Longevity in Untreated Congenital Growth Hormone Deficiency Due to a Homozygous Mutation in the GHRH Receptor Gene

Aguiar‐Oliveira, Manuel H.; Oliveira, Francielle T; Pereira, Rossana M. C.; Oliveira, Carla R. P.; Blackford, Amanda L.; Valença, Eugênia H O; Santos, Elenilde G.; Gois-Junior, Miburge B; Meneguz‐Moreno, Rafael Alexandre; Araújo, Vanessa P.; Oliveira-Neto, Luis A; Almeida, Roque Pacheco de; Santos, Mário A.; Farias, Natália T.; Silveira, Débora Consuelo Rocha; Cabral, Gabriel W.; Calazans, Flavia R.; Seabra, Juliane Dantas; Lopes, Tiago Falcón; Rodrigues, Endrigo O.; Porto, Lívia Amorim; Oliveira, Igor Pereira; Melo, Enaldo Vieira de; Martari, Marco; Salvatori, Roberto

doi:10.1210/jc.2009-1879

Cited by 99 publications

(86 citation statements)

References 37 publications

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“…The lack of complete protection against cancer in the patients with GHRHR mutations and those with congenital MPHD could be due either to the fact that some patients still secrete small amounts of GH (16), that some are sensitive to the exogenously administered hGH treatment or other environmental noxae and/or belonging to a familial genetic trend for malignancy.…”

Section: Discussionmentioning

confidence: 99%

Congenital IGF1 deficiency tends to confer protection against post-natal development of malignancies

Steuerman

Shevah²,

Laron

2011

European Journal of Endocrinology

192

111

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Objective: To investigate whether congenital IGF1 deficiency confers protection against development of malignancies, by comparing the prevalence of malignancies in patients with congenital (secondary) deficiency of IGF1 with the prevalence of cancer in their family members. Method: Only patients with an ascertained diagnosis of either Laron syndrome (LS), congenital IGHD, congenital multiple pituitary hormone deficiency (cMPHD) including GH or GHRHR defect were included in this study. In addition to our own patients, we performed a worldwide survey and collected data on a total of 538 patients, 752 of their first-degree family members, of which 274 were siblings and 131 were further family members. Results: We found that none of the 230 LS patients developed cancer and that only 1 out of 116 patients with congenital IGHD, also suffering from xeroderma pigmentosum, had a malignancy. Out of 79 patients with GHRHR defects and out of 113 patients with congenital MPHD, we found three patients with cancer in each group. Among the first-degree family members (most heterozygotes) of LS, IGHD and MPHD, we found 30 cases of cancer and 1 suspected. In addition, 31 malignancies were reported among 131 further relatives. Conclusions: Our findings bear heavily on the relationship between GH/IGF1 and cancer. Homozygous patients with congenital IGF1 deficiency and insensitivity to GH such as LS seem protected from future cancer development, even if treated by IGF1. Patients with congenital IGHD also seem protected.

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Section: Discussionmentioning

confidence: 99%

Congenital IGF1 deficiency tends to confer protection against post-natal development of malignancies

Steuerman

Shevah²,

Laron

2011

European Journal of Endocrinology

192

111

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“…The phenotype includes reduced, but not absent, serum GH, and low IGF-I levels, resulting in proportionate growth failure, which becomes evident in the first year of life [31,64]. The largest cohort of patients with dwarfism caused by homozygous GHRHR mutations comprises more than 100 individuals from Itabaianinha, a rural area in the north-eastern Brazilian State of Sergipe [65].…”

Section: Cancer On States Of Gh and Igf-i Deficiencymentioning

confidence: 99%

Growth hormone, insulin-like growth factor system and carcinogenesis

Boguszewski

Kopchick

2015

Endokrynologia Polska

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The growth hormone (GH) and insulin-like growth factor (IGF) system plays an important role in the regulation of cell proliferation, differentiation, apoptosis, and angiogenesis. In terms of cell cycle regulation, the GH-IGF system induces signalling pathways for cell growth that compete with other signalling systems that result in cell death; thus the final effect of these opposed forces is critical for normal and abnormal cell growth. The association of the GH-IGF system with carcinogenesis has long been hypothesised, mainly based on in vitro studies and the use of a variety of animal models of human cancer, and also on epidemiological and clinical evidence in humans. While ample experimental evidence supports a role of the GH-IGF system in tumour promotion and progression, with several of its components being currently tested as central targets for cancer therapy, the strength of evidence from patients with acromegaly, GH deficiency, or treated with GH is much weaker. In this review, we will attempt to consolidate this data. StreszczenieOś hormon wzrostu (GH)-insulinopodobny czynnik wzrostu (IGF) odgrywa istotną rolę w regulacji proliferacji i różnicowania komórek, apoptozy i angiogenezy. Oś GH-IGF wpływa na regulację cyklu komórkowego przez pobudzenie szlaku wzrostu komórki w stosunku do szlaków sygnałowych prowadzących do śmierci komórki, a ostateczny efekt oddziaływania tych dwóch sił ma podstawowe znaczenie dla prawidłowego lub nieprawidłowego wzrostu komórki. Hipotezy na temat powiązań osi GH-IGF z karcynogenezą pojawiły się wiele lat temu, głównie w oparciu o wyniki badań in vitro oraz badań z wykorzystaniem różnych zwierzęcych modeli raka występującego u ludzi. Chociaż liczne dane doświadczalne potwierdzają rolę osi GH-IGF sprzyjającą rozwojowi i progresji nowotworów, a nad kilkoma składowymi tej osi trwają obecnie badania oceniające ich przydatność jako główne cele terapii przeciwnowotworowej, to jednak siła dowodów uzyskanych u chorych z akromegalią, niedoborem GH lub osób leczonych GH jest znacznie słabsza. W niniejszej pracy przeglądowej spróbowano zebrać wszystkie te dane.

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“…These individuals have very low serum GH and insulin-like growth factor 1 (IGF1), reduced fat-free mass, increased percentage of fat mass, total and LDL, CRP levels, systolic blood pressure (SBP), and waist:hip ratio. Despite these cardiovascular risk factors, they have no premature atherosclerosis, no insulin resistance, and normal longevity (7,8,9,10,11).…”

Section: Introductionmentioning

confidence: 99%

Arrest of atherosclerosis progression after interruption of GH replacement in adults with congenital isolated GH deficiency

Araújo

Aguiar‐Oliveira

Oliveira

et al. 2012

European Journal of Endocrinology

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Objective: GH replacement therapy (GHRT) in adult-onset GH deficiency (AOGHD) reduces carotid intima-media thickness (IMT) and increases myocardial mass, with improvement of systolic and diastolic function. These observations have reinforced the use of GHRT on AOGHD. Conversely, we have previously reported that in adults with lifetime congenital and severe isolated GH deficiency (IGHD) due to a mutation in GHRH receptor gene (GHRHR), a 6-month treatment with depot GH increased carotid IMT, caused the development of atherosclerotic plaques, and an increase in left ventricular mass index (LVMI), posterior wall, and septal thickness and ejection fraction. Such effects persisted 12 months after treatment (12-month washout -12mo). Methods: We have studied the cardiovascular status (by echocardiography and carotid ultrasonography) of these subjects 60 months after completion of therapy (60-month washout -60mo). Results: Carotid IMT reduced significantly from 12 to 60mo, returning to baseline (pre-therapy) value. The number of individuals with plaques was similar at 12 and 60mo, remaining higher than pretherapy. LVMI, relative posterior wall thickness, and septum thickness did not change between 12 and 60mo, but absolute posterior wall increased from 12 to 60mo. Systolic function, evaluated by ejection fraction and shortening fraction, was reduced at 60mo in comparison with 12mo returning to baseline levels. The E/A wave ratio (expression of diastolic function) decreased at 60mo compared with both 12mo and baseline. Conclusions: In adults with lifetime congenital IGHD, the increase in carotid IMT elicited by GHRT was transitory and returned to baseline 5 years after therapy discontinuation. Despite this, the number of subjects with plaques remained stable at 60mo and higher than at baseline. 166 977-982 European Journal of Endocrinology

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Longevity in Untreated Congenital Growth Hormone Deficiency Due to a Homozygous Mutation in the GHRH Receptor Gene

Abstract: In a selected genetic background, lifelong untreated IGHD does not affect longevity.

Cited by 99 publications

References 37 publications

Congenital IGF1 deficiency tends to confer protection against post-natal development of malignancies

Congenital IGF1 deficiency tends to confer protection against post-natal development of malignancies

Growth hormone, insulin-like growth factor system and carcinogenesis

Arrest of atherosclerosis progression after interruption of GH replacement in adults with congenital isolated GH deficiency

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