Manuel H. Aguiar-Oliveira

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

CONTEXT Reduced longevity observed in hypopituitarism has been attributed to GH deficiency (GHD). It is, however, unclear whether GHD or other confounding factors cause this early mortality. OBJECTIVE The aim was to study longevity in subjects from a large kindred with untreated, lifetime isolated GHD (IGHD) due to a homozygous mutation in the GHRH receptor gene and in heterozygous carriers of the mutation. DESIGN, SETTING, AND PARTICIPANTS We carried out a retrospective cohort study on three groups. We first compared mortality risk of 65 IGHD individuals and their 128 unaffected siblings from 34 families. We then compared mean age of death of the IGHD to the general population. A transversal study was carried out to compare the rate of heterozygosity for the mutation in two groups of young (20-40 yr old) and old (60-80 yr old) normal-appearing subjects from the same county. MAIN OUTCOME MEASURE We measured longevity. RESULTS The risk of death of IGHD subjects was not different from their siblings. Life span in IGHD individuals was shorter than the general population. When stratified by sex, this difference persisted only in females, due to a high frequency of IGHD deaths in females aged 4-20. There was no significant difference in life span between IGHD subjects and siblings or the general population when analyzing subjects who reached age 20. The prevalence of heterozygosity did not differ in young and old groups, suggesting no survival advantage or disadvantage. CONCLUSIONS In a selected genetic background, lifelong untreated IGHD does not affect longevity.

Serum leptin and body composition in children with familial GH deficiency (GHD) due to a mutation in the growth hormone-releasing hormone (GHRH) receptor

The relationship between GH, body composition and leptin in children remains ill‐defined. We have therefore examined the impact of severe GH deficiency (GHD) due to a mutation in the GHRH receptor on serum leptin concentrations and body composition in childhood.

Insulin Sensitivity and β-Cell Function in Adults with Lifetime, Untreated Isolated Growth Hormone Deficiency

CONTEXT GH reduces insulin sensitivity (IS), whereas IGF-I increases it. IGF-I seems to be critical for the development of the β-cells, and impaired IS has been reported in GH deficiency (GHD). OBJECTIVE The aim of the study was to assess IS and β-cell function in adult patients with untreated isolated GHD (IGHD) due to a homozygous mutation in the GHRH receptor gene. DESIGN, SETTING, AND PATIENTS We conducted a cross-sectional study in 24 GH-naive adult IGHD subjects and 25 controls. INTERVENTION We performed an oral glucose tolerance test with glucose and insulin measurements at 0, 30, 60, 90, 120, and 180 min. MAIN OUTCOME MEASURES IS was assessed by homeostasis model assessment index of insulin resistance (IR), quantitative IS check index, oral glucose IS in 2 h (OGIS2) and 3 h (OGIS3). β-Cell function was assayed by homeostasis model assessment index-β, insulinogenic index, and area under the curve of insulin-glucose ratio. RESULTS During the oral glucose tolerance test, glucose levels were higher in IGHD subjects (P<0.0001), whereas insulin response presented a trend toward reduction (P=0.08). The number of individuals with impaired glucose tolerance was higher in the IGHD group (P=0.001), whereas the frequency of diabetes was similar in the two groups. Homeostasis model assessment index of IR was lower (P=0.04), and quantitative IS check index and OGIS2 showed a nonsignificant trend toward elevation (P=0.066 and P=0.09, respectively) in IGHD. OGIS3 showed no difference between the groups. Homeostasis model assessment index-β, insulinogenic index, and ratio of the areas of the insulin and glucose curves were reduced in the IGDH group (P=0.015, P<0.0001, and P=0.02, respectively). CONCLUSIONS Adult subjects with lifetime congenital untreated IGHD present reduced β-cell function, no evidence of IR, and higher frequency of impaired glucose tolerance.

Adipokine Profile and Urinary Albumin Excretion in Isolated Growth Hormone Deficiency

BACKGROUND GH deficiency (GHD) is often associated with cardiovascular risk factors, including abdominal fat accumulation, hypercholesterolemia, and increased C-reactive protein. Despite the presence of these risk factors, adults with congenital lifetime isolated GHD (IGHD) due to an inactivating mutation in the GHRH receptor gene do not have premature atherosclerosis. OBJECTIVE The aim was to study the serum levels of adiponectin and leptin (antiatherogenic and atherogenic adipokine, respectively), and the urinary albumin excretion (UAE) in these IGHD individuals. DESIGN AND PATIENTS We conducted a cross-sectional study of 20 IGHD individuals (seven males; age, 50.8 +/- 14.6 yr) and 22 control subjects (eight males; age, 49.9 +/- 11.5 yr). MAIN OUTCOME MEASURES Anthropometric factors, body composition, blood pressure, serum adiponectin, leptin, and UAE were measured. RESULTS Adiponectin was higher [12.8 (7.1) vs. 9.7 (5) ng/ml; P = 0.041] in IGHD subjects, whereas no difference was observed in leptin [7.3 (6.3) vs. 9.3 (18.7 ng/ml] and UAE [8.6 (13.8) vs. 8.5 (11.1) microg/min]. CONCLUSIONS Subjects with lifetime untreated IGHD have an adipokine profile with high adiponectin and normal leptin levels that may delay vascular damage and lesions of the renal endothelium.

Sizes of abdominal organs in adults with severe short stature due to severe, untreated, congenital GH deficiency caused by a homozygous mutation in the GHRH receptor gene

Objective  To assess the sizes of intra‐abdominal organs of adult subjects with untreated severe congenital isolated GH deficiency (IGHD) due to lack of functional GHRH receptor (GHRH‐R), and to verify whether there is proportionality between size of organ and adult stature and body surface area (BSA).

Consequences of lifetime isolated growth hormone (GH) deficiency and effects of short-term GH treatment on bone in adults with a mutation in the GHRH-receptor gene

Objective  Growth hormone (GH) influences bone mass maintenance. However, the consequences of lifetime isolated GH deficiency (IGHD) on bone are not well established. We assessed the bone status and the effect of 6 months of GH replacement in GH‐naïve adults with IGHD due to a homozygous mutation of the GH‐releasing hormone (GHRH)‐receptor gene (GHRHR).

Programa de triagem neonatal para hipotireoidismo congênito no nordeste do Brasil: critérios diagnósticos e resultados

Avaliamos as concentracoes do TSH em papel-filtro colhido no calcanhar (TSHneo) de 48.039 criancas triadas do programa de triagem neonatal (PTN) para o hipotireoidismo congenito (HC) de Sergipe, as concentracoes de TSH, T4 total e T4 livre colhidas em sangue periferico nas criancas convocadas suspeitas de HC, a idade nas diversas fases do programa, a cobertura e a frequencia do PTN de janeiro de 2005 a agosto de 2006, comparando-as com dados da literatura. Utilizamos para analise os seguintes parâmetros: media, mediana, coeficiente de variacao e distribuicao de frequencia. A idade da crianca por ocasiao da coleta em papel filtro no calcanhar foi 10 ± 9 dias (media ± desvio-padrao) e a idade na reali-zacao do ensaio do TSHneo foi de 31 ± 13 dias. Em 2005, a cobertura do PTN, para o interior e para a capital de Sergipe, foi de 77% e 73%, respectivamente. Verificamos que em 99,484% das criancas triadas as concentracoes do TSH coletado em papel-filtro encontravam-se entre 0,01 e 5,20 µU/mL. As concentracoes do TSH decrescem com o aumento da idade ate estabilizar entre 11 e 15 dias de vida. Foram convocadas 248 criancas a partir do TSH coletado em papel-filtro (1/194). Na convocacao, as concentracoes do TSH, T4 e T4 livre coletado por puncao venosa estavam normais em 119 criancas (1/404). A frequencia de HC suspeito foi de 1/485 (99 casos), de HC foi de 1/6.005 (8 casos) e de hipotiroxinemia foi de 1/16.013 (3 casos). A terapia para o HC foi iniciada com 51 ± 12 dias.

Metabolic effects of growth hormone (GH) replacement in children and adolescents with severe isolated GH deficiency due to a GHRH receptor mutation

Background  The interpretation of the true effect of GH replacement therapy (GHRT) on metabolic status in GH deficiency (GHD) is often complicated by differing aetiologies of GHD and by the presence of additional hormone deficits.

Evolução do programa de triagem neonatal para o hipotireoidismo congênito e fenilcetonúria no Estado de Sergipe de 1995 a 2003

An evaluation was made of the timing delays in the various phases of the Screening Program for Congenital Hypothyroidism (HC) and Phenylketonuria (PKU), the coverage and incidence in the State of Sergipe from 1998 to 2003. The results were compared to the data from 1995. The age of the children in the sampling was 12 ± 11 days (mean ± standard deviation) lower than the 30 ± 19 days in the second semester of 1995. In the second half of 2003, the results were analyzed by the physician after 28 ± 15 days for HC and 25 ± 15 days for PKU, lower than 80 ± 40 days for the second semester of 1995. The period between the receipt of the samples at the laboratory and the assay in the second half of 2003 was 6 ± 4 days for TSH and 3 ± 2 days for phenylalanine. The coverage in 2003 for the interior of the State and the Capital was 67% and 85%, compared with 5% and 42% in the second semester of 1995, respectively. The incidence from 1998 to 2003 in the Public Health Service of Sergipe for HC was 1/4928 and 1/23406 for PKU. From 1998 to 2003 the therapy was initiated after 49 ± 17 days and 51 ± 12 days for HC and PKU, respectively. The reduction in the program timing delays and the increase in the coverage indicate development in the referred program.

Climacteric in untreated isolated growth hormone deficiency

Objective:To study the time, intensity of symptoms, hormonal profile, and related morbidity of climacteric in women with untreated isolated growth hormone (GH) deficiency (IGHD). Design:Women belonging to a large Brazilian kindred with IGHD due to a homozygous mutation in the GH-releasing hormone receptor gene were studied. None of them had ever received GH replacement therapy. A two-step protocol was performed. In the first case-control experiment, aimed to determine the age at climacteric, we compared eight women with IGHD and 32 normal women between 37 and 55 years of age. In the second cross-sectional experiment, aimed to determine the severity of climacteric symptoms, seven women with IGHD (aged 47-65 y) were compared with 13 controls (aged 44-65 y). The Kupperman Index scores, serum follicle-stimulating hormone, luteinizing hormone, prolactin, and estradiol levels were determined, and pelvic and mammary ultrasonography, mammography, and colpocytology were performed. Results:The number of women with follicle-stimulating hormone above 20 mIU/mL was higher in women with IGHD than controls. Kuppermans Index was not different between the two groups. Menarche had been delayed and parity was lower in women with IGHD. Hormonal profile was similar, but prolactin was lower in women with IGHD. Uterine volume was smaller in women with IGHD, and endometrial thickness and ovarian volume were similar in the two groups. No difference in breast images or in colpocytology was observed between the two groups. Conclusions:Menarche was delayed and the beginning of climacteric is anticipated in untreated lifetime IGHD, but menopausal symptoms and hormonal profile resemble the normal climacteric.