RESUMO
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.
Assuntos
Estatura/genética , Receptores de Neuropeptídeos/genética , Receptores de Hormônios Reguladores de Hormônio Hipofisário/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos Transversais , Feminino , Estudos de Associação Genética , Heterozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Mutação Puntual , Adulto JovemRESUMO
OBJECTIVE: Growth hormone (GH)/insulin-like growth factor (IGF) axis and insulin are key determinants of bone remodelling. Homozygous mutations in the GH-releasing hormone receptor (GHRHR) gene (GHRHR) are a frequent cause of genetic isolated GH deficiency (IGHD). Heterozygosity for GHRHR mutation causes changes in body composition and possibly an increase in insulin sensitivity, but its effects on bone quality are still unknown. The objective of this study was to assess the bone quality and metabolism and its correlation with insulin sensitivity in subjects heterozygous for a null mutation in the GHRHR. PATIENTS AND METHODS: A cross-sectional study was performed on 76 normal subjects (68·4% females) (N/N) and 64 individuals (64·1% females) heterozygous for a mutation in the GHRHR (MUT/N). Anthropometric features, quantitative ultrasound (QUS) of the heel, bone markers [osteocalcin (OC) and CrossLaps], IGF-I, glucose and insulin were measured, and homeostasis model assessment of insulin resistance (HOMA(IR) ) was calculated. RESULTS: There were no differences in age or height between the two groups, but weight (P = 0·007) and BMI (P = 0·001) were lower in MUT/N. There were no differences in serum levels of IGF-I, glucose, T-score or absolute values of stiffness and OC, but insulin (P = 0·01), HOMA(IR) (P = 0·01) and CrossLaps (P = 0·01) were lower in MUT/N. There was no correlation between OC and glucose, OC and HOMA(IR) in the 140 individuals as a whole or in the separate MUT/N or N/N groups. CONCLUSIONS: This study suggests that one allele mutation in the GHRHR gene has a greater impact on energy metabolism than on bone quality.
Assuntos
Remodelação Óssea/genética , Haploinsuficiência , Resistência à Insulina/genética , Receptores de Neuropeptídeos/genética , Receptores de Hormônios Reguladores de Hormônio Hipofisário/genética , Adulto , Idoso , Densidade Óssea/genética , Remodelação Óssea/fisiologia , Brasil , Estudos de Casos e Controles , Estudos Transversais , Feminino , Hormônio do Crescimento/deficiência , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Osteocalcina/sangue , Receptores de Neuropeptídeos/deficiência , Receptores de Hormônios Reguladores de Hormônio Hipofisário/deficiênciaRESUMO
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-naive adults with IGHD due to a homozygous mutation of the GH-releasing hormone (GHRH)-receptor gene (GHRHR). PATIENTS AND METHODS: We studied 20 individuals (10 men) with IGHD at baseline, after 6 months of depot GH treatment, and 6 and 12 months after discontinuation of GH. Quantitative ultrasound (QUS) of the heel was performed and serum osteocalcin (OC) and C-terminal cross-linking telopeptide of type I collagen (ICTP) were measured. QUS was also performed at baseline and 12 months later in a group of 20 normal control individuals (CO), who did not receive GH treatment. RESULTS: At baseline, the IGHD group had a lower T-score on QUS than CO (-1.15 +/- 0.9 vs.-0.07 +/- 0.9, P < 0.001). GH treatment improved this parameter, with improvement persisting for 12 months post-treatment (T-score for IGHD = -0.59 +/- 0.9, P < 0.05). GH also caused an increase in serum OC (baseline vs. pGH, P < 0.001) and ICTP (baseline vs. pGH, P < 0.01). The increase in OC was more marked during treatment and its reduction was slower after GH discontinuation than in ICTP. CONCLUSIONS: These data suggest that lifetime severe IGHD is associated with significant reduction in QUS parameters, which are partially reversed by short-term depot GH treatment. The treatment induces a biochemical pattern of bone anabolism that persists for at least 6 months after treatment discontinuation.
Assuntos
Calcâneo/diagnóstico por imagem , Hormônio do Crescimento Humano/deficiência , Hormônio do Crescimento Humano/uso terapêutico , Receptores de Neuropeptídeos/genética , Receptores de Hormônios Reguladores de Hormônio Hipofisário/genética , Adulto , Calcâneo/efeitos dos fármacos , Calcâneo/metabolismo , Colágeno Tipo I , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Osteocalcina/sangue , Fragmentos de Peptídeos/sangue , Peptídeos , Pró-Colágeno/sangue , UltrassonografiaRESUMO
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). SUBJECTS AND METHODS: By using ultrasound, we studied the sizes (absolute and corrected by height, weight and BSA) of the intra-abdominal organs of 18 adult subjects with IGHD (eight females, IGHD group) who have never received GH replacement therapy. They were all homozygous for the same null mutation (IVS1 + 1G --> A) in the GHRH receptor gene (GHRH-R). They were compared with normal controls from the same region. RESULTS: After correction for BSA, subjects lacking a functional GHRH-R have normal prostate and ovaries size, small spleen and uterus, and large liver, pancreas and kidney. CONCLUSIONS: Size of individual abdominal organs is influenced in different ways by severe and congenital lack of GH due to a GHRH-R mutation.
Assuntos
Abdome , Transtornos do Crescimento/genética , Transtornos do Crescimento/patologia , Hormônio do Crescimento Humano/deficiência , Tamanho do Órgão , Receptores de Neuropeptídeos/genética , Receptores de Hormônios Reguladores de Hormônio Hipofisário/genética , Adulto , Estatura/genética , Índice de Massa Corporal , Estudos de Casos e Controles , Feminino , Transtornos do Crescimento/congênito , Homozigoto , Terapia de Reposição Hormonal , Hormônio do Crescimento Humano/uso terapêutico , Humanos , Masculino , Pessoa de Meia-Idade , Mutação/fisiologia , Tamanho do Órgão/efeitos dos fármacos , Tamanho do Órgão/genéticaRESUMO
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. Kupperman's 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.
Assuntos
Climatério , Nanismo Hipofisário/fisiopatologia , Hormônio do Crescimento Humano/deficiência , Adulto , Idoso , Nanismo Hipofisário/sangue , Estradiol/sangue , Feminino , Hormônio Foliculoestimulante/sangue , Humanos , Hormônio Luteinizante/sangue , Pessoa de Meia-Idade , Prolactina/sangueRESUMO
CONTEXT: Biallelic mutations in the GHRH receptor (GHRHR) gene (GHRHR) are a frequent cause of isolated GH deficiency (IGHD). Although heterozygous carriers of these mutations appear normal, we hypothesized that heterozygosity for a GHRHR mutation might be associated with a subclinical phenotype. METHODS: We studied members of a large Brazilian kindred with IGHD (Itabaianinha cohort) caused by a homozygous null GHRHR mutation. We compared 76 adult subjects (age, 25-75 yr) heterozygous for the mutation (WT/MT) with 77 sex-matched controls from the same population who are homozygous for the wild-type GHRHR allele (WT/WT). RESULTS: We found no difference in adult height and sd score for serum IGF-I between the two groups. Body weight, body mass index, skin folds, waist and hip circumferences, and lean mass were all reduced in WT/MT subjects. Percentage fat mass and waist/hip ratio were similar in the two groups. Fasting insulin and homeostasis model assessment of insulin resistance were lower in WT/MT. The other biochemical parameters [total and fractionated cholesterol, triglycerides, lipoprotein (a), and C-reactive protein] were not different between the two groups. CONCLUSIONS: Heterozygosity for a null GHRHR mutation is not associated with reduction in adult stature or in serum IGF-I but is associated with changes in body composition and possibly an increase in insulin sensitivity. These effects do not seem to be modulated by changes in circulating IGF-I.
Assuntos
Composição Corporal/genética , Estatura/genética , Heterozigoto , Receptores de Neuropeptídeos/genética , Receptores de Hormônios Reguladores de Hormônio Hipofisário/genética , Adulto , Idoso , Envelhecimento , Índice de Massa Corporal , Brasil , Feminino , Humanos , Resistência à Insulina/genética , Fator de Crescimento Insulin-Like I/metabolismo , Masculino , Pessoa de Meia-Idade , Mutação , FenótipoRESUMO
BACKGROUND: GH deficiency (GHD) in adults is associated with increased abdominal adiposity and systolic blood pressure, total and low-density lipoprotein cholesterol, and C-reactive protein. METHODS: We have studied the effects of 6-month GH replacement therapy in 20 adult members of a large Brazilian kindred with lifelong severe and isolated GHD due to a homozygous mutation in GHRH receptor gene (46 +/- 14.5 yr; 122 +/- 7.7 cm; 36.7 +/- 5.4 kg; 10 men). Subjects were studied at baseline, after 6-month bimonthly depot GH injections (Nutropin Depot; Genentech, Inc., South San Francisco, CA) [post GH (pGH)], and after 6- and 12-month washout. RESULTS: Despite modest trough serum IGF-I increase, GH replacement therapy caused a decrease in skinfolds and in waist-hip ratio, with a rebound increase at 12 months. Total and low-density lipoprotein cholesterol were reduced pGH and returned to baseline at 6 months. High-density lipoprotein cholesterol increased pGH, but at 12 months was lower than baseline. A progressive increase in left ventricular mass index, posterior wall, and septum thickness occurred from pGH to 12 months, and of carotid intima-media thickness, from 6 to 12 months. Individuals were 6, 16, and 52 times more likely to have an atherosclerotic carotid plaque at pGH, 6 and 12 months, respectively, when compared with baseline. CONCLUSION: In patients with lifetime isolated GHD, 6-month treatment with GH has reversible beneficial effects on body composition and metabolic profile, but it causes a progressive increase in intima-media thickness and in the number of atherosclerotic carotid plaques.
Assuntos
Aterosclerose/induzido quimicamente , Aterosclerose/epidemiologia , Hormônio do Crescimento/efeitos adversos , Hormônio do Crescimento/uso terapêutico , Terapia de Reposição Hormonal , Hormônio do Crescimento Humano/deficiência , Adulto , Antropometria , Aterosclerose/patologia , Pressão Sanguínea/fisiologia , Artérias Carótidas/patologia , HDL-Colesterol/sangue , LDL-Colesterol/sangue , Preparações de Ação Retardada , Ecocardiografia , Exercício Físico/fisiologia , Feminino , Hormônio do Crescimento/administração & dosagem , Frequência Cardíaca/fisiologia , Hormônio do Crescimento Humano/sangue , Humanos , Resistência à Insulina , Fator de Crescimento Insulin-Like I/metabolismo , Masculino , Pessoa de Meia-Idade , Fatores de RiscoRESUMO
OBJECTIVE: To evaluate the hearing status of growth hormone (GH)-naive adults with isolated GH deficiency (IGHD) belonging to an extended Brazilian kindred with a homozygous mutation in the GH-releasing hormone receptor gene. STUDY DESIGN: Cross-sectional. SETTING: Divisions of Endocrinology and Otorhinolaryngology of the Federal University of Sergipe. SUBJECTS AND METHODS: Twenty-six individuals with IGHD (age, 47.6 ± 15.1 years; 13 women) and 25 controls (age, 46.3 ± 14.3 years; 15 women) were administered a questionnaire on hearing complaints and hearing health history. We performed pure-tone audiometry, logoaudiometry, electroacoustic immittance, and stapedial reflex. To assess outer hair cell function in the cochlea, we completed transient evoked otoacoustic emissions (TEOAEs). To assess the auditory nerve and auditory brainstem, we obtained auditory brainstem responses (ABRs). RESULTS: Misophonia and dizziness complaints were more frequent in those with IGHD than in controls (P = .011). Patients with IGHD had higher thresholds at 250 Hz (P = .005), 500 Hz (P = .006), 3 KHz (P = .008), 4 KHz (P = .038), 6 KHz (P = .008), and 8 KHz (P = .048) and mild high-tones hearing loss (P = .029). Stapedial reflex (P < .001) and TEOAEs (P = .025) were more frequent in controls. There were no differences in ABR latencies. Hearing loss in patients with IGHD occurred earlier than in controls (P < .001). CONCLUSION: Compared with controls of the same area, subjects with untreated, congenital lifetime IGHD report more misophonia and dizziness, have predominance of mild high-tones sensorineural hearing loss, and have an absence of stapedial reflex and TEOAEs.
Assuntos
Nanismo Hipofisário/fisiopatologia , Perda Auditiva/fisiopatologia , Audição/fisiologia , Adulto , Audiometria de Tons Puros , Brasil/epidemiologia , Estudos Transversais , Nanismo Hipofisário/complicações , Feminino , Perda Auditiva/epidemiologia , Perda Auditiva/etiologia , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Emissões Otoacústicas Espontâneas , Inquéritos e QuestionáriosRESUMO
The GH/IGF-I axis has essential roles in regulating bone and vascular status. The age-related decrease in GH secretion ("somatopause") may contribute to osteoporosis and atherosclerosis, commonly observed in the elderly. Adult-onset GH deficiency (GHD) has been reported to be associated with reduced bone mineral density (BMD), increased risk of fractures, and premature atherosclerosis. We have shown the young adult individuals with isolated GHD (IGHD) due to a homozygous for the c.57+1G>A GHRH receptor gene mutation have normal volumetric BMD (vBMD), and not develop premature atherosclerosis, despite adverse risk factor profile. However, the bone and vascular impact of lifetime GHD on the aging process remains unknown. We studied a group of ten older IGHD subjects (≥60 years) homozygous for the mutation, comparing them with 20 age- and gender-matched controls (CO). Areal BMD was measured, and vBMD was calculated at the lumbar spine and total hip. Vertebral fractures and abdominal aortic calcifications (expressed as calcium score) were also assessed. Areal BMD was lower in IGHD, but vBMD was similar in the two groups. The percent of fractured individuals was similar, but the mean number of fractures per individual was lower in IGHD than CO. Calcium score was similar in the two groups. A positive correlation was found between calcium score and number of fractures. Untreated lifetime IGHD has beneficial consequences on bone status and does not have a deleterious effect on abdominal aorta calcification.
Assuntos
Envelhecimento/fisiologia , Doenças da Aorta/epidemiologia , Densidade Óssea , Nanismo Hipofisário/epidemiologia , Calcificação Vascular/epidemiologia , Idoso , Idoso de 80 Anos ou mais , Aorta Abdominal/patologia , Estudos de Casos e Controles , Nanismo Hipofisário/genética , Feminino , Nível de Saúde , Hormônio do Crescimento Humano/deficiência , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Receptores de Neuropeptídeos/genética , Receptores de Hormônios Reguladores de Hormônio Hipofisário/genética , Fraturas da Coluna Vertebral/epidemiologia , Coluna VertebralRESUMO
Nonalcoholic fatty liver disease (NAFLD) is known to be associated with insulin resistance, atherosclerosis, and low serum IGF1 levels. We have described a large cohort of patients with isolated GH deficiency (IGHD) due to the c.57+1GâA mutation in the GHRH receptor gene. These subjects have increased insulin sensitivity (IS), delayed atherosclerosis, and normal longevity. We hypothesized that, despite visceral obesity, NAFLD would be absent or mild due to the increased IS. To assess the prevalence and severity of NAFLD in adult subjects with lifetime, congenital, untreated IGHD, we studied 22 IGHD adults and 25 controls (COs) matched for age and sex. NAFLD was assessed by a comprehensive liver function panel, and ultrasonographic pattern (hyperechogenic pattern, HP) coded as follows: 0, absent; 1, mild; 2, moderate; and 3, severe. Compared with COs, IGHD individual had lower serum IGF1 (P<0.0001), higher total cholesterol (P=0.027), lower prothrombin time (P=0.017), and similar activated partial thromboplastin time and fibrinogen values. Alanine transaminase (ALT) values were similar in the two groups, but aspartate transaminase was higher in IGHD (P=0.013). However, more IGHD subjects (7/22) than COs (3/23) had ALT above the upper limit of normal (P=0.044). The prevalence of NAFLD was higher in IGHD than COs (61 vs 29%, P=0.032), and the HP score was higher in IGHD than COs (P=0.041), but severe NAFLD was not observed in any IGHD (or CO) individual. Liver HP score is increased in lifetime, untreated, congenital IGHD, but the increase in transaminases is mild, suggesting a lack of advanced forms of NAFLD.
RESUMO
OBJECTIVES: GH therapy is still controversial, except in severe GH deficiency (SGHD). The objective of this study was to compare the response to growth hormone (GH) therapy in children with partial GH insensitivity (PGHIS) and mild GH deficiency (MGHD) with those with SGHD. SUBJECTS AND METHODS: Fifteen PGHIS, 11 MGHD, and 19 SGHD subjects, followed up for more than one year in the Brazilian public care service, were evaluated regarding anthropometric and laboratory data at the beginning of treatment, after one year (1st year) on treatment, and at the last assessment (up to ten years in SGHD, up to four years in MGHD, and up to eight years in PGHIS). RESULTS: Initial height standard deviation score (SDS) in SGHD was lower than in MGHD and PGHIS. Although the increase in 1 st year height SDS in comparison to initial height SDS was not different among the groups, height-SDS after the first year of treatment remained lower in SGHD than in MGHD. There was no difference in height-SDS at the last assessment of the children among the three groups. GH therapy, in the entire period of observation, caused a trend towards lower increase in height SDS in PGHIS than SGHD but similar increases were observed in MGHD and SGHD. CONCLUSION: GH therapy increases height in PGHIS and produces similar height effects in MGHD and SGHD.
Assuntos
Hormônio do Crescimento Humano/uso terapêutico , Fator de Crescimento Insulin-Like I/análise , Síndrome de Laron/tratamento farmacológico , Adolescente , Determinação da Idade pelo Esqueleto , Análise de Variância , Estatura/efeitos dos fármacos , Índice de Massa Corporal , Brasil , Criança , Hormônio do Crescimento Humano/sangue , Humanos , Medições Luminescentes , Proteínas Recombinantes/uso terapêutico , Estudos RetrospectivosRESUMO
Growth hormone (GH) and prolactin share similarities in structure and function. We have previously shown that women with congenital isolated GH deficiency (IGHD) caused by a homozygous mutation in the GHRH receptor gene (GHRHR) (MUT/MUT) have a short reproductive life, with anticipated climacteric. At climacteric, they have lower prolactin levels than normal controls (N/N). Because they are able to breast feed, we hypothesized that this prolactin reduction is limited to climacteric, as result of lower estradiol exposure of the lactotrophs. The purposes of this work were to assess prolactin levels in broader age adults homozygous and heterozygous (MUT/N) for the mutation and in normal controls (N/N), and to correlate them to sex steroids levels. We enrolled 24 GH-naïve MUT/MUT (12 female), 25 MUT/N (14 female), and 25 N/N (11 female) subjects, aged 25-65 years. Anthropometric data and serum prolactin, estradiol, total testosterone, and sex hormone binding globulin (SHBG) were measured. Free testosterone was calculated. Prolactin levels were similar in the three groups. In males, testosterone and SHBG levels were higher in MUT/MUT in comparison to N/N. There was no difference in free testosterone among groups. In all 74 individuals, prolactin correlated inversely with age (p < 0.0001) and directly with serum estradiol (p = 0.018). Prolactin levels in subjects with IGHD due to a homozygous GHRHR mutation are similar to heterozygous and normal homozygous, but total testosterone and SHBG are higher in male MUT/MUT, with no difference in free testosterone. The reduced prolactin level is limited to climacteric period, possibly due to reduced estrogen exposure.
Assuntos
Nanismo Hipofisário/sangue , Hormônios Esteroides Gonadais/sangue , Prolactina/sangue , Adulto , Idoso , Estudos de Casos e Controles , Nanismo Hipofisário/epidemiologia , Nanismo Hipofisário/genética , Feminino , Humanos , Resistência à Insulina/fisiologia , Masculino , Pessoa de Meia-Idade , Mutação de Sentido Incorreto , Receptores de Neuropeptídeos/genética , Receptores de Hormônios Reguladores de Hormônio Hipofisário/genética , Globulina de Ligação a Hormônio Sexual/análiseRESUMO
OBJECTIVES: Adult subjects with untreated, lifetime, isolated GH deficiency (IGHD) due to a homozygous GHRH receptor gene mutation (MUT/MUT) residing in Itabaianinha, Brazil, present with lower BMI, higher prevalence of impaired glucose tolerance (IGT), increased insulin sensitivity (IS), and reduced ß-cell function (ßCF) when compared with non-BMI-matched homozygous normal controls. However, the prevalence of diabetes mellitus (DM) in this cohort is unknown. Comparing their IS and ßCF with BMI-matched individuals heterozygous for the same mutation (MUT/N) may be useful to elucidate the role of the GH-IGF1 axis in IS and ßCF. The purposes of this work were to verify the prevalence of IGT and DM in adult MUT/MUT subjects from this kindred and to compare IS and ßCF in MUT/MUT and MUT/N. DESIGN: Cross-sectional study. METHODS: We studied most (51) of the living IGHD adults of this kindred who are GH naive. The oral glucose tolerance test (OGTT) could be performed in 34 subjects, fasting glucose was measured in 15, while two had a previous diagnosis of DM. The OGTT results of 24 MUT/MUT subjects were compared with those of 25 BMI-matched MUT/N subjects. IS was assessed by homeostatic model assessment of insulin resistance (HOMA-IR), quantitative IS check index, and oral glucose IS index for 2 and 3âh. ßCF was assayed by HOMA-ß, insulinogenic index, and the area under the curve of insulin:glucose ratio. RESULTS: The prevalence of DM and IGT in IGHD was 15.68 and 38.23% respectively. IS was increased and ßCF was reduced in MUT/MUT in comparison with MUT/N. CONCLUSIONS: Lifetime, untreated IGHD increases IS, impairs ßCF, and does not provide protection from diabetes.
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CONTEXT: The GH/IGF-I axis is important for bone growth, but its effects on joint function are not completely understood. Adult-onset GH-deficient individuals have often reduced bone mineral density (BMD). However, there are limited data on BMD in adult patients with untreated congenital isolated GH-deficient (IGHD). We have shown that adult IGHD individuals from the Itabaianinha, homozygous for the c.57+1G>A GHRHR mutation, have reduced bone stiffness, but BMD and joint status in this cohort are unknown. OBJECTIVE: The goal is to study BMD, joint function, and osteoarthritis score in previously untreated IGHD adults harboring the c.57+1G>A GHRHR mutation. DESIGN: This is a cross-sectional study. METHODS: Areal BMD by dual-energy X-ray absorptiometry was measured in 25 IGHD and 23 controls (CO). Volumetric BMD (vBMD) was calculated at the lumbar spine and total hip. Joint function was assessed by goniometry of elbow, hips, and knees. X-rays were used to measure the anatomic axis of knee and the severity of osteoarthritis, using a classification for osteophytes (OP) and joint space narrowing (JSN). RESULTS: Genu valgum was more prevalent in IGHD than CO. The osteoarthritis knees OP score was similar in both groups, and knees JSN score showed a trend to be higher in IGHD. The hips OP score and JSN score were higher in IGHD. Areal BMD was lower in IGHD than CO, but vBMD was similar in the two groups. Range of motion was similar in elbow, knee, and hip in IGHD and CO. CONCLUSIONS: Untreated congenital IGHD due to a GHRHR mutation causes hip joint problems and genu valgum, without apparent clinical significance, reduces bone size, but does not reduce vBMD of the lumbar spine and hip.
Assuntos
Nanismo Hipofisário/genética , Geno Valgo/genética , Osteoartrite do Quadril/genética , Osteoartrite do Joelho/genética , Receptores de Neuropeptídeos/genética , Receptores de Hormônios Reguladores de Hormônio Hipofisário/genética , Absorciometria de Fóton , Adulto , Densidade Óssea , Estudos Transversais , Nanismo Hipofisário/diagnóstico por imagem , Nanismo Hipofisário/epidemiologia , Feminino , Geno Valgo/diagnóstico por imagem , Geno Valgo/epidemiologia , Articulação do Quadril/diagnóstico por imagem , Articulação do Quadril/patologia , Homozigoto , Humanos , Fator de Crescimento Insulin-Like I/metabolismo , Masculino , Pessoa de Meia-Idade , Modelos Biológicos , Osteoartrite do Quadril/diagnóstico por imagem , Osteoartrite do Quadril/epidemiologia , Osteoartrite do Joelho/diagnóstico por imagem , Osteoartrite do Joelho/epidemiologia , Mutação Puntual , Prevalência , Adulto JovemRESUMO
CONTEXT: GH reduces insulin sensitivity (IS), whereas IGF-I increases it. IGF-I seems to be critical for the development of the ß-cells, and impaired IS has been reported in GH deficiency (GHD). OBJECTIVE: The aim of the study was to assess IS and ß-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). ß-Cell function was assayed by homeostasis model assessment index-ß, 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-ß, 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 ß-cell function, no evidence of IR, and higher frequency of impaired glucose tolerance.
Assuntos
Nanismo Hipofisário/fisiopatologia , Intolerância à Glucose/fisiopatologia , Resistência à Insulina/fisiologia , Células Secretoras de Insulina/fisiologia , Adulto , Glicemia/metabolismo , Estudos Transversais , Nanismo Hipofisário/sangue , Feminino , Intolerância à Glucose/sangue , Teste de Tolerância a Glucose , Humanos , Insulina/sangue , Masculino , Pessoa de Meia-IdadeRESUMO
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 - 12 mo). METHODS: We have studied the cardiovascular status (by echocardiography and carotid ultrasonography) of these subjects 60 months after completion of therapy (60-month washout - 60 mo). RESULTS: Carotid IMT reduced significantly from 12 to 60 mo, returning to baseline (pre-therapy) value. The number of individuals with plaques was similar at 12 and 60 mo, remaining higher than pre-therapy. LVMI, relative posterior wall thickness, and septum thickness did not change between 12 and 60 mo, but absolute posterior wall increased from 12 to 60 mo. Systolic function, evaluated by ejection fraction and shortening fraction, was reduced at 60 mo in comparison with 12 mo returning to baseline levels. The E/A wave ratio (expression of diastolic function) decreased at 60 mo compared with both 12 mo 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 60 mo and higher than at baseline.
Assuntos
Aterosclerose/metabolismo , Aterosclerose/patologia , Pressão Sanguínea , Artérias Carótidas/patologia , Terapia de Reposição Hormonal , Hormônio do Crescimento Humano/administração & dosagem , Hormônio do Crescimento Humano/deficiência , Hipertrofia Ventricular Esquerda/patologia , Disfunção Ventricular Esquerda/fisiopatologia , Idoso , Artérias Carótidas/diagnóstico por imagem , Artérias Carótidas/metabolismo , Espessura Intima-Media Carotídea , Fatores de Confusão Epidemiológicos , Progressão da Doença , Ecocardiografia , Feminino , Humanos , Hipertrofia Ventricular Esquerda/diagnóstico por imagem , Hipertrofia Ventricular Esquerda/metabolismo , Masculino , Pessoa de Meia-Idade , Volume Sistólico , Fatores de Tempo , Ultrassonografia Doppler , Disfunção Ventricular Esquerda/diagnóstico por imagem , Disfunção Ventricular Esquerda/metabolismoRESUMO
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.
Assuntos
Adiponectina/sangue , Albuminúria/urina , Hormônio do Crescimento Humano/deficiência , Leptina/sangue , Adulto , Idoso , Estudos Transversais , Feminino , Humanos , Resistência à Insulina , Masculino , Pessoa de Meia-Idade , Receptores de Neuropeptídeos/genética , Receptores de Hormônios Reguladores de Hormônio Hipofisário/genética , Análise de RegressãoRESUMO
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.
Assuntos
Hormônio do Crescimento Humano/deficiência , Longevidade , Mutação , Receptores de Neuropeptídeos/genética , Receptores de Hormônios Reguladores de Hormônio Hipofisário/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Feminino , Heterozigoto , Homozigoto , Hormônio do Crescimento Humano/fisiologia , Humanos , Masculino , Pessoa de Meia-Idade , Estudos RetrospectivosRESUMO
OBJECTIVES: Deficiency of 21-hydroxylase is the most common form of congenital adrenal hyperplasia (CAH-21OH). The aim of this study was to determine, by allele-specific PCR, the frequency of microconversions of the CYP21A2, in sixteen patients with the classical forms and in 5 patients with the nonclassical (NC) form of CAH-21OH and correlate genotype with phenotype. METHODS: Genotypes were classified into 3 mutation groups (A, B and C), based on the degree of enzymatic activity. Screening for 7 microconversions by allele-specific PCR diagnosed 74.3% (n=26) of the 35 unrelated alleles. RESULTS: The most frequent mutations were Q318X (25.7%), V281L (17.1%), I2 Splice (14.3%), I172N (14.3%), and R356W (14.3%). Genotype was identified in 57.1% of the patients. We observed correlation between genotype and phenotype in 91.7% of the cases. CONCLUSION: The highest frequency for Q318X (25.7%) when compared to other studies may reflect individual sample variations in this Northeastern population.
Assuntos
Hiperplasia Suprarrenal Congênita/genética , Frequência do Gene/genética , Mutação/genética , Esteroide 21-Hidroxilase/genética , Adolescente , Hiperplasia Suprarrenal Congênita/classificação , Brasil , Pré-Escolar , Feminino , Genótipo , Humanos , Recém-Nascido , Masculino , FenótipoRESUMO
Impaired quality of life (QoL) is commonly described as being associated with growth hormone (GH) deficiency (GHD), and beneficial effects of GH replacement therapy on QoL have been reported. However, most studies examined heterogeneous cohorts of patients GHD of varying etiologies, severities and age of onset. Most of these patients miss other pituitary hormones, whose replacement can also influence QoL. We studied the QoL of a homogeneous cohort of 20 adults with isolated GH deficiency (IGHD) due to the same mutation in the GH-releasing hormone receptor gene (IGHD, 10 men) using the Life Satisfaction Hypopituitarism Module (QLS-H), and compared them with 20 matched controls residing in the same community (CO, 10 men). Additionally, the IGHD group was evaluated after 6 months of treatment with bi-monthly depot GH, and after 12 months from its interruption. There was no difference in the total score of QoL (TSQoL) or in any of the nine categories that composes the questionnaire between IGHD and CO. Similar results were obtained when data were analyzed by sex. GH treatment only increased satisfaction with physical endurance, but did not cause an increase in the TSQoL. We conclude that in this unique population congenital, untreated, lifetime IGHD does not reduce QoL, and treatment with GH for 6 months only causes improvement in satisfaction with physical resistance.