Megestrol acetate-induced diabetes mellitus 365 Postgrad Med J: first published as 10.1136/pgmj.72.848.365 on 1 June 1996. Downloaded from Insulin resistance and development of diabetes mellitus associated with megestrol acetate therapy

Prasoon Jain, Luigi S Girardi, Lawrence Sherman, Michael Berelowicz, Lawrence G Smith

Summary triglyceride 11.5 mmol/l, cholesterol 5.7 We describe a case of diabetes mellitus mmol/l, amylase 111 U/I (normal 7 - 59 U/1), induced by megestrol acetate in a patient and lipase 140 U/i (normal 0-88 U/1). Arterial with the acquired immunodeficiency syn- blood gas: pH 7.45, pCO2 20 mmHg, PO2 drome. Metabolic studies including an 127 mmHg on room air. Serum osmolality was arginine infusion test excluded an insuli- 322 mOsm/kg. Serum and urinary ketone were nopenic state and suggested insulin resis- negative. Chest X-ray, electrocardiogram and tance as the underlying mechanism for computed tomography (CT) scan of the abdo- hyperglycaemia. Withdrawal of megestrol men were normal. acetate resulted in rapid correction of all Intravenous fluids and insulin were admi- metabolic abnormalities and eliminated nistered with resultant rapid improvement in the need for exogenous insulin therapy. condition. Over the next several days, the patient required up to 75 units of insulin in Keywords: diabetes mellitus, megestrol acetate, 24 hours for glycaemic control. AIDS, insulin resistance Careful review of his records revealed that the patient was started on megestrol acetate, 240 mg/day, three months prior to admission Megestrol acetate, a synthetic orally active for progressive anorexia and weight loss. One progestational agent has recently been used week after starting megestrol acetate, hypergly- for the treatment of weight loss and cachexia caemia was noted for the first time on random associated with cancer and the acquired blood glucose testing. An oral glucose toler- immunodeficiency syndrome (AIDS). It is ance test six weeks later was abnormal (table thought that megestrol acetate promotes 1). Megestrol acetate induced diabetes mellitus weight gain by stimulating appetite; however, was therefore strongly suspected and further the exact mechanism remains unknown. In metabolic studies were pursued. A fasting C- general, the drug is well-tolerated with few peptide level was 1.09 mmol/l (normal 0.1- potential adverse effects including peripheral 1.22 mmol/l). Anti-insulin antibodies were http://pmj.bmj.com/ oedema, impotence, menstrual irregularities, negative. Pancreatic islet cell function was deep vein thrombosis and hyperpnea. Re- studied after intravenous infusion of arginine cently, we encountered a case of diabetes (0.5 g/kg over 30 min). C-Peptide, insulin and mellitus induced by megestrol acetate in a glucagon responses were normal (table 2). patient with AIDS. These results demonstrated that islet cell function was intact. Megestrol acetate was Case report subsequently discontinued, and insulin re- on September 28, 2021 by guest. Protected copyright. quirements rapidly declined, stopping alto- A 36-year-old homosexual man with AIDS was gether after one week. The patient remained admitted to with a of Department of hospital diagnosis euglycaemic and a repeat oral glucose toler- Internal Medicine, hyperosmolar nonketotic syndrome. One year ance test after two weeks was within normal State University of prior to admission, the patient had suffered limits (table 1). A repeat serum triglyceride at New York, Health from Pneumocystis carinii pneumonia, success- this time was 2.86 mmol/l, also consistent with Science Center, Stony fully treated with intravenous pentamidine. the correction of insulin resistance. Brook, New York, USA Since then he had been maintained on dapsone Division of Medicine for P Jain secondary prophylaxis without recurrence LG Smith of the P carinii pneumonia. Antiretroviral Division of Infectious therapy consisted of dideoxyinosine which Diseases was discontinued six months prior to admis- Table 1 Oral glucose tolerance test after 75 g LS Girardi sion because of persistent but asymptomatic of glucose performed six weeks after starting Division of elevation of pancreatic enzymes. megestrol acetate and two weeks after with- Endocrinology Physical examination revealed dehydration, drawing the drug L Sherman mild confusion and slurring of speech. No M Berelowicz Blood glucose (mmol/l) organomegaly or signs of localised infection Six weeks after Two weeks after Correspondence to were noted. His height, weight and body mass Lawrence G Smith MD, Time (min) starting stopping The Mount Sinai Medical index were 172 cm, 66 kg and 22.3 kg/mi, Center, 1 Gustave L Place, respectively. o 5.0 4.3 Box #1118, New York, Laboratory data included the following: 30 11.5 6.9 NY 10029-6574, USA 60 11.5 8.2 blood glucose 51 mmol/l, sodium 129 mmol/l, 120 12.0 7.6 Accepted 16 October 1995 potassium 5.4 mmol/l, bicarbonate 17 mmol/l, 366 Jain, Girardi, Sherman, Berelowicz, Smith

Table 2 C-Peptide, insulin, glucagon response Endocrine abnormalities and AIDS after intravenous infusion of arginine (0.5 g/kg over 30 min) * acute pancreatitis: complication of Postgrad Med J: first published as 10.1136/pgmj.72.848.365 on 1 June 1996. Downloaded from dideoxyinosine, pentamidine, and Time (min) C peptide Insulin** Glucagont trimethoprin - sulfamethoxazole therapy * hypoglycaemia: complication of intravenous 0 1.0 136 210 pentamidine therapy (beta cell toxicity) 30 2.0 230 530 * diabetes mellitus: complication of intravenous 60 2.4 244 530 pentamine and megestrol 90 2.7 179 210 120 3.5 244 260 *Normal 0.1-1.22 mmol/1; **normal 35-145 pmol/; Box 1 tnormal 50-100 ng/1 Summarynlearning points * in appropriate clinical settings, megestrol Discussion acetate-induced insulin resistance should be included in the differential diagnosis of Many observations suggest that megestrol hyperglycaemia in patients with AIDS acetate precipitated diabetes mellitus in this * withdrawal of megestrol acetate may result in patient. A strong temporal relation was noted rapid correction of all metabolic abnormalities between initiation of megestrol acetate therapy and the onset of hyperglycaemia and an Box 2 abnormal oral glucose tolerance test. While receiving megestrol acetate, the patient re- quired large doses of insulin to maintain transport,8 noted in animal studies, may partly adequate glycaemic control after correction of explain a progesterone-induced insulin resis- his hyperglycaemic nonketotic state. Rapid tant state. In humans, mild and subclinical decrease in insulin needs, subsequent main- alterations in glucose tolerance and presum- tenance of euglycaemia without insulin, and ably insulin resistance has been noted with the normalisation of oral glucose tolerance test use of continuous subdermal levonorgestrel.9 upon discontinuation of the drug clearly Interestingly, no adverse effect on blood indicate a primary role of megestrol acetate. glucose'0 or lipid profile5 have been noted in Various endocrine abnormalities have been cancer patients treated with high-dose meges- observed in patients with AIDS (box 1). 14 We trol acetate. It is commonly accepted that strongly suspect megestrol-induced insulin patients with AIDS show a higher incidence resistance to be the cause of diabetes mellitus of adverse drug reactions. For this reason, in our patient. A high-normal fasting C- patients with AIDS may be particularly at risk peptide level during the hyperglycaemic state of developing severe glucose disturbances and an adequate insulin and glucagon secre- while taking megestrol acetate. http://pmj.bmj.com/ tory response to arginine infusion ruled out the We realise that some patients presenting possibility of drug-induced islet cell damage with hyperosmolar nonketotic coma show resulting from prior pentamidine therapy. rapid improvement in metabolic profile after Insulin resistance is also suggested by the receiving intensive supportive care with intra- presence of gross hypertriglyceridaemia when venous fluid and insulin. This is especially true the patient was admitted to hospital, with rapid when an underlying precipitating cause is normalisation of triglyceride levels after me- promptly identified and corrected. Some of on September 28, 2021 by guest. Protected copyright. gestrol acetate therapy was withdrawn. these individuals may not require long-term The exact metabolic alterations leading to insulin therapy to control blood glucose. weight gain with megestrol acetate therapy are However, a majority of these patients continue unknown. Loprinzi et alF performed body to show some evidence of metabolic derange- composition studies before and two months ment on formal glucose tolerance testing. after starting megestrol acetate in 12 patients Although we cannot exclude this possibility with advanced cancer and showed that in- with absolute certainty, complete normaliza- creases in fat account for most of the weight tion of all metabolic abnormalities after the gained during therapy. In an in vitro model, withdrawal of megestrol acetate argue against megestrol acetate promoted differentiation of this scenario in our case. Therefore, we suggest 3T3-L1 Swiss mouse embryo fibroblasts to that blood glucose should be monitored during adipocytes.6 The effects of megestrol acetate, a megestrol acetate therapy in AIDS patients. progestational agent, on glucose metabolism This is especially important since life-threaten- are also poorly understood. Henry et al ing metabolic derangements may occur, as in postulated glucocorticoid-like activity of me- our patient, which rapidly normalise once the gestrol as the possible cause of insulin resis- medication is discontinued, obviating the need tance in their patient. Inhibitory effects of for insulin therapy. Further studies are needed progesterone on phosphorylation of glucose to define the incidence and mechanism of into glucose-6-phosphate7 and inhibition of insulin resistance induced by megestrol acetate insulin-stimulated transmembrane glucose in patients with AIDS. Megestrol acetate-induced diabetes mellitus 367

1 Bouchard PH, Sai P, Reach G, Caubarrere I, Ganeval D, 7 Sutter-Dub M-Th, Dazey B, Hamden E, Vergnaud M-Th. Assan R. Diabetes mellitus following pentamidine-induced Progesterone and insulin resistance: studies of progesterone hypoglycemia in humans. Diabetes 1982; 31: 40-5. action on glucose transport, lipogenesis and lipolysis in

2 Vendrell J, Nubiola A, Goday A, et al. HIV and the isolated fat cell of the female rat. J Endocrinol 1981; 88: Postgrad Med J: first published as 10.1136/pgmj.72.848.365 on 1 June 1996. Downloaded from pancreas. Lancet 1987; ii: 1212. 455- 62. 3 Henry K, Rathgaber S, Sullivan C, McCabe K. Diabetes 8 Rushakoff RJ, Kalkhoff RK. Effect of pregnancy and sex mellitus induced by megestrol acetate in a patient with steroid administration on skeletal muscle metabolism in the AIDS and cachexia. Ann Intern Med 1992; 116: 53-4. rats. Diabetes 1981; 30: 545-50. 4 Panwalker AP. Hyperglycemia induced by megestrol 9 Konje JC, Otolorin EO, Ladipo OA. The effect of acetate. Ann Intern Med 1992; 116: 878. continuous subdermal levonorgestrel (Norplant) on carbo- 5 Loprinzi CL, Schaid DJ, Dose AM, Burnham NL, Jensen hydrate metabolism. Am J Obstet Gynecol 1992; 166: 15-9. MD. Body composition changes in patients who gain weight 10 Feliu J, Gonzalez-Baron M, Berrocal A, et al. Usefulness of while receiving megestrol acetate. J Clin Oncol 1993; 11: megestrol acetate in cancer cachexia and anorexia. Am J 152-4. CGin Oncol 1992; 15: 436-40. 6 Hamburger AW, Parnes H, Gordon GB, Shantz LM, O'Donnell KA, Aisner J. Megestrol acetate induced differentiation of 3T3-L1 adipocytes in vitro. Semin Oncol 1988; 15 (suppl 1): 76-7.

Digoxin toxicity presenting as encephalopathy

JR Greenaway, B Abuaisha, MG Bramble

Summary growth, normal glucose and mildly raised We describe two cases of digoxin toxicity protein at 0.63 g/l (normal <0.4 g/l). Electro- presenting with clinical and electroence- encephalogram (EEG) showed focal right phalographic evidence of encephalopathy anterior quadrant delta slowing consistent with without other features of digoxin toxicity. Herpes encephalitis. However, following a telephone conversation with her general practi- Keywords: digoxin toxicity, encephalography tioner it transpired that her digoxin dose had been doubled to 250 ug daily approximately one month prior to admission. Her digoxin Digoxin toxicity often presents with gastro- level when checked was > 5 jug/l. Digoxin was intestinal side-effects such as anorexia, nausea withheld and the patient gradually woke up. or vomiting. 1 Other side-effects include cardiac One week later she was back to normal dysrhythmias, visual disturbance and drowsi- (digoxin level 0.3 ,ug/l). http://pmj.bmj.com/ ness.2 Case 1 Case 2 A 68-year-old woman was admitted to hospital A 66-year-old woman with a previous history with a one-week history of profound somno- of rheumatic valvular heart disease (mitral and lence. She had been non-specifically unwell in aortic valve replacements), atrial fibrillation,

the preceding month and had fallen twice chronic congestive cardiac failure and angio- on September 28, 2021 by guest. Protected copyright. without any history of head injury. There was no history of anorexia, nausea, vomiting or visual disturbance. Her past medical history Digoxin: CNS side-effects consisted of ischaemic heart disease, conges- tive cardiac failure, atrial fibrillation, cerebro- * lethargy and fatigue vascular disease and chronic airflow limitation. * weakness Medication comprised frusemide 120 mg, * headache spironolactone 100 mg, prednisolone 5 mg, * visual disturbances (colour perception ranitidine 150 mg, digoxin problems (including xanthopsia), reduced 250 yug, all daily, visual acuity, visual field defects, pain on eye with isosorbide mononitrate 20 mg and nife- movement) dipine SR 10 mg both twice daily. * depression Clinical examination revealed no focal neu- * psychosis Department of rological signs but confirmed extreme drowsi- * drowsiness Medicine, ness. Investigations revealed no abnormality of * confusion Middlesbrough * delerium General Hospital, full blood count, urea and electrolytes, liver * encephalopathy Ayresome Green Lane, function tests, blood glucose, thyroid function * hallucinations Middlesbrough, tests or B12 and folate. Blood cultures and * epileptic seizures Cleveland TS5 SAZ, VDRL were negative. Chest X-ray was normal * choreiform movements UK and electrocardiogram showed sinus rhythm * dysphonia JR Greenaway with lateral ST depression. Computed tomo- * dysphagia B Abuaisha * trigeminal neuralgia MG Bramble graphy (CT) scan of brain revealed no abnormality and lumbar puncture resulted in Accepted 21 September 1995 clear, colourless cerebrospinal fluid with no Box 1