Lifetime, untreated isolated GH deficiency due to a GH-releasing hormone receptor mutation has beneficial consequences on bone status in older individuals, and does not influence their abdominal aorta calcification

Souza, Anita H. O.; Farias, Marta Cristina Vieira; Salvatori, Roberto; Silva, Gabriella M. F.; Santana, João A. M.; Pereira, Fernanda Aparecida Castro; Paula, Francisco José Albuquerque de; Valença, Eugênia H O; Melo, Enaldo Vieira de; Barbosa, Rita A. A.; Pereira, Rossana M. C.; Gois-Junior, Miburge B; Aguiar‐Oliveira, Manuel H.

doi:10.1007/s12020-013-0118-5

Cited by 15 publications

(15 citation statements)

References 56 publications

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“…Subjects with congenital untreated GHD due to a homozygous mutation in the GHRH receptor gene present reduced beta-cell function and higher frequency of impaired glucose tolerance [27], despite these subjects also have normal bone status and do not develop premature atherosclerosis [28].…”

Section: Discussionmentioning

confidence: 99%

The visceral adiposity index is associated with insulin sensitivity and IGF-I levels in adults with growth hormone deficiency

2016

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The visceral adiposity index, based on anthropometric and metabolic parameters, has been shown to be related to adipose tissue function and insulin sensitivity. We aimed to evaluate the performance of the visceral adiposity index in adult patients with growth hormone deficiency. We enrolled 52 patients(mean age 51 ± 13 years) with newly diagnosed growth hormone deficiency and 50 matched healthy subjects as controls at baseline. At baseline and after 12 and 24 months of treatment we evaluated anthropometric measures, lipid profile, glucose and insulin during an oral glucose tolerance test, hemoglobin A1c, homeostasis model assessment estimate of insulin resistance, quantitative insulin sensitivity check index, insulin sensitivity index Matsuda, insulin-like growth factor-I and visceral adiposity index. At baseline growth hormone deficiency patients showed higher waist circumference (p < 0.001), low-density lipoprotein cholesterol (p < 0.001) and visceral adiposity index (p = 0.003) with lower insulin sensitivity index (p = 0.007) and high-density lipoprotein cholesterol (p = 0.001) than controls. During growth hormone treatment we observed a significant increase in insulin-like growth factor-I (p < 0.001), high-density lipoprotein (p < 0.001) with a trend toward increase in insulin sensitivity index (p = 0.055) and a significant decrease in total cholesterol (p < 0.001) and visceral adiposity index (p < 0.001), while no significant changes were observed in other clinical and metabolic parameters. The visceral adiposity index was the only parameter that significantly correlated with growth hormone peak at diagnosis (p < 0.001) and with insulin-like growth factor-I and insulin sensitivity index both at diagnosis (p = 0.009 and p < 0.001) and after 12 (p = 0.026 and p = 0.001) and 24 months (p < 0.001 and p = 0.001) of treatment. The visceral adiposity index, which has shown to be associated with both insulin-like growth factor-I and insulin sensitivity, proved to be the most reliable index of metabolic perturbation, among the most common indexes of adiposity assessment and a marker of benefit during treatment in adult growth hormone deficiency patients.

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Section: Discussionmentioning

confidence: 99%

The visceral adiposity index is associated with insulin sensitivity and IGF-I levels in adults with growth hormone deficiency

2016

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“…Similarly, these individuals do not exhibit increase in carotid intima medial thickness (IMT), or evidence of coronary atherosclerosis when assessed by stress echocardiograms (48). In addition, they have similar coronary (49) and aortic abdominal calcium scores as controls (50). Not surprisingly, they do not show any evidence of increased mortality (51).…”

Section: Metabolic and Cardiovascular Consequencesmentioning

confidence: 91%

“…However, although smaller, the bones of these individuals seem to be structurally appropriated to their muscles. Reduced heel quantitative ultrasound and areal bone mineral density (BMD) scores reflect the small size of the bones, but calculated volumetric BMD are similar to controls (50,66,67), and the prevalence of vertebral fractures is actually reduced in older IGHD individuals. Accordingly, these individuals do not seem to be prone to fractures, including the ones playing in the local soccer team, which competes well with normal statured teams.…”

Section: Bone Growth and Structurementioning

confidence: 99%

“…These features have been published in 42 different publications (2,19,22,25,27,29,30,31,32,33,36,37,38,40,41,44,45,46,47,48,49,50,51,52,53,54,56,57,61,62,63,64,66,67,68,74,75,76,77,78,79,80). We have used this experiment of nature to discover 'usual laws of nature' as suggested by William Harvey, and to understand some aspects of more common conditions such as short stature, insulin resistance, diabetes, atherosclerosis, osteoporosis, cancer and ultimately longevity.…”

Section: Introductionmentioning

confidence: 99%

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MECHANISMS IN ENDOCRINOLOGY: The multiple facets of GHRH/GH/IGF-I axis: lessons from lifetime, untreated, isolated GH deficiency due to a GHRH receptor gene mutation

Aguiar‐Oliveira

Souza

Oliveira

et al. 2017

European Journal of Endocrinology

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Twenty years ago, we described kindred of 105 individuals with isolated GH deficiency (IGHD) in Itabaianinha County, in northeast Brazil, carrying a homozygous mutation in the GH-releasing hormone receptor gene. These subjects exhibit markedly reduced GH responsiveness to stimulatory tests, and anterior pituitary hypoplasia. Serum concentrations of IGF-I, IGF binding protein type 3 and the acid-labile subunit are markedly reduced, with a lesser reduction of IGF-II. The most striking physical findings of these IGHD individuals are the proportionate short stature, doll facies, high-pitched voice and visceral obesity with reduced fat-free mass. There is neither microphallus, nor neonatal hypoglycemia. Puberty is delayed, menopause anticipated, but fertility is preserved in both genders. The reduction in bone sizes is not even, with mean standard deviation scores for height of −7.2, total maxillary length of −6.5, total facial height of −4.3 and cephalic perimeter of −2.7. In addition, the non-osseous growth is not uniform, preserving some organs, like pancreas, liver, kidney, brain and eyes, and compromising others such as thyroid, heart, uterus and spleen. These subjects present higher prevalence of dizziness, mild high-tones sensorineural hearing loss, reduction of vascular retinal branching points, increase of optic disk, genu valgum and increased systolic blood pressure. Biochemically, they have high low density lipoprotein cholesterol and C-reactive protein levels, but maintain increased insulin sensitivity, and do not show premature atherosclerosis. Finally, they have normal immune function, and normal longevity. This review details the findings and summarizes 20 years of clinical research carried out in this unique population.

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“…10 Despite this, they have normal volumetric bone mineral density both below 11 and above 60 years of age. 12 Although the consequences of bi-allelic GHRHR mutations are obvious, the phenotype of heterozygous carriers (MUT/N) may be revealed only in childhood and senescence, when the activity of the GH/insulin-like growth factor-I axis is sub-maximal. In agreement with this argument, MUT/N individuals of the Pakistani cohort of Sindh (a smaller kindred with 18 affected individuals carrying a different mutation in the same gene) showed short stature only in children and adolescents.…”

Section: Introductionmentioning

confidence: 99%

Older individuals heterozygous for a growth hormone-releasing hormone receptor gene mutation are shorter than normal subjects

et al. 2015

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Growth hormone (GH)-releasing hormone (GHRH) is the most important stimulus for GH secretion by the pituitary gland. Subjects homozygous for GHRH receptor (GHRHR) gene (GHRHR) inactivating mutations have severe GH deficiency, resulting in severe short stature if not treated. We previously reported that young adults heterozygous for the c.57+1G>A null GHRHR mutation (MUT/N) have reduced weight and body mass index (BMI) but normal stature. Here we have studied whether older MUT/N have an additional phenotype. In a cross-sectional study, we measured height, weight and blood pressure, and calculated BMI in two groups (young, 20-40 years of age) and old (60-80 years) of individuals heterozygous for the same GHRHR mutation, and compared with a large number of individuals of normal genotype residing in the same geographical area. Standard deviation score (SDS) of weight was lower, and BMI had a trend toward reduction in young heterozygous compared with young normals, without significant difference in stature. Conversely, SDS of height was lower in older heterozygous individuals than in controls, corresponding to a reduction of 4.2 cm. These data show a reduced stature in older subjects heterozygous for the c.57+1G>A GHRHR mutation, indicating different effects of heterozygosis through lifespan.

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Lifetime, untreated isolated GH deficiency due to a GH-releasing hormone receptor mutation has beneficial consequences on bone status in older individuals, and does not influence their abdominal aorta calcification

Cited by 15 publications

References 56 publications

The visceral adiposity index is associated with insulin sensitivity and IGF-I levels in adults with growth hormone deficiency

The visceral adiposity index is associated with insulin sensitivity and IGF-I levels in adults with growth hormone deficiency

MECHANISMS IN ENDOCRINOLOGY: The multiple facets of GHRH/GH/IGF-I axis: lessons from lifetime, untreated, isolated GH deficiency due to a GHRH receptor gene mutation

Older individuals heterozygous for a growth hormone-releasing hormone receptor gene mutation are shorter than normal subjects

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