Tight control of growth hormone: an attainable outcome for acromegaly treatment.

Acromegaly, an insidious neuroendocrine disorder, leads to debilitating acral and metabolic disturbances (1). The disease has long been recognized to be associated with enhanced mortality due to cardiovascular, pulmonary, and neoplastic disease (2–6). Enhanced surgical microtechniques, improved stereotactic radiation, and the advent of potent peptide analog therapy to effectively inhibit pituitary adenoma GH hypersecretion (7), together with development of ultrasensitive GH assays (8, 9), have allowed a more stringent biochemical remission to be both defined and attained. Accordingly, sensitive imaging, biochemical and epidemiologic techniques have been applied to more accurately determine therapeutic outcomes in acromegaly. Successful therapy of acromegaly should normalize GH and insulin-like growth factor I (IGF-I) secretion, ablate or contain the adenoma mass and its local pressure effects, improve systemic morbidity, and ultimately, normalize mortality (7). In this issue of JCEM, two comprehensive papers address the important question of long-term acromegaly treatment outcomes (see pages 3411 and 3419) (10, 11). Remarkably, the initial results of surgical resection of GHsecreting adenomas, as reported by these two highly experienced neurosurgical groups are quite similar. Abosch et al. (10) report short-term remission (GH , 5 mg/L) in 76% of 254 patients, with the majority of 129 ascertainable patients remaining in long-term remission. Clearly, the biochemical parameter of “basal” GH less than 5 mg/L does not reflect normalization of GH hypersecretion, as GH secretion is normally pulsatile, with peaks often reaching 20 mg/L or more. Nevertheless, the impressive finding of this study is that, even using this less stringent criterion of remission, the mortality rate achieved was equivalent to that in matched controls, in contrast to the 2.4–4.8-fold enhanced mortality in those patients with persistent disease. However, many of their patients appeared to harbor microadenomas, as assessed by older insensitive and imprecise imaging techniques, and thus, extrapolation of earlier observations may not reflect current experience with improved magnetic resonance imaging, sensitive GH assays, and sophisticated biochemical follow-up. In their study, Swearingen et al. (11), using more stringent criteria for remission (normalized IGF-I levels or GH suppression to ,2 mg/L after glucose loading), report that over 90% of patients harboring microadenomas successfully achieved these criteria. Significantly, however, less than 50% of patients harboring macroadenomas were biochemically controlled. Unfortunately, the majority of patients in their series (129/162) harbored macroadenomas, similar to reported experience in most other studies (1). Importantly, the mortality risk in 86 patients cured at surgery did not differ from controls, while in those patients with persistent disease, even after adjuvant radiation or medical therapy, mortality remained significantly increased (almost 2-fold). Thus, both these studies confirm two earlier less comprehensive reports suggesting that the level of attained GH is the single most important determinant of mortality in acromegaly (5–6). Regardless of treatment mode, therefore, normalization of GH levels appears to restore mortality risk to that of age-matched population controls. Conversely, disease persistence postoperatively is associated with a 3.5-fold relative mortality risk. In both these series, postoperative complications occurred in approximately 5–8% of patients. These surgically related adverse events included permanent diabetes insipidus, cerebrospinal fluid leaks requiring repair, meningitis, severe sinusitus, and hypopituitarism. Thus, significant perioperative morbidity remains of concern, especially for patients operated on by less experienced surgeons. Two adjuvant modes of therapy, irradiation and somatotropin releaseinhibiting factor (SRIF) analogs, also have their respective disadvantages, including development of pituitary failure in most irradiated patients, local central nervous system damage in a small number of patients, and asymptomatic gallstones in up to 30% of patients receiving SRIF analogs. The challenge of tight GH control can now be met with greater stringency. Pituitary radiation may be administered but usually requires up to 12 yr or more for suppression of GH levels to less than 5 mg/L (12). Recently, the relative failure of irradiation to effectively normalize IGF-I levels in the long-term has also been documented, implying persistent albeit low levels of GH hypersecretion in these patients (13). Novel radiosurgical techniques, including stereotactic technology and use of the gamma knife, now offer focused tumor ablation, although long-term safety and efficacy are not yet known. Long-acting somatostatin analogs (14) are effective and safe in managing GH hypersecretion and the resultant systemic effects of acromegaly in patients in whom surgical resection has failed to achieve a stringent biochemical remission. SRIF analogs are also of use in those patients who have undergone irradiation and in whom GH levels may remain unacceptably elevated for up to 15 yr (15). Somatostatin analogs may also be offered as primary therapy, especially in those patients who refuse surgery or have other medical risk factors (7). As now confirmed in this issue (10, 11), most patients harboring macroadenomas have persistent postsurgical GH hypersecretion, and use of SRIF analogs should be weighed against radiotherapy for these patients. Long-acting injectable depot analogs administered once every 14–30 days enhance patient convenience and compliance Received August 12, 1998. Accepted August 12, 1998. Address correspondence and requests for reprints to: Shlomo Melmed, M.D., Academic Affairs, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Room 2015, Los Angeles, California 90048. E-mail: melmed@csmc.edu. 0021-972X/98/$03.00/0 Vol. 83, No. 10 Journal of Clinical Endocrinology and Metabolism Printed in U.S.A. Copyright © 1998 by The Endocrine Society