Aseptic necrosis in HIV seropositive patients: a possible etiologic role for megestrol acetate.

The association between pharmacologic doses of corticosteroids and the development of aseptic bone necrosis has been well documented. Recent reports have described the corticosteroid activity of megestrol acetate. A retrospective review of adverse events reported to the U.S. Food and Drug Administration identified three human immunodeficiency virus (HIV) seropositive patients who developed avascular necrosis of the femoral head during treatment with megestrol acetate. All were males, ages 34, 36, and 55 years, and were on therapy for 6, 1.5, and 18 months, respectively, when symptoms of aseptic necrosis occurred in the absence of antecedent trauma. Megestrol acetate doses were 640, 320, and 600-1200 mg/d, respectively. Two patients had no history of corticosteroid use whereas the third had taken an undisclosed dose and duration of corticosteroids concurrent with pentamidine administration. Notably, despite the predominant use of megestrol in women for hormone sensitive malignancies, none of the reports of aseptic necrosis occurred in this population. Megestrol acetate may be associated with the development of avascular necrosis via its glucocorticoid-like effects. Cachectic acquired immunodeficiency syndrome (AIDS) patients may have additional risk factors that predispose them to aseptic necrosis when receiving megestrol acetate.

In vitro and in vivo responses to short-term recombinant human insulin-like growth factor-1 (IGF-I) in a severely growth-retarded girl with ring chromosome 15 and deletion of a single allele for the type 1 IGF receptor gene.

OBJECTIVES: Patients with single allele defects in the gene encoding the type 1 IGF receptor have been reported to have growth failure, but fibroblasts from affected patients have not exhibited insensitivity to the effects of IGF-I in vitro. The in vitro and in vivo responses to short-term recombinant human IGF-I (rhIGF-I) in a severely growth-retarded girl with ring chromosome 15 and deletion of a single allele for the type 1 IGF receptor gene have been investigated. DESIGN AND PATIENT: The child exhibited prenatal and severe post-natal growth failure, and delayed psychomotor development. Southern blotting revealed a 50% reduction in IGF-I receptor DNA, and in an RNase protection assay (RPA), a quantitatively similar reduction in steady-state mRNA for type 1 IGF receptor. rhIGF-I was administered in graded doses of 40, 60 and 80 microg/kg twice daily by subcutaneous injection for periods of 2-2.5 days each. RESULTS: During rhIGF-I treatment, mean urinary nitrogen excretion was unchanged and urinary calcium rose to 60% greater than in the pre-treatment period. rhIGF-I injections produced only a modest decrease in indices of GH secretion, assessed by frequent (every 20 min) sampling over periods of 12 h. There was no significant difference between the mean GH concentrations during rhIGF-I treatment (5.32 +/- 6.2 mU/l) compared with that before rhIGF-I treatment (8.46 +/- 10.2 mU/l). Mean IGFBP-3-values were increased (4.5 mg/l before vs. 5.4 mg/l during rhIGF-I). TSH values after injection of TRH were not significantly reduced by IGF-I (mean of all values, 18.6 mU/l vs. 15.5 mU/l during rhIGF-I treatment). In vitro binding of radiolabelled IGF-I to the patient's fibroblasts was less than that bound by control fibroblasts (patient, 0.69% binding by 248 000 cells, vs. 1.41% binding by 260 000 fibroblasts from an age-matched control). However, the patient's fibroblasts exhibited a growth response in vitro to the addition of IGF-I in a fashion similar to that of control fibroblasts. CONCLUSIONS: These studies show evidence in each of the indices examined of in vivo resistance to IGF-I and suggest that the growth retardation observed in such patients may be the direct result of the absence of one of the alleles encoding the type 1 IGF receptor.

Retinal changes mimicking diabetic retinopathy in two nondiabetic, growth hormone-treated patients.

A role for GH in the pathogenesis of diabetic retinopathy has long been postulated. Previous clinical studies, however, have been confounded by hyperglycemia. We have identified 2 cases of retinopathy associated with exogenous GH therapy in nondiabetic patients. Cases were identified through the MedWatch drug surveillance system of the U.S. Food and Drug Administration. Causality by concomitant medications was excluded by a search of the literature and the FDA data base. The first patient, an obese, 31-yr-old male with traumatic hypothalamic injury, presented with nonproliferative retinopathy and macular edema, resulting in decreased visual acuity (OD 20/40-1; OS count fingers), which required laser surgery. Human GH had been initiated at 0.009 mg/ kg.day, 14 months earlier, and titrated to 0.017 mg/kg.day. The second patient, a nonobese, 11-yr-old girl receiving GH for the management of short stature in Turner's Syndrome, presented with neovascularization. GH doses were 0.033 mg/kg.day for the first 17 months and 0.043 mg/ kg.day for the following 5 months. Cumulative laboratory and clinical observations suggest that GH and related peptides have a role in retinal pathology independent of the degree of glucose tolerance.

Glucocorticoidlike activity of megestrol. A summary of Food and Drug Administration experience and a review of the literature.

Sporadic single case reports linking glucocorticoidlike activity to megestrol acetate have been reported in the literature. These findings have important implications for patient care. Adverse drug experience reports to the US Food and Drug Administration from 1984 through 1996 and a MEDLINE search of the literature from 1984 through 1996 provided the case reports. Five cases of Cushing syndrome, 12 cases of new-onset diabetes, and 16 cases of adrenal insufficiency were identified in association with megestrol therapy. Twelve cases in which preexisting diabetes was exacerbated and 17 cases of possible adrenal insufficiency were identified. Therapy with megestrol can result in clinical manifestations of glucocorticoidlike activity, including Cushing syndrome, diabetes, and adrenal insufficiency. Clinicians need to be aware of this association as these complications can be life-threatening if not recognized.

Papilledema in 15 renally compromised patients treated with growth hormone.

Intracranial hypertension with papilledema has been reported in renal patients, but a survey of the literature suggests that the incidence rate is low. We present reports of 15 of approximately 1,670 patients with renal disorders, who were treated with growth hormone for impaired growth and subsequently developed symptoms and/or signs of intracranial hypertension. The male:female ratio was 6.5:1, and the median age was 12 years. The median duration of growth hormone treatment before onset of symptoms or signs was 13 weeks. All but 2 patients were symptomatic. In the patients in whom growth hormone therapy is known to have been discontinued, the symptoms and signs of intracranial hypertension abated. At least 4 of these patients experienced a recurrence when re-exposed to growth hormone. Many of the affected patients presented with predisposing conditions, but growth hormone appears to have been the precipitating factor. Prospective funduscopic evaluation may be warranted in patients with renal disorders who are receiving growth hormone.

Benign intracranial hypertension in children with growth hormone deficiency treated with growth hormone.

We report 13 cases of benign intracranial hypertension (IH) in children with growth hormone (GH) deficiency treated with GH in the United States. The group consisted of eight boys and five girls, 3 to 16 years of age (median, 9 years). The interval from starting GH therapy to diagnosis of IH was 2 weeks or less in six patients, between 2 and 12 weeks in four, 8 months in one, 5 years in one, and unknown in one. Seven patients were not known to have previously described IH risk factors; the other six had at least one factor each. All patients but one had headache, nausea, vomiting, and visual changes. All had papilledema, and cerebrospinal fluid pressures were elevated (> 250 mm H2O) in all nine patients tested. The GH dosage range was 0.17 to 0.35 mg per kilogram body weight per week (median, 0.30 mg/kg per week) for the 11 patients with dosage data. After discontinuation of GH and treatment with lumbar punctures and/or medications, signs and symptoms resolved in eight children; in two of these children signs and symptoms reappeared when GH therapy was restarted. In four patients signs and symptoms resolved while GH therapy was continued; one child was treated with a ventriculoperitoneal shunt because of an arachnoid cyst, after which GH was restarted without subsequent IH. In the 12 patients with idiopathic GH deficiency the course of IH was benign, with complete resolution of all signs and symptoms. Because doses and scheduling of GH administration have changed since the introduction of recombinant GH, higher doses and increased frequency of administration may be contributing to the development of IH in some patients. We suggest beginning therapy at the lowest recommended dose, with gradual titration to higher doses, and the performance of routine funduscopic examinations during initiation of GH therapy and whenever signs or symptoms of IH develop.

Prepubertal gynecomastia during growth hormone therapy.

We report 22 cases of prepubertal gynecomastia diagnosed during growth hormone (GH) treatment. The age and dose range were 2 to 12 years and 0.18 [corrected] to 0.3 mg/kg per week, respectively. In most of the patients, gynecomastia appeared between 0.5 and 7 months after GH was started. Three boys were using drugs other than GH. This condition appears to be self-limited and benign.