioning macroadenomas. Radiotherapy had also been used for persisting hormone secretion after surgery and for prolactinomas on medical therapy. All patients were treated by GH dose titration to maintain serum IGF-I between the median and upper end of the age-related reference range as previously reported (6). Where necessary, pituitary hormone deficits were appropriately replaced with hydrocortisone, thyroxine, gonadal steroids, and desmopressin. Sixty-two percent of the patients with prolactinomas did not require specific treatment for residual hyperprolactinaemia, and the remaining 38% were on maintenance cabergoline or bromocriptine.

Patients gave written informed consent to the anonymized collection of safety surveillance data during GH replacement therapy.

Scans

Pituitary imaging was performed in all patients before the commencement of GH and after 6 and 12 months, and in 92 patients at 2 yr, in 63 at 3 yr, and again in 23 cases at 4 yr. In 94 cases, this was obtained with high resolution magnetic resonance imaging (MRI) with and without gadolinium contrast medium, but computed tomography scans were performed in six patients in which MRI was not feasible due to claustrophobia or the patient’s habitus. All of the scans were reported by a single neuroradiologist (J.E.) and were classified as normal, empty/partially empty sella, intrasellar adenoma, or extrasellar adenoma.

Serum IGF-I assay

Serum IGF-I was measured by standard RIA after formic acid/acetone extraction (9). The interassay coefficient of variation was less than 10%.

Results

The median GH dose that was required to maintain serum IGF-I in the upper half of the age-adjusted normal range was 0.8 IU/day for males and 1.2 IU/day for females (range, 0.4–1.6 and 0.8–2.4 IU/day, respectively; 3 IU = 1 mg). Mean serum IGF-I before commencement of GH was 95 ± 36 ng/ml (SD; range, 46–166) for males and 84 ± 32 ng/ml (SD; range, 45–174) for females, rising by six months to 221 ± 56 ng/ml (range, 172–332) and 198 ± 55 ng/ml (range, 156–298) in males and females, respectively. Levels were maintained thereafter, and there was no statistically significant change in serum IGF-I in either males or females at any interval after 6 months.

The imaging characteristics in terms of the quantity of residual tissue in the pituitary fossa/suprasellar region are summarized in Table 1. In only one patient did the amount of tissue within the pituitary fossa increase after commencement of GH. In this patient, a 40-yr-old man who had been treated by transsphenoidal surgery and external radiotherapy 3 yr previously for a clinically functionless pituitary tumor, residual intrasellar tissue expanded to fill the previously partially empty pituitary fossa during the first 6 months of GH therapy (Fig. 1, A and B). The patient did not interrupt his therapy, and no further increase was noted on subsequent imaging at 12 months (Fig. 1C). There were no associated adverse clinical or biochemical sequelae. In all other patients, the amount of pituitary/peripituitary tissue was unchanged or decreased during follow-up on GH replacement.

View larger version (136K): [in this window] [in a new window]   Figure 1. Saggital reconstructions of serial enhanced computed tomography scans before and during GH replacement in a 40-yr-old patient with a clinically functionless pituitary adenoma, treated with transsphenoidal surgery and radiotherapy 3 yr previously. A, Baseline scan before surgery with GH; B, after 6-month therapy with GH; C, after 12-month therapy with GH. Residual intrasellar tissue expanded to fill the pituitary fossa after 6-month therapy, but was unchanged after 12 months.

Since the publication of a number of placebo-controlled trials of the use of GH therapy in the treatment of adult hypopituitarism (1, 2, 3, 4, 5), GH replacement is now being offered to selected hypopituitary adults with symptomatic and biochemically severe GHD. Although there is substantial evidence that hypopituitarism is associated with premature mortality and that AO-GHD is associated with an adverse cardiovascular risk profile (10, 11, 12), it will require several years of careful follow-up to establish whether the use of GH replacement restores mortality toward that of an age-matched control population. In the interim, it is imperative that GH replacement protocols minimize any potential adverse effects of therapy. In addition to avoiding adverse consequences of excess GH exposure on variables such as insulin sensitivity (13) and left ventricular mass (14), there is a need for careful surveillance of the potential mitogenic effects of GH. Several lines of evidence contribute to this concern. First, there is widespread agreement that excess GH exposure in the context of acromegaly is associated with an increased incidence of neoplasia, including adenomatous colonic polyps and carcinoma (15). Second, epidemiological studies have suggested that an individual’s long-term risk of malignancy of the prostate (men) (16) and breast (women) (17) is, at least in part, dictated by the serum level of IGF-I within the normal range. Third, in the earliest reports of the association of hypopituitarism with decreased longevity, there was a suggestion of a decrease in malignant disease among male patients, but this was not statistically significant (18). However, it should be recognized that in some studies, the association between serum IGF-I and prostate cancer has been modest (19) or absent (20, 21). In the present study, serum IGF-I was maintained above the median but within the age-adjusted normal range by careful dose titration as previously reported (6). There is widespread consensus that such a strategy is an effective way of avoiding excess GH exposure, with its possible adverse effects (22).

The background rate of pituitary tumor recurrence is of the order of 1–2% per year in patients treated by surgery alone (23, 24), a figure that is reduced by the use of postoperative external pituitary irradiation. More recent studies have underlined the effectiveness of administering radiotherapy after initial surgery to reduce the risk of tumor regrowth. In Oxford, UK, a cohort of 73 patients with nonfunctioning pituitary adenomas, treated with transsphenoidal surgery without radiotherapy, were followed up by imaging for a mean period of 76 months (25). Lifetable analysis on the group showed 82% recurrence-free survival at 5 yr and 56% at 10 yr, with a regrowth rate approaching 50%. In 1998, Gittoes et al. (26) published a retrospective study on 126 patients with nonfunctioning pituitary adenomas treated at two institutions in the United Kingdom. One hospital used radiotherapy routinely within 12 months of the initial surgery, whereas the other used it rarely. Although there were no significant differences in terms of sex, age, initial tumor size, and surgical techniques, the progression-free survival was 93% at both 10 and 15 yr for the radiotherapy-treated group, compared with 68 and 33%, respectively, for the nontreated group. Gittoes et al. concluded that the only prognostic factor for nonfunctioning tumor regrowth was the administration of radiotherapy to the pituitary region.

These data in patients treated with postoperative radiotherapy are broadly similar to the results of Brada et al. (27), who reported 411 patients with pituitary adenoma followed for 20 yr after surgery and conventional three field external beam radiotherapy. The results showed the prevalence of 10- and 20-yr progression-free status (no enlargement or recurrence of the tumor) to be 94 and 88%, respectively, in patients with nonfunctioning pituitary adenomas and 97 and 92% in patients with secreting tumors, in a population with a median age of 47 yr. Studies from other centers reported similar results (80–95% 10-yr progression free) (28, 29). Clearly, it is postoperative surveillance that is vital, and a strong case can be made for postoperative follow-up with MRI, reserving external irradiation for those patients who demonstrate evidence of tumor regrowth (30).

It should be noted that our patient group was heterogeneous. Some would have had an inherently lower risk of tumor recurrence (prolactinomas on medical therapy or small corticotropinomas with hormonal evidence of cure). Others might present a more substantial risk of regrowth (macroadenomas). The majority of our patients had received conventional external beam irradiation, reflecting the clinical policy prevailing at the time when they received primary therapy and which, as indicated above, would have reduced but not eliminated the risk of tumor recurrence. Furthermore, we must acknowledge that our patients were deemed to have no evidence of active tumor regrowth at the time at which GH was commenced and might thus be regarded as having an inherently lower risk of subsequent tumor recurrence. Nonetheless, although continued surveillance is clearly imperative, our data provide reassurance that the use of GH replacement titrated against serum IGF-I is not associated with an obvious early increase in the rate of hypothalamo-pituitary tumor recurrence compared with historical control series, at least if pituitary radiotherapy is given. Comparison with similar prospective, longitudinal, observational studies of GH replacement in patients who have not received postoperative irradiation is desirable.

Footnotes

The Department of Endocrinology at St. Bartholomew’s Hospital receives financial support from Pharmacia Corporation for its research on GH and growth factors.

Abbreviations: AO, Adult-onset; GHD, GH deficiency; MRI, magnetic resonance imaging; rhGH, recombinant human GH.

Received May 14, 2001.

Accepted August 6, 2001.

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