Cancer in growth hormone excess and growth hormone deficit.

The relationship between growth hormone (GH) excess and cancer is a controversial matter. Until 2016, most studies in patients with acromegaly found links with colon and thyroid neoplasms. However, recent studies found increased risks in gastric, breast, and urinary tract cancer also. Concordantly, clinical situations where GH and insulin-like growth facto-I deficits exist are indeed associated with diminished malignancy incidence. In line with these observations, gain-of-function mutations of various enzymes belonging to the GH and IGF-I signaling pathways have been associated with increased carcinogenesis; similarly, loss-of-function mutations of other enzymes that usually work as tumor repressors are also associated with augmented cancer risk. In a study performed in Ecuador, it was demonstrated that subjects in the Ecuadorian cohort with Laron syndrome (ELS), who have a mutant GH receptor and greatly diminished GH and IGF-I signaling, display diminished incidence of cancer. Along with absent action of GH and IGF-I, ELS individuals also have low serum insulin levels and decreased insulin resistance. Furthermore, hyperglycemia and hyperinsulinemia are indispensable for fast cell mitosis, including that of those cells present in the benign and malignant neoplasms. Notably, and despite their obesity, subjects with the ELS display normoglycemia and hypo-insulinemia, along with diminished incidence of malignancies. We believe that the dual low-IGF-I/low insulin serum levels are responsible for the cancer protection, especially considering that the insulin/INSR signaling is a central site for energy generation in the form of ATP and GDP, which are indispensable for all and every GH/IGF-I physiologic as well as pathologic events.

Cancer in Ecuadorian subjects with Laron syndrome (ELS).

Meta-analyses from 2018-2022 have shown that obesity increases the risk of various cancers such as acute myeloid lymphoma, chronic myeloid lymphoma, diffuse beta cell lymphoma, Hodgkin's lymphoma, leukemia, multiple myeloma, non-Hodgkin's lymphoma, bladder, breast, cholangiocarcinoma, colorectal, ovarian, esophageal, kidney, liver, prostate, thyroid, and uterus. Contextually, obesity, and its comorbidities, is the largest, most lethal pandemics in the history of mankind; hence, identification of underlying mechanisms is needed to adequately address this global health threat. Herein, we present the metabolic and hormonal mechanisms linked to obesity that might etiologically contribute to neoplasia, including hyperinsulinemia and putative places in the insulin-signaling pathway. Excess insulin, acting as a growth factor, might contribute to tumorigenesis, while abundant ATP and GDP supply the additional energy needed for proliferation of rapidly dividing cells. Our observations in the Ecuadorian cohort of subjects with Laron syndrome (ELS) prove that obesity does not always associate with increased cancer risk. Indeed, despite excess body fat from birth to death, these individuals display a diminished incidence of cancer when compared to their age- and sex-matched relatives. Furthermore, in cell cultures exposed to potent oxidizing agents, addition of ELS serum induces less DNA damage as well as increased apoptosis. ELS individuals have absent growth hormone (GH) counter-regulatory effects in carbohydrate metabolism due to a defective GH receptor. The corresponding biochemical phenotype includes extremely low basal serum concentrations of insulin and insulin-like growth factor-I, lower basal glucose and triglyceride (TG) levels, and diminished glucose, TG, and insulin responses to orally administered glucose or to a mixed meal.

Recommended IGF-I dosage causes greater fat accumulation and osseous maturation than lower dosage and may compromise long-term growth effects.

CONTEXT: The maximum dose of IGF-I recommended for treatment of GH insensitivity is commonly used. OBJECTIVE: The aim was to test the hypothesis that a lower dose is as effective as a high dose of IGF-I in growth promotion and has fewer deleterious effects. DESIGN AND SETTING: Subjects were treated for 3 years with regular examinations including bone age and dual energy x-ray absorptiometry and for 1 year with abdominal ultrasound studies at a clinical research institute in Quito, Ecuador. SUBJECTS: The study included 21 subjects ages 3.2-15.9 years with GH insensitivity due to the same splice site mutation on the GH receptor gene. INTERVENTIONS: Subjects were allocated to receive 120 (n = 14) or 80 (n = 7) µg/kg IGF-I twice daily. MAIN OUTCOME MEASURES: Height velocity, osseous maturation, height SD scores (SDS), body composition, abdominal organ growth, and side effects were assessed. RESULTS: There were no differences in growth velocity or height SDS increment by dosage, and the SDS increase was greater than in other reported series. Osseous maturation over 3 years with the high dose was nearly twice as rapid as with the lower dose (P < .001) and correlated with an increase in percentage body fat (r = .64; P < .001) and with adrenal size increase over 1 year (r = .32; P = .03). The ratio of bone age to height age was lower in the high-dose group after 3 years of treatment (P = .007). CONCLUSIONS: The commonly used IGF-I dosage of 120 µg/kg twice a day is excessive in comparison to a dose of 80 µg/kg twice a day, disproportionately accelerating osseous maturation, probably from the combined effects of obesity and inappropriate adrenal growth, thus likely compromising adult height potential. Moreover, the lower dose decreases direct treatment cost by one-third.

Growth hormone receptor deficiency is associated with a major reduction in pro-aging signaling, cancer, and diabetes in humans.

Mutations in growth signaling pathways extend life span, as well as protect against age-dependent DNA damage in yeast and decrease insulin resistance and cancer in mice. To test their effect in humans, we monitored for 22 years Ecuadorian individuals who carry mutations in the growth hormone receptor (GHR) gene that lead to severe GHR and IGF-1 (insulin-like growth factor-1) deficiencies. We combined this information with surveys to identify the cause and age of death for individuals in this community who died before this period. The individuals with GHR deficiency exhibited only one nonlethal malignancy and no cases of diabetes, in contrast to a prevalence of 17% for cancer and 5% for diabetes in control subjects. A possible explanation for the very low incidence of cancer was suggested by in vitro studies: Serum from subjects with GHR deficiency reduced DNA breaks but increased apoptosis in human mammary epithelial cells treated with hydrogen peroxide. Serum from GHR-deficient subjects also caused reduced expression of RAS, PKA (protein kinase A), and TOR (target of rapamycin) and up-regulation of SOD2 (superoxide dismutase 2) in treated cells, changes that promote cellular protection and life-span extension in model organisms. We also observed reduced insulin concentrations (1.4 µU/ml versus 4.4 µU/ml in unaffected relatives) and a very low HOMA-IR (homeostatic model assessment-insulin resistance) index (0.34 versus 0.96 in unaffected relatives) in individuals with GHR deficiency, indicating higher insulin sensitivity, which could explain the absence of diabetes in these subjects. These results provide evidence for a role of evolutionarily conserved pathways in the control of aging and disease burden in humans.

Is ultrasonography useful in predicting thyroid cancer in children with thyroid nodules and apparently benign cytopathologic features?

BACKGROUND/AIMS: To assess whether the presence of certain findings on thyroid ultrasonography (US) correctly diagnoses malignancy even when a fine-needle aspiration biopsy (FNAB) suggests a benign lesion. METHODS: We reviewed the charts of 35 children and adolescents with a thyroid nodule who had had an US and a FNAB, and for whom final pathology was available. RESULTS: The global accuracy of FNAB was 83%, with a sensitivity of 75% and a specificity of 94%. 14 FNABs suggested malignancy (40%), only 1 of which was a false positive (7%). By contrast, 5 of the 21 FNABs suggesting benign lesions were false negatives (24%). These 5 cases had US findings suggestive of malignancy. When FNAB suggested a benign lesion, US had a good sensitivity (80%) but a poor specificity and accuracy (50 and 57%, respectively); its negative predictive value was 90% and its positive predictive value 36%. CONCLUSIONS: US complements FNAB in the evaluation of thyroid nodules in children. A more aggressive approach is warranted in children with a thyroid nodule and a benign FNAB if US findings suggest malignancy.