Diagnosis and Management of Pituitary Tumors

306 QUABBE AND PLÖCKINGEReven after 10 yr of therapy (252). In patients with acromegalyowing to ectopic GHRH secretion, octreotide suppresses bothGHRH from the ectopic source and GH from the hyperplasticpituitary gland (253).Inhibition of GH secretion and tumor size reduction are poorlycorrelated during octreotide therapy (194). This may be partlyowing to a marked heterogeneity of the individual cells insomatotroph adenomas. Cells differ in their GH secretory activity.Actively secreting cells respond to octreotide with a larger reductionof hormone secretion (254). Therefore, an important GHdecrease may be owing to an octreotide effect on only a minorityof cells, which could explain the absence of tumor volume reduction.Minor effects of octreotide on PRL (suppression) and thepituitary–thyroid axis have been reported (207,255), but have noclinical importance.Beneficial clinical effects—reduction of headaches, sweating,joint pain, snoring, and sleep apnea—are sometimes more pronouncedthan the degree of GH suppression would suggest. Thismay be owing to a direct suppressive effect of octreotide on IGF-1generation (256) and to stimulation of the IGF-1 binding protein 1(IGF-BP1 [257,258]). Increased IGF-1 binding to IGF-BP1 woulddecrease the availability of free IGF-1. General improved wellbeingmay also result from a direct central nervous effect. Somesomatostatin analogs have been shown to bind to brain opioidreceptors (259). The rapid reduction of headaches—sometimeswithin minutes of sc injection—also suggests a central effect (260).Octreotide—like its mother substance, somatostatin—hasmany other actions in addition to its GH-lowering effect (for arecent review, see 261). Inhibition of insulin secretion may inducecarbohydrate intolerance. The insulin-releasing intestinal incretin,glucagon-like peptide (7-36) amide (GLP-1), is also suppressed(261a). On the other hand, octreotide-induced GH suppressiontends to improve carbohydrate tolerance (262,263). The net outcomedepends on the relative importance of these opposing effectsfor the individual patient (e.g., pre-existing insulin resistanceowing to obesity, genetic predisposition for diabetes mellitus andso forth). In clinical experience, both development of carbohydrateintolerance as well as amelioration do occur.Side effects of octreotide treatment include gastrointestinaldiscomfort and diarrhea, which usually subside within days orweeks, and the development of gallstones. Gallstones usuallyremain silent owing to the inhibition of gallbladder motility by thedrug. However, complications may arise, when octreotide is discontinued,necessitating in some cases acute cholecystectomy(264). Gallbladder hypermotility has been described to occurwithin 24–96 h after cessation of octreotide therapy. Therefore, adrug-free period each week has been proposed for patients onchronic octreotide therapy in order to flush the gallbladder fromsludge (265,266). However, GH concentrations also rise aftercessation of octreotide (251), although this may occur more slowlythan the restoration of gallbladder motility. The development ofgallstones can be prevented and existing cholesterol gallstonescan be dissolved with cheno/ursodeoxycholic acid preparations(267,268). Long-term octreotide treatment also predisposes tochronic gastritis (251,269,270)and vitamin B-12 deficiency (269).Reversible loss of scalp hair in four of seven women has beendescribed during long-term octreotide treatment in a single report(271). Antibody formation against octreotide has been detected ina few patients, but does not seem to diminish the GH-suppressiveeffect of the drug (272–274).Figure 17-6 Treatment scheme for acromegaly. Simplified treatmentscheme for acromegaly. Individual treatment choices depend onadditional considerations (e.g., age, risk factors for surgery, patient’spreferences, and so forth). A GH value of 2 µg/L (others use 2.5 µg/L)indicates “normalization of GH concentration” and, hence, no needfor further treatment. It does not assure “cure of disease.” For details,see text.COMBINATION TREATMENT When octreotide treatmentalone fails to normalize the GH concentration, combination ofoctreotide and bromocriptine (or probably any other dopamineagonist drug) has been suggested to give more favorable results insome patients. When either 50 µg of octreotide, 2.5 mg bromocriptine,or a combination of both drugs was given acutely toacromegalic patients, the combination was slightly, but significantlybetter than either drug alone to suppress GH (275). This wasalso seen in a subacute study on 12 patients in which octreotidealone (200 µ twice daily) was compared with bromocriptine alone(5 mg twice daily) and the combination of both drugs (276). However,in a third study, when treatment conditions more closelyresembled the pattern usually applied in clinical practice (octreotide3 × 100 µg/d plus bromocriptine 2 × 5 mg/d), no difference wasfound between the two regimens (277). Thus, the value of combinationtherapy as compared with octreotide alone is at presentuncertain and marginal at best. A schematic outline of the decisiontree for the treatment of a patient with acromegaly is shown inFigure 6.GROWTH HORMONE RECEPTOR ANTAGONIST Agrowth hormone receptor antagonist, pegvisomant, has recentlybeen developed by molecular engineering of the human growthhormone molecule. Eight amino acid substitutions at the first bindingsite increase its affinity to the receptor and one amino acidsubstitution at the second binding site abolishes binding to a secondreceptor. In normal subjects the antagonist lowered serumIGF-1 concentrations in a 12 wk trial without causing a (rebound)GH increase (22a). In 112 patients with acromegaly the antagonistnormalized serum IGF-1 concentrations in almost 90% of thepatients (22b). Since IGF-1 exerts a negative feedback on thepituitary somatotroph, a GH increase and growth of the GH-secretingadenoma are potential unwanted effects (prior radiation therapywould probably prevent tumor regrowth). A significant, dose-dependentGH elevation did indeed occur. Although an increase in thesize of the pituitary adenoma has recently been observed in onepatient on long-term treatment (277a), this antagonist will probablybe a valuable additional tool in the spectrum of treatmentstrategies.FOLLOW-UP Patients with acromegaly who have beentreated by surgery, irradiation, or who are under medical therapy