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.
Manuel H Aguiar-Oliveira, Anita H O Souza, Carla R P Oliveira, Viviane C Campos, Luíz A Oliveira-Neto and Roberto Salvatori
Francielle T Oliveira, Roberto Salvatori, José Marcondes, Larissa B Macena, Alecia A Oliveira-Santos, Augusto C N Faro, Viviane C Campos, Carla R P Oliveira, Ursula M M Costa and Manuel H Aguiar-Oliveira
GH-releasing hormone (GHRH) exerts hypnotic actions increasing the non-rapid eye movement (NREM) sleep. Conversely, GH stimulates the REM sleep. GH deficiency (GHD) often leads to sleep problems, daytime fatigue and reduced quality of life (QoL). GHD may be due to lack of hypothalamic GHRH or destruction of somatotroph cells. We have described a cohort with isolated GHD (IGHD) due to GHRH resistance caused by a homozygous null mutation (c.57 + 1G > A) in the GHRH receptor gene. They have normal QoL and no obvious complaints of chronic tiredness. The aim of this study was to determine the sleep quality in these subjects.
A cross-sectional study was carried out in 21 adult IGHD subjects, and 21 age- and gender-matched controls. Objective sleep assessment included polygraphic records of the awake, stages NREM [N1 (drowsiness), N2 and N3 (already sleeping)] and REM (R). Subjective evaluation included the Pittsburgh Sleep Quality Index, the Insomnia Severity Index and the Epworth Sleepiness Scale.
IGHD subjects showed a reduction in sleep efficiency (P = 0.007), total sleep time (P = 0.028), duration of N2 and R in minutes (P = 0.026 and P = 0.046 respectively), but had increased duration and percentage of N1 stage (P = 0.029 and P = 0.022 respectively), wake (P = 0.007) and wake-time after sleep onset (P = 0.017). There was no difference in N3 or in sleep quality questionnaire scores.
Patients with IGHD due to GHRH resistance exhibit objective reduction in the sleep quality, with changes in NREM and REM sleep, with no detectable subjective consequences. GHRH resistance seems to have a preponderant role over GHD in the sleep quality of these subjects.
Vanessa P Araujo, Manuel H Aguiar-Oliveira, Joselina L M Oliveira, Hertaline M N Rocha, Carla R P Oliveira, Tânia M A Rodrigues, Marco A Nunes, Isabella M P A Britto, Roberto Ximenes, Jose A S Barreto-Filho, Rafael A Meneguz-Moreno, Rossana M C Pereira, Eugênia H O Valença, Luiz A Oliveira-Neto, Taisa A R Vicente, Amanda Blackford and Roberto Salvatori
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).
We have studied the cardiovascular status (by echocardiography and carotid ultrasonography) of these subjects 60 months after completion of therapy (60-month washout – 60mo).
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 pre-therapy. 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.
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.