Risk of leukemia after treatment with pituitary growth hormone.

OBJECTIVE: To determine whether pituitary-derived human growth hormone treatment increases the subsequent risk of developing leukemia and lymphoma. DESIGN: Cohort study. SETTING: United States. PARTICIPANTS: A total of 6284 recipients of pituitary-derived human growth hormone distributed by the National Hormone and Pituitary Program between 1963 and 1985. MAIN OUTCOME MEASURES: Leukemia and lymphoma. RESULTS: Three cases of leukemia occurred in 59,736 patient-years of follow-up from the start of growth hormone therapy to case ascertainment at interview; this number was not significantly higher (P = .23) than the 1.66 cases expected in the US age-, race-, and gender-matched general population. Three additional cases, found in an extended follow-up that provided 83,917 person-years of risk, yielded a minimum rate of leukemia that was significantly increased (six cases found, 2.26 expected; P = .028). The relative risk of leukemia in pituitary growth hormone recipients compared with the general population was 1.8 (90% confidence interval [CI], 0.82 to 7.5) for the defined follow-up and 2.6 (90% CI, 1.2 to 5.2) for the extended follow-up. Five of the six subjects who developed leukemia had antecedent cranial tumors (four craniopharyngioma, one astrocytoma) as the cause of growth hormone deficiency, and four had received radiotherapy. There was no increase in leukemia in patients with idiopathic growth hormone deficiency. The association of leukemia and craniopharyngioma was significant (P < .001). There was no excess of lymphoma in the cohort. CONCLUSIONS: This cohort of growth hormone recipients had a significantly increased rate of leukemia compared with the age-, race-, and gender-matched general population. However, the upper bound CI of the relative risk in our population (5.2) is well below the other estimates (7.6). Compared with the general population, our study population had more possible risk factors for leukemia (radiation, tumor) that may have contributed to the excess observed. The clustering of cases of leukemia in craniopharyngioma patients should be further evaluated.

Creutzfeldt-Jakob disease in pituitary growth hormone recipients in the United States.

To assess the magnitude of Creutzfeldt-Jakob disease (CJD) occurrence among recipients of pituitary-derived human growth hormone (HGH), we conducted an epidemiologic follow-up of 6284 recipients of HGH distributed through the National Hormone and Pituitary Program. Seven neuropathologically confirmed cases of CJD have occurred in this population to date: six patients with clinical CJD presented with ataxia and imbalance, rather than with altered mentation, which is the most common initial manifestation in sporadic CJD, and one patient died in the preclinical incubation state of the disease. All seven cases occurred among the nearly 700 HGH recipients who started therapy before 1970. Since only 10% of the cohort has been followed up for the 15-year average incubation interval from midpoint of HGH treatment to onset of symptoms, the great majority of potentially exposed patients have not yet attained the requisite incubation period for expression of CJD. The median duration of HGH therapy of 100 months in the CJD cases was significantly longer than 41 months for all patients starting treatment before 1970; thus, the duration of pituitary HGH therapy is a major risk factor for CJD.

Iodide-induced thyrotoxicosis.

Iodide-induced thyrotoxicosis (IIT) occurs in patients with: 1) endemic goiter; 2) nonendemic goiter; 3) no previous thyroid disease. Iodine prophylaxis for endemic goiter caused transient increase of 0.01-0.04% over the basal incidence of hyperthyroidism peaking at 1-3 years and normalizing in 3-10 years despite continued iodide exposure. Elderly subjects with large nodular goiters of long standing are at greater risk. In nonendemic areas, iodine-containing drugs such as amiodarone, radiographic contrast media or iodochlorhydroxyquinoline are implicated in IIT more often than iodides. With nonendemic goiter, IIT occurs more commonly in women whereas, in the absence of preexisting thyroid disease, men are more often affected. In both groups, exophthalmos and antithyroid antibodies are absent, radioiodine uptake is low, there is no thyroid tenderness or pain, and the hyperthyroidism is self-limited (1-6 months) and should thus be treated conservatively. IIT occurs more frequently in areas of marginal iodine intake (Europe) than in the U.S. In view of the extensive exposure to iodine, it is a rare complication in this country. It is postulated that defective autoregulation of hormone biosynthesis may contribute to IIT.

Forskolin stimulation of thyroid adenylate cyclase and cyclic 3',5'-adenosine monophosphate accumulation.

The diterpene forskolin is a potent (100-fold) stimulator of guinea pig thyroid cAMP accumulation with half-maximal activation occurring at 40 microM. Forskolin stimulation is more rapid than that of TSH, attaining a 5-fold increase within 1 min of exposure. The stimulation is also rapidly reversible. The diterpene does not sensitize thyroid cAMP accumulation to TSH, and the concentration yielding half-maximal response is not altered by the presence of low levels of forskolin. At maximally stimulating concentrations, the effects of TSH and forskolin on cAMP accumulation are additive. Forskolin stimulates thyroid adenylate cyclase approximately 10-fold in membranes from several species with half-maximal effects occurring at 3--9 microM through an action on the maximum velocity and not the Km for ATP. The activation of thyroid membranes is readily reversible. Guanyl nucleotides are not required for stimulation by forskolin, and they do not sensitize to forskolin. Moreover, the drug did not sensitize the membrane adenylate cyclase to guanosine 5'-[beta, gamma-imido]triphosphate or to isoproterenol and was equally effective with either Mg++ or Mn++ as the divalent cation. Forskolin stimulation is additive with that of guanyl nucleotides and F-. The site of action of forskolin in the adenylate cyclase complex is uncertain. Data from Bordetella pertussis, testicular, and S-49 lymphoma mutant cyclases suggest that one of the guanyl nucleotide regulatory proteins may be required to promote the forskolin effect. We conclude that forskolin is a useful activator of thyroid adenylate cyclase both in vitro and in intact tissue, which will be useful in elucidating the coupling process of the adenylate cyclase system and in differentiating cAMP-mediated from other forms of activation of the thyroid.

Adenosine receptor-mediated accumulation of adenosine 3',5'-monophosphate in guinea pig thyroid tissue.

The cAMP content of guinea pig thyroid fragments was increased 2- to 3-fold by adenosine analogs, 5'-N-ethylcarboxamide adenosine (NECA), the most potent, caused half-maximal stimulation of 0.7 microM, whereas N6-phenylisopropyl adenosine was much less potent (half-maximal stimulation at 20 microM). Exogenous adenosine by itself was slightly active, and its activity was increased in the presence of adenosine deaminase or transport inhibitors. Although adenosine analogs are partial agonists compared to TSH or the diterpene cyclase activator forskolin, the fractional rate of cAMP accumulation is greater for NECA than for TSH. The stimulatory effect of NECA was antagonized by theophylline. These effects of adenosine and its analogs on cAMP formation in intact thyroid tissue are characteristic of stimulatory adenosine receptors.

2-keto-3-deoxygluconate 6-phosphate aldolase mutants of Escherichia coli.

A new mutation in Escherichia coli, giving inability to grow on gluconic, glucuronic, or galacturonic acids, has been identified as complete deficiency of 2-keto-3-deoxygluconate 6-phosphate (KDGP) aldolase activity. The genetic map position of the locus, eda, is about 35 min. The inability to grow on the uronic acids was expected, because the aldolase is on the sole known pathway of their metabolism. However, inability to grow on gluconate was less expected, because the hexose monophosphate shunt might be used, as happens in mutants blocked in the previous step, edd, of the Entner-Doudoroff pathway. The likely explanation of gluconate negativity is inhibition by accumulated KDGP, because gluconate is inhibitory to growth on other substances, and one type of gluconate revertant is eda(-), edd(-). KDGP is probably the inducer of KDGP aldolase.