Luiz A. Oliveira-Neto

Cephalometric features in isolated growth hormone deficiency

OBJECTIVE To analyze cephalometric features in adults with isolated growth hormone (GH) deficiency (IGHD). MATERIALS AND METHODS Nine adult IGHD individuals (7 males and 2 females; mean age, 37.8 ± 13.8 years) underwent a cross-sectional cephalometric study, including 9 linear and 5 angular measurements. Posterior facial height/anterior facial height and lower-anterior facial height/anterior facial height ratios were calculated. To pool cephalometric measurements in both genders, results were normalized by standard deviation scores (SDS), using the population means from an atlas of the normal Brazilian population. RESULTS All linear measurements were reduced in IGHD subjects. Total maxillary length was the most reduced parameter (-6.5 ± 1.7), followed by a cluster of six measurements: posterior cranial base length (-4.9 ± 1.1), total mandibular length (-4.4 ± 0.7), total posterior facial height (-4.4 ± 1.1), total anterior facial height (-4.3 ± 0.9), mandibular corpus length (-4.2 ± 0.8), and anterior cranial base length (-4.1 ± 1.7). Less affected measurements were lower-anterior facial height (-2.7 ± 0.7) and mandibular ramus height (-2.5 ± 1.5). SDS angular measurements were in the normal range, except for increased gonial angle (+2.5 ± 1.1). Posterior facial height/anterior facial height and lower-anterior facial height/anterior facial height ratios were not different from those of the reference group. CONCLUSIONS Congenital, untreated IGHD causes reduction of all linear measurements of craniofacial growth, particularly total maxillary length. Angular measurements and facial height ratios are less affected, suggesting that lGHD causes proportional blunting of craniofacial growth.

Voice Quality in Short Stature With and Without GH Deficiency

OBJECTIVE The aim of this study was to analyze the individual impact of short stature (SS) or untreated isolated growth hormone deficiency (IGHD) on voice quality and the influence of IGHD on voice aging. METHODS A cross-sectional study was carried out on 73 adults: 33 IGHD, 10 SS, and 30 normal controls (CO), by evaluating vocal perception using Voice-Related Quality-of-Life (V-RQOL) scores and fundamental frequency (ƒ0). Analysis of variance with Bonferroni post-test was used to compare groups, and the Student t test was used to verify the influence of aging. RESULTS Stature of the SS and IGHD groups was similarly reduced in comparison to CO. Cephalic perimeter (CP) in SS males was larger than CO (P<0.05), and this was larger than in IGHD (P<0.0001). CP was similar in SS and CO females, and both were larger than in IGHD (P<0.0001). V-RQOL scores were lower in IGHD than in SS and CO. ƒ0 (Hz) was similar in IGHD females and SS and higher than in CO (P<0.05). f0 of IGHD males was higher than in SS (P=0.01) and CO (P=0.001). IGHD abolished the effect of aging on ƒ0 exhibited by CO. CONCLUSIONS Lower vocal perception and higher ƒ0 were found in IGHD in comparison to CO in both genders; in comparison to SS, higher ƒ0 was only found in IGHD males. Because SS males have higher CP than IGHD, this suggests that CP and craniofacial growth can influence voice in IGHD. Finally, IGHD seems to abolish the effects of aging on voice.

Periodontal disease in adults with untreated congenital growth hormone deficiency: a case-control study

AIM The aim of this study was to investigate the possible associations between isolated growth hormone deficiency (IGHD) and periodontal attachment loss (PAL) in adults affected by congenital IGHD. MATERIALS AND METHODS Forty-five previously identified IGHD subjects were eligible for this study. The final study sample comprised 32 cases (gender:20M/12F; age:44.8 ± 17.5) matched for age, gender, diabetes, smoking status and income to 32 controls (non-IGHD subjects). Participants were submitted to a full-mouth clinical examination of six sites per tooth and were interviewed using a structured, written questionnaire. Periodontitis was defined as proximal PAL≥5 mm affecting ≥30% of teeth. RESULTS No significant differences were observed in the percentage of sites with visible plaque between IGHD and non-IGHD subjects (59.4% versus 46.9%, p=0.32). IGHD subjects had significant less supragingival calculus (31.3% versus 59.4%, p=0.02) and more bleeding on probing (71.9% versus 18.8%, p<0.01) than controls. PAL≥5 mm was significantly more prevalent (100% versus 71.9%, p<0.01) and affected more teeth (30.5% versus 6.7%, p<0.01) in cases than in controls. After adjusting for supragingival calculus, IGHD cases had a higher likelihood of having periodontitis than controls (OR=17.4-17.8, 95% CI=2.3-134.9, p=0.004-0.005). CONCLUSION Congenital IGHD subjects have a greater chance of having PAL.

The consequences of growth hormone-releasing hormone receptor haploinsufficiency for bone quality and insulin resistance

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.

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

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.

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

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.

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

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.

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

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.

Effects of Therapy With Semi-occluded Vocal Tract and Choir Training on Voice in Adult Individuals With Congenital, Isolated, Untreated Growth Hormone Deficiency

OBJECTIVES Voice is produced by the vibration of the vocal folds expressed by its fundamental frequency (Hz), whereas the formants (F) are fundamental frequency multiples, indicating amplification zones of the vowels in the vocal tract. We have shown that lifetime isolated growth hormone deficiency (IGHD) causes high pitch voice, with higher values of most formant frequencies, maintaining a prepuberal acoustic prediction. The objectives of this work were to verify the effects of the therapy with a semi-occluded vocal tract (SOVTT) and choir training on voice in these subjects with IGHD. We speculated that acoustic vocal parameters can be improved by SOVTT or choir training. STUDY DESIGN This is a prospective longitudinal study without control group. METHODS Acoustic analysis of isolated vowels was performed in 17 adults with IGHD before and after SOVTT (pre-SOVTT and post-SOVTT) and after choir training (post training), in a 30-day period. RESULTS The first formant was higher in post training compared with the pre-SOVTT (P = 0.009). The second formant was higher in post-SOVTT than in pre-SOVTT (P = 0.045). There was a trend of reduction in shimmer in post-choir training in comparison with pre-SOVTT (P = 0.051), and a reduction in post-choir training in comparison with post-SOVTT (P = 0.047). CONCLUSIONS SOVTT was relevant to the second formant, whereas choir training improved first formant and shimmer. Therefore, this speech therapy approach was able to improve acoustic parameters of the voice of individuals with congenital, untreated IGHD. This seems particularly important in a scenario in which few patients are submitted to growth hormone replacement therapy.

MECHANISMS IN ENDOCRINOLOGY: The multiple facets of GH: lessons from lifetime, untreated isolated GH deficiency due to GHRH receptor mutation

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.