Rossana M. C. Pereira

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

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

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

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

Adipokine Profile and Urinary Albumin Excretion in Isolated Growth Hormone Deficiency

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

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

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

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

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

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

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

Climacteric in untreated isolated growth hormone deficiency

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

Quality of life in congenital, untreated, lifetime isolated growth hormone deficiency.

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.

Isolated GH Deficiency due to a GHRH Receptor Mutation Causes Hip Joint Problems and Genu Valgum, and Reduces Size but not Density of Trabecular and Mixed Bone

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.

Hearing Status in Adult Individuals with Lifetime, Untreated Isolated Growth Hormone Deficiency

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.