Brain morphometry and estimation of aging brain in subjects with congenital untreated isolated GH deficiency.

PURPOSE: Individuals with isolated GH deficiency (IGHD) due to a mutation in the GHRH receptor gene have a normal life expectancy and above 50 years of age, similar total cognitive performance, with better attention and executive function than controls. Our objectives were to evaluate their brain morphometry and brain aging using MRI. METHODS: Thirteen IGHD and 14 controls matched by age, sex, and education, were enrolled. Quantitative volumetric data and cortical thickness were obtained by automatic segmentation using Freesurfer software. The volume of each brain region was normalized by the intracranial volume. The difference between the predicted brain age estimated by MRI using a trained neuronal network, and the chronological age, was obtained. p < 0.005 was considered significant and 0.005 < p < 0.05 as a suggestive evidence of difference. RESULTS: In IGHD, most absolute values of cortical thickness and regional brain volumes were similar to controls, but normalized volumes were greater in the white matter in the frontal pole and in the insula bilaterally, and in the gray matter, in the right insula and in left Caudate (p < 0.005 for all comparisons) We also noticed suggestive evidence of a larger volume in IGHD in left thalamus (p = 0.006), right thalamus (p = 0.025), right caudate (p = 0.046) and right putamen (p = 0.013). Predicted brain ages were similar between groups. CONCLUSION: IGHD is primarily associated with similar absolute brain measurements, and a set of larger normalized volumes, and does not appear to alter the process of brain aging.

Cognitive performance during senescence in untreated congenital isolated GH deficiency.

Individuals with untreated isolated GH deficiency (IGHD) due to a mutation in the GHRH receptor gene from Itabaianinha Brazil have increased insulin sensitivity, normal life expectancy, and an extended health span, i.e. the period of life free from disabilities. We hypothesize that their prolonged health span is accompanied by a delayed cognitive decline in senescence. To test this hypothesis, we have administered the Literacy-Independent Cognitive Assessment (LICA) to 15 IGHD individuals aged over 50 years and 15 controls matched by age, sex, years of education, and percentage of illiteracy. All individuals were negative for HIV and syphilis serology, and there were no differences in serum levels of folate, vitamin B12 and TSH between the two groups, while free T4 was higher in the IGHD group. IGHD subjects had a higher total LICA score than controls, 215 (22.7) vs 204.2 (18.1), without reaching statistical significance. Scores of memory, visuoconstruction, language and calculation were similar between the two groups, with better attention (9.5 (1.4) vs 8.3 (1.1), P = 0.01) and executive function (38.3 (4.8) vs 35.1 (2.5), P = 0.03) scores in IGHD. MANCOVA revealed that group (but no age) had a significant effect on the LICA variables (partial eta squared of 0.455, power of 0.812, P = 0.02). This effect is verified on attention (partial eta squared 0.216, power of 0.749, P = 0.01) and executive function (partial eta squared 0.154, power of 0.570, P = 0.03. In conclusion, IGHD in senescence is associated with similar total cognitive performance but better attention and executive function than controls.

Function and form of the shoulder in congenital and untreated growth hormone deficiency.

OBJECTIVES: The shoulder is the most mobile joint in the entire human body. During arm elevation, it requires the integrity of a set of muscles, bones, and tendons. Individuals with short stature often need to raise their arms above the shoulder girdle and may have functional restriction or shoulder injuries. The impact of isolated GH deficiency (IGHD) on joints remains not well defined. The purpose of this work is to evaluate the function and structure of the shoulder in short-statured adult individuals with untreated IGHD due to the same homozygous mutation in the GHRH receptor gene. METHODS: A cross-sectional study (evidence 3) was carried out in 20 GH-naive IGHD subjects and 20 age-matched controls. They completed the disabilities of the arm, shoulder, and hand (DASH) questionnaire and shoulder ultrasound (US). Thickness of the anterior, medial, and posterior portions of the supraspinatus tendon and of subacromial space was measured, and the number of individuals with tendinosis or tearing of the supraspinatus tendon was registered. RESULTS: DASH score was similar between IGHD and controls, but IGHD subjects complained less of symptoms (p = 0.002). The number of individual with tears was higher in the controls (p = 0.02). As expected, the absolute US measurements were lower in IGHD, but the magnitude of the reduction was most pronounced in the thickness of the anterior portion of the supraspinatus tendon. CONCLUSION: Adults with lifetime IGHD do not have functional shoulder restrictions, complain less of problems in performing upper extremity activities, and have fewer tendinous injuries than controls.

Quantitative measures of the vascular and neural components of the retina in adult individuals with congenital and untreated growth hormone deficiency.

BACKGROUND: The somatotrophic axis, including hypothalamic growth hormone (GH)-releasing hormone (GHRH), pituitary GH and circulating IGF-I, is critical for body size. However, the local production of GH/IGF-I (and IGF-II) and other peptides is relevant for other body functions, such as vascular, brain, and retinal function. The consequences of GH deficiency (GHD) on the retinal structure are still unclear, possibly reflecting the heterogeneity of patients and the different types of assessment in previous publications. Our purpose was to assess quantitative measures of the vascular and neural components of the retina in subjects with severe congenital isolated GHD (IGHD). METHODS: A cross-sectional study was carried out in 25 adult IGHD subjects and 25 age- and gender-matched controls. Interview, physical examination, laboratory data, optical coherence tomography (OCT) and OCT angiography (OCTA) were performed. RESULTS: OCT revealed no difference in the areas of the nerve fiber layer average, nor in the areas of superior, inferior, or nasal quadrants, between the two groups. However, areas of the temporal quadrant (p = 0.041), the optical disc (p = 0.042), the cup (p < 0.0001), as well as the cup/disc ratio (p < 0.0001), were higher in IGHD subjects than controls. The rim area was smaller (p = 0.002), although still normal. In OCTA, there was no difference in the minimum foveal thickness, central fovea, foveal avascular zone, and retinal density in any assessed area. CONCLUSIONS: In conclusion, congenital IGHD does not affect quantitative measures of the vascular and neural retina, and it is associated with increased optical disc in this genetically homogeneous cohort.

Growth of teeth and bones in adult subjects with congenital untreated isolated growth hormone deficiency.

OBJECTIVE: To understand the growth of teeth and mandibular and maxillary bones in subjects with isolated growth hormone deficiency (IGHD). MATERIAL AND METHODS: Mesiodistal tooth width of 28 maxillary and mandibular dental models of 14 adult IGHD subjects (9 men) were digitalized and compared to 40 models of 20 normal-statured controls (11 men). The mean SDS of the maxillary and mandibular teeth were compared with height, cephalic perimeter, total anterior facial height, total maxillary and mandibular length, and maxillary and mandibular arches. RESULTS: All average mesiodistal dimensions in absolute values of the 14 dental pairs were reduced in the IGHD group. Eight of 28 (28.6%) mesiodistal dimensions in IGHD subjects of both sexes had an average SDS below -2, thirteen of them (46.4%) had mean SDS between -1 and - 2, and seven of them (25.0%) had SDS above -1. The highest SDS values were the upper lateral incisor (-0.32 in women), and the upper canine (-0.91 in men). The lowest SDS values were the 2nd upper molar (-3.51 in men), and the 2nd upper premolar (-2.64 in women). The ascending order of the mean SDS was height, total maxillary length, total mandibular length, total anterior height of the face, cephalic perimeter, the maxillary arches width, the mesiodistal width of the mandibular teeth, the mesiodistal width of the maxillary teeth and the mandibular arches width. CONCLUSIONS: Reduction in mesiodistal width is present in untreated IGHD adults with magnitude of tooth size reduction being lower than height, cephalic perimeter, total anterior facial height, and most jaw measurements. IGHD abolishes the sexual dimorphism in mesiodistal dental measures.

Dental arches in inherited severe isolated growth hormone deficiency.

OBJECTIVES: The growth of the dental arches depends on GH and insulin-like growth factor type 1 (IGF1), but the consequences of GH deficiency (GHD) on their growth are still unclear, probably due to the acquired etiology of GHD in most described series, often associated with additional pituitary deficits (thyrotrophic, corticotrophic and gonadotrophic hormones), and imperfections of related replacement therapies, which may affect the dental arch growth. To avoid these limitations, we took advantage of a unique cohort of subjects with isolated GH deficiency (IGHD) due the same mutation in the GH releasing hormone receptor gene, living with very low serum GH and low to undetectable circulating IGF1 levels. Our purpose was to analyze the dimensions of maxillary and mandibular dental arches. METHODS: 22 adult IGHD (15 untreated and 7 previously partially treated with GH) and 33 controls were enrolled in a cross-sectional study using the Ortho Insight 3D and MeshMixer software, RESULTS: In untreated IGHD subjects all maxillary arch measures were smaller than controls, while among mandibular arches, only the mandibular canine width and the mandibular arch length were reduced. In partially GH treated subjects only the palate depth, the maxillary canine width, the maxillary and mandibular arch lengths remained smaller than controls. CONCLUSIONS: IGHD reduces the growth of maxillary arch to a greater degree than the mandibular arch, suggesting different control of superior and inferior dental arches. GH treatment increases some of these measures.

Circulating microRNA profile in humans and mice with congenital GH deficiency.

Reduced inflammation, increased insulin sensitivity, and protection against cancer are shared between humans and mice with GH/IGF1 deficiency. Beyond hormone levels, miRNAs are important regulators of metabolic changes associated with healthy aging. We hypothesized that GH deficiency in humans alters the abundance of circulating miRNAs and that a subset of those miRNAs may overlap with those found in GH-deficient mice. In this study, subjects with untreated congenital isolated GH deficiency (IGHD; n = 23) and control subjects matched by age and sex (n = 23) were recruited and serum was collected for miRNA sequencing. Serum miRNAs from young (6 month) and old (22 month) Ames dwarf (df/df) mice with GH deficiency and their WT littermates (n = 5/age/genotype group) were used for comparison. We observed 14 miRNAs regulated with a genotype by age effect and 19 miRNAs regulated with a genotype effect independent of age in serum of IGHD subjects. These regulated miRNAs are known for targeting pathways associated with longevity such as mTOR, insulin signaling, and FoxO. The aging function was overrepresented in IGHD individuals, mediated by hsa-miR-31, hsa-miR-146b, hsa-miR-30e, hsa-miR-100, hsa-miR-181b-2, hsa-miR-195, and hsa-miR-181b-1, which target the FoxO and mTOR pathways. Intriguingly, miR-181b-5p, miR-361-3p, miR-144-3p, and miR-155-5p were commonly regulated in the serum of humans and GH-deficient mice. In vitro assays confirmed target genes for the main up-regulated miRNAs, suggesting miRNAs regulated in IGHD individuals can regulate the expression of age-related genes. These findings indicate that systemic miRNAs regulated in IGHD individuals target pathways involved in aging in both humans and mice.

Individuals with isolated congenital GH deficiency due to a GHRH receptor gene mutation appear to cope better with SARS-CoV-2 infection than controls.

PURPOSE: Several interactions exist between the GH/IGF axis and the immune system, including effects on innate immunity and humoral and cellular response. Acquired GH deficiency (GHD) has been recently proposed as a risk factor for severity of COVID-19 infections. However, acquired GHD is often associated to other factors, including pituitary tumors, surgery, radiotherapy, and additional pituitary hormones deficits and their replacements, which, together, may hinder an accurate analysis of the relationship between GHD and COVID-19. Therefore, we decided to assess the seroprevalence of SARS-CoV-2 antibodies and the frequency of symptomatic cases of COVID-19 in adults subjects with untreated isolated GHD (IGHD) due to a homozygous null mutation in the GHRH receptor gene. METHODS: A cross-sectional study was carried out in 27 adult IGHD subjects and 27 age- and gender-matched local controls. Interview, physical examination, bio-impedance, hematological and SARS-CoV-2 IgM and IgG antibodies were analyzed. RESULTS: There was no difference in the prevalence of positivity of anti-SARS-CoV-2 IgM and IgG antibodies between the two groups. Conversely, no IGHD individual had a previous clinical diagnosis of COVID-19 infection, while 6 control subjects did (p = 0.023). CONCLUSION: The production of anti-SARS-CoV-2 antibodies was similar between IGHD subjects due to a GHRH receptor gene mutation and controls, but the evolution to symptomatic stages of the infection and the frequency of confirmed cases was lower in IGHD subjects than in GH sufficient individuals.

Reduced fibroblast growth factor 21 and ß-Klotho secretion in untreated congenital isolated GH deficiency.

PURPOSES: Increasing evidence suggests that the FGF-Klotho endocrine system and the somatotropic system (pituitary and extra-pituitary GH) may have important metabolic and immune relationships, thus contributing to the pathophysiology of aging-related disorders, including diabetes, atherosclerosis, and cancer. The status of these interactions in isolated GH deficiency (IGHD) is unknown. The objective of this study was to assess the response of both FGF21 and ß-Klotho levels to a standard meal in a homogeneous group of adults with congenital untreated IGHD due to a homozygous mutation in the GHRH receptor gene. METHODS: In a cross-sectional study, we measured the levels of FGF21 and ß-Klotho, before and 30, 60, 120, and 180 min after a standardized test meal in 20 (11 males) IGHD and 20 (11 males) age-matched controls. Areas under the curves (AUC) of FGF21 and ß-Klotho were calculated. RESULTS: Baseline levels of FGF21 were similar, but baseline levels of ß-Klotho were lower in IGHD subjects. The IGHD individuals exhibited lower AUC for FGF21 and ß-Klotho levels than control subjects. There was a positive correlation between IGF1 and ß-Klotho levels in the pooled groups. No correlation was found between IGF1 and FGF21 levels. CONCLUSIONS: Subjects with lifetime, untreated IGHD exhibit reduced FGF21 and ß-Klotho levels response to a mixed meal. This difference may have consequences on metabolism and aging.

Cerebral vasoreactivity, a surrogate marker of cerebrovascular disease, is not impaired in subjects with lifetime, untreated, congenital isolated GH deficiency.

OBJECTIVES: Cerebrovascular disease (CeVD) is a major cause of death and disability. The role of the GH/IGF-I axis on CeVD risk is controversial. Patients with GH deficiency (GHD) in the setting of hypopituitarism often exhibit CeVD predisposing factors, like low nitric oxide generation, endothelial dysfunction, increased visceral fat mass, increased levels of LDL cholesterol, and increased intima-media thickness, a surrogate marker of atherosclerosis. However, several confounders such as the primary hypothalamic-pituitary lesion, hormonal replacement therapies, consequences of surgery and radiotherapy, may influence this relationship. Therefore, we decided to assess cerebral vasoreactivity, a surrogate marker of CeVD, in adult subjects with untreated isolated GHD (IGHD) due to the same homozygous null mutation in the GHRH receptor gene. METHODS: A cross-sectional study was carried out in 25 adult IGHD subjects and 25 age- and gender-matched controls. Interview, physical examination, laboratory data, intima-media thickness measurement, and transcranial Doppler were performed. The intracranial hemodynamics (mean flow velocity, pulsatility and resistance indexes) were measured, and the response to the vasodilatory stimulus by breath-holding maneuver (breath-holding index) was calculated. RESULTS: IGHD and control groups were similar in Framingham risk score and intima-media thickness. Similarly, there was no difference in mean flow velocity, pulsatility, resistance, and breath-holding index. CONCLUSIONS: Lifetime, untreated IGHD does not cause impaired cerebral vasoreactivity.

Sweat and vitamin D status in congenital, lifetime, untreated GH deficiency.

PURPOSE: A reciprocal relationship exists between the skin and the GH/IGF-I axis. Skin produces both IGF- I and vitamin D, and GH and IGF-I exert several actions in the skin. Reduced sweating and altered phosphor-calcium homeostasis are occasionally reported in subjects with GH deficiency (GHD), mostly in the setting of hypopituitarism, therefore associated to other hormonal deficiencies. It is unclear whether these findings are due to GHD. The aim of this study was to assess skin function in subjects with isolated GHD (IGHD) due to a mutation in the GHRH receptor gene. METHODS: In a cross-sectional study we enrolled 20 IGHD and 20 local controls. Sweating (volume, conductivity and chloride content) was assessed by a 30 min pilocarpine iontophoresis test, using the Macroduct® Sweat Collection System. IGF-I, Insulin, PTH, 25-hydroxyvitamin D, C-reactive protein (CRP), CPK, glucose, calcium, phosphate, alkaline phosphatase, total proteins and fractions, urinary calcium, and insulin were measured. HOMA-IR was calculated. RESULTS: IGHD presented lower sweating, but normal vitamin D and phosphor-calcium homeostasis. Additionally, IGHD subjects presented lower HOMA-IR, higher CRP and reduced CPK. CONCLUSION: Untreated IGHD cause reduction in sweating, but does not affect phosphor-calcium homeostasis.

Walking and postural balance in adults with severe short stature due to isolated GH deficiency.

OBJECTIVES: Walking and postural balance are extremely important to obtain food and to work. Both are critical for quality of life and ability to survive. While walking reflects musculoskeletal and cardiopulmonary systems, postural balance depends on body size, muscle tone, visual, vestibular and nervous systems. Since GH and IGF-I act on all these systems, we decided to study those parameters in a cohort of individuals with severe short stature due to untreated isolated GH deficiency (IGHD) caused by a mutation in the GHRH receptor gene. These IGHD subjects, despite reduction in muscle mass, are very active and have normal longevity. METHODS: In a cross-sectional study, we assessed walking (by a 6-min walk test), postural balance (by force platform) and fall risk (by the 'Timed Up and Go' test) in 31 IGHD and 40 matched health controls. RESULTS: The percentage of the walked distance measured in relation to the predicted one was similar in groups, but higher in IGHD, when corrected by the leg length. Absolute postural balance data showed similar velocity of unipodal support in the two groups, and better values, with open and closed eyes and unipodal support, in IGHD, but these differences became non-significant when corrected for height and lower-limb length. The time in 'Timed Up and Go' test was higher in IGHD cohort, but still below the cut-off value for fall risk. CONCLUSION: IGHD subjects exhibit satisfactory walking and postural balance, without increase in fall risk.

Enteroendocrine Connections in Congenital Isolated GH Deficiency Due to a GHRH Receptor Gene Mutation.

CONTEXT: GH and IGF-1 are crucial for attainment of normal body size and regulation of food intake, nutrient storage, and insulin sensitivity. Enteroendocrine connections exist between the GH-IGF-1 axis and insulin, ghrelin, and glucagon-like peptide 1 (GLP-1). The status of these connections in GH deficiency (GHD) is unknown. OBJECTIVE: To study the enteroendocrine connections before and after a standard meal test in a homogeneous population of adults with congenital untreated isolated GHD (IGHD) due to a mutation in the GHRH receptor gene. DESIGN: In a cross-sectional study of 20 individuals with IGHD and 20 control subjects, we measured glucose, insulin, ghrelin, and GLP-1 before and 30, 60, 120, and 180 minutes after a standardized test meal. Homeostasis model assessment index of insulin resistance (HOMA-IR) and homeostasis model assessment (HOMA)-ß were calculated. Participants scored feelings of hunger, fullness, and prospective food consumption on a visual analog scale. MAIN OUTCOME MEASURES: Area under the curve (AUC) values of glucose, insulin, ghrelin, GLP-1, hunger, fullness, and prospective food consumption. RESULTS: Fasting HOMA-IR and HOMA-ß were lower in individuals with IGHD than in control subjects (P = 0.002 and P = 0.023, respectively). AUC was higher for hunger (P < 0.0001), glucose (P = 0.0157), ghrelin (P < 0.0001), and GLP-1 (P < 0.0001) and smaller for fullness (P < 0.0001) in individuals with IGHD compared with control subjects. There was no difference in AUC for prospective food consumption or insulin. CONCLUSIONS: Untreated IGHD is associated with increased GLP-1 secretion and reduced postprandial ghrelin and hunger attenuation in response to a mixed meal. These enteroendocrine connections can result in a favorable outcome in terms of environmental adaptation and guaranteeing appropriate food intake and can confer metabolic benefits.

Altered sleep patterns in patients with non-functional GHRH receptor.

OBJECTIVES: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Ocular findings in adult subjects with an inactivating mutation in GH releasing hormone receptor gene.

OBJECTIVE: Ocular function is fundamental for environmental adaptation and survival capacity. Growth factors are necessary for a mature eyeball, needed for adequate vision. However, the consequences of the deficiency of circulating growth hormone (GH) and its effector insulin-like growth factor I (IGF-I) on the physical aspects of the human eye are still debated. A model of untreated isolated GH deficiency (IGHD), with low but measurable serum GH, may clarify this issue. The aim of this study was to assess the ocular aspects of adult IGHD individuals who have never received GH therapy. DESIGN: Cross sectional study. METHODS: Setting: University Hospital, Federal University of Sergipe, Brazil. PATIENTS: Twenty-five adult (13 males, mean age 50.1years, range 26 to 70years old) IGHD subjects homozygous for a null mutation (c.57+1G>A) in the GHRH receptor gene, and 28 (15 males, mean age 51.1years, range 26 to 67years old) controls were submitted to an endocrine and ophthalmological assessment. Forty-six IGHD and 50 control eyes were studied. MAIN OUTCOME MEASURES: Visual acuity, intraocular pressure, refraction (spherical equivalent), ocular axial length (AL), anterior chamber depth (ACD), lens thickness (LT), vitreous depth (VD), mean corneal curvature (CC) and central corneal thickness (CCT). RESULTS: IGHD subjects exhibited unmeasurable serum IGF-I levels, similar visual acuity, intraocular pressure and LT, higher values of spherical equivalent and CC, and lower measures of AL, ACD, VD and CCT in comparison to controls, but within their respective normal ranges. While mean stature in IGHD group was 78% of the control group, mean head circumference was 92% and axial AL was 96%. CONCLUSIONS: These observations suggest mild ocular effects in adult subjects with severe IGF-I deficiency due to non-treated IGHD.

Subjects with isolated GH deficiency due to a null GHRHR mutation eat proportionally more, but healthier than controls.

The GH/IGF-I axis has important interactions with the alimentary system and with the balance between energy intake (EI) and energy requirement (ER). Reduced EI has been described in adult-onset acquired GH deficiency (GHD). Individuals from the Brazilian Itabaianinha cohort, with isolated GHD (IGHD) due to a homozygous mutation (c.57+1G→A) in the GHRH receptor gene, are an ideal model to study the consequences of lifetime GHD. The purpose of this study is to evaluate EI and ER in this untreated IGHD cohort. Cross-sectional study of 24 adult IGHD patients and 23 controls from the same region, matched for age and gender. Estimated EI (EEI) was evaluated by dietary recall, and estimated ER (EER) by the equation of the Dietary Reference Intakes. Fat mass was assessed by DXA. Both EEI and EER were lower in IGHD than controls. However, when corrected by body weight, EEI was higher in IGHD (p = 0.005). IGHD individuals consume in percentage more proteins (p < 0.0001), less carbohydrates (p = 0.013), and equal amount of lipids in comparison to controls. The higher EEI per body weight suggests a possible increase of orexigenic mechanisms in untreated IGHD individuals, ensuring greater caloric intake, which would have adaptive advantages for small-sized individuals in environments with limited access to food. IGHD individuals seem to have a healthier dietary pattern than CO.

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.

Liver status in congenital, untreated, isolated GH deficiency.

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+1G→A 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.

Increased visceral adiposity and cortisol to cortisone ratio in adults with congenital lifetime isolated GH deficiency.

CONTEXT: Adult-onset GH deficiency (GHD) increases visceral adiposity and the activity of the enzyme 11ß-hydroxysteroid dehydrogenase, which converts cortisone (E) to cortisol (F), both linked to insulin resistance and increased cardiovascular risk. Conversely, we reported that adults with congenital isolated GHD (IGHD) have increased insulin sensitivity. OBJECTIVE: To assess the type of fat distribution and the amount of visceral and sc fat and to correlate them to the F/E ratio in adults with untreated IGHD due to a mutation in the GHRH receptor gene. METHODS: Body composition was assessed by dual-energy x-ray absorptiometry, thickness of sc and visceral fat was measured by sonography, and serum F and E were measured in 23 IGHD subjects and 21 age-matched controls. RESULTS: Waist/hip ratio (WHR), trunk fat, and trunk/extremity fat (TR/EXT) ratio were higher in IGHD subjects. Visceral fat index (VFI) (but not sc fat index [SFI]) was higher in IGHD. F and F/E ratio were also higher in IGHD. In all 44 individuals, WHR correlated with TR/EXT ratio, thickness of visceral fat, VFI/SFI ratio, F, and F/E ratio. TR/EXT ratio correlated with visceral fat thickness, VFI/SFI ratio, and F. Age had a significant effect on VFI and on F/E ratio. Body mass index SD score and WHR have a similar significant effect on TR/EXT ratio and on F/E ratio. CONCLUSIONS: Lifetime congenital untreated IGHD causes increased visceral adiposity with a high F/E ratio. However, the increased insulin sensitivity suggests that visceral adiposity needs a minimal GH secretion to translate into increased insulin resistance.