Diagnosis and Management of Pituitary Tumors

CHAPTER 14 / MEDICAL THERAPY 257absorption may be clinically significant, and vitamin K deficiencycausing an abnormal prothrombin time has been reported (183).Active gastritis has also been reported in 9 of 10 patients studiedprospectively by Plöckinger et al. (201) with damage to the superficialand deeper layers of the mucosa and focal atrophy. However,in another study by Anderson et al. (202), 10 of 33 (30%) patientshad gastritis before any therapy with octreotide, 17 of 36 (47%)patients had gastritis while taking octreotide, and 3 of 21 (14%)patients developed gastritis during treatment; only 2 of the 48 patientsin the whole group spontaneously complained of dyspepsia. Inthese studies, there was a highly significant association betweenthe presence of gastritis and the presence of Helicobacter pylori(201,202). Although Plöckinger et al. (201) found a decrease inserum vitamin B-12 concentrations in all of their patients andabnormally low levels in four, Anderson et al. (202) found thatonly 4 of 33 tested patients had parietal cell antibodies and two ofthese had no gastritis on gastroscopy. At present, it would appearto be prudent to check serum vitamin B-12 concentrations andprothrombin times periodically, and to consider that gastritis maybe present in patients with dyspepsia. Specific treatment of theH. pylori, if found, may then prove useful.The multicenter studies have also documented that gallstonesare present in 4–15% of patients before starting octreotide, andasymptomatic gallstones develop over 6–12 mo in another 10–15% (178,180–184). Over the course of more prolonged treatment,Newman et al. (183) noted the development of sludge in36% and gallstones in 24% of patients, with resolution occurringwithout stopping treatment in 36.1% of the patients with sludgeand 29.2% of the patients with stones. Of those patients initiallywith sludge, only 16.7% went on to develop stones. The developmentof sludge and gallstones was not related to dosage ofoctreotide (183). In this series of Newman et al. (183), most patientshad little or no symptoms. Of three patients who had elective cholecystectomiesbecause of vague abdominal symptoms, the symptomspersisted postoperatively. One patient had a cholecystectomybecause of an episode consistent with biliary colic. Other smallerseries have shown similar results (203–208). The mechanisminvolves an octreotide-induced inhibition of cholecystokininrelease with resulting inhibition of gallbladder contraction followinga meal (203,205,206). The inhibition of postprandial gallbladdercontractility by octreotide lasts for at least 4 h followinginjection and contractility reverts to normal by 8 h (203,206).Because most patients who develop stones are asymptomatic andrarely develop cholecystitis, the finding of asymptomatic gallstonesis not an indication to stop treatment. There are some datato suggest that ursodeoxycholic acid may cause dissolution ofstones, and this may be worth trying in the rare, symptomaticpatient. Furthermore, given the low morbidity of laparascopiccholecystectomy now, that procedure would appear warranted inthe symptomatic patient rather than stopping octreotide, if theoctreotide treatment is effecting a good clinical and biochemicalresponse. Because of the normal contractility that occurs by 8 hafter stopping octreotide, it has been suggested that the morningdose be withheld until 1–2 h after breakfast to allow at least onegood contraction per day; long-term studies showing benefit ofthis approach have not been reported as yet.Use with Bromocriptine In patients who have been tried onboth bromocriptine and octreotide, a better response is usuallyseen with octreotide (209,210). Some studies have shown thatsome patients respond acutely to a combination of bromocriptineand octreotide who do not respond to either drug alone (211) andchronic use also shows synergy between these two drugs (210).Part of this synergistic effect may be owing to altered pharmacokinetics;although the pharmacokinetics of octreotide areunchanged by coadministration of bromocriptine, the bioavailabilityof bromocriptine is increased by 40% when octreotide iscoadministered (210).GH-RECEPTOR ANTAGONISTS A new approach to themedical treatment of acromegaly is the development of an antagonistthat inhibits the binding of GH to its receptor. Normally, GHinitially causes a dimerization of the extracellular domain of thereceptor with binding of the single GH molecule. One antagonistof this binding, termed “pegvisomant,” blocks this dimerizationand binding, resulting in a decrease in GH action. In a preliminarystudy of its efficacy over 12 wk in 112 acromegalic patients, IGF-1levels were normalized in 89.3% of patients treated with the highestdose, 20 mg/d, with significant improvements in the symptomsof soft tissue swelling, excessive perspiration, and fatigue (211a).In one patient serum transaminase levels increased to normal afterthe drug was stopped but no other adverse effects were seen otherthan local irritation at the site of injection (211a). Longer studiesmust be completed before it can be seen how this medication fitsinto the overall therapeutic armamentarium for acromegaly.CUSHING’S DISEASEThe medical therapy of Cushing’s disease has been less successfulthan that of PRL- and GH-secreting tumors. A number ofmedications have been used over the past 20 years with varyingsuccess. At present, the most useful drug appears to be ketoconazole,which combines efficacy with tolerability. Clearly, some patientsrespond to the other drugs as well, but because of lower efficacy rates,their use is limited to the occasional patient who does not respondto other modalities.KETOCONAZOLE Pharmacology Ketoconazole is animidazole derivative with broad-spectrum antifungal propertiesthat has been found to interfere with steroid synthesis. Ketoconazoleinhibits several cytochrome P-450 enzymes in this pathway,including the cholesterol side-chain cleavage 17,20 lyase and11 β-hydroxylase steps (212). The drug also binds to glucocorticosteroidreceptors and serves as a competitive inhibitor to cortisol.Unfortunately, ketoconazole also blocks the 17,20 lyase stepin the testes, which is necessary for converting 17-hydroxyprogesteroneto androstenedione, which ultimately is converted totestosterone (212). The inhibition of other P-450 enzyme systemsresults in altered metabolism of a number of drugs, includingrifampin, phenytoin, cyclosporin, and warfarin.In addition to its effects on adrenal steroid synthesis and action,ketoconazole has also been shown to inhibit ACTH secretion bycorticotrophs in a dose-dependent action (213). It inhibits basaland corticotropin-releasing hormone (CRH)-stimulated cAMPcontent and release, and ACTH mRNA transcription and ACTHrelease (213) via a direct effect on the catalytic subunit ofadenylyl cyclase (214). In two patients with Nelson’s syndromewhose tumors were studied in short-term cultures in vitro, theaddition of ketoconazole to the medium resulted in decreasedACTH secretion accompanied by cellular involution with reductionin endoplasmic reticulum surface density, granule size, andlysosomal size (215).The hormonal changes caused by a single dose of ketoconazoleare reversible, recovery occurring between 8 and 16 h after an oraldose (216). Peak serum concentrations occur at 2 h, and the plasma