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Characterization of adult onset growth hormone deficiency syndrome in patients with hypothalamopituitary diseases: Asian Indian data TR Bandgar, M Prashanth, SR Joshi, PS Menon, NS ShahDepartment of Endocrinology, Seth G. S. Medical College and K. E. M. Hospital, Parel, Mumbai, India
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/0022-3859.40777
Background: Hardly any data is available on Adult onset growth hormone deficiency (AOGHD) in Patients with hypothalamopituitary diseases in India. Aims: To characterize Asian Indian AOGHD syndrome in hypothalamopituitary diseases. Settings and Design: Cross-sectional analysis of data from a tertiary care hospital. Materials and Methods: Thirty patients with AOGHD were compared with 30 age-, sex-, body mass index-matched controls with respect to endocrine evaluation, biochemistry, body composition (BC), bone mineral density (BMD), cardiovascular risk profile and quality of life (QoL). Statistical Analysis Used: Comparisons were performed using two-tailed Student's test (SPSS Software version 10.0). Results: Most of the patients had abnormal BC with central obesity [Truncal FM (%): males {33.9±4.4 (patient) vs. 29.31±6.2 (control); P -0.027}; females {39.87±5.93 (patient) vs. 35.76±3.16 (control); P - 0.025}] and poor QoL. Patients aged over 45 years did not show low bone mass or lipid abnormalities as compared to controls. Low BMD and abnormal lipid profile {Triglycerides [mg/dl]:170.55±72.5 (patient) vs101.24±31.0 (control); P -0.038}; {very low density lipoprotein cholesterol [mg/dl]: 33.54±14.9 (patient) vs. 20.25±6.18 (control); P - 0.05} was seen in female patients less than 45 years of age. Conclusions: Male and female (more than 45 years) AOGHD patients have increased cardiovascular risk factors and poor QoL while BMD is unaffected. Females less than 45 years of age have the major characteristics of AOGHD and would be the group to benefit maximally with recombinant human Growth Hormone treatment, which is similar to that in the western literature. Keywords: Adult onset growth hormone deficiency syndrome, Asian Indian data, hypothalamopituitary diseases
Adult onset growth hormone deficiency syndrome (AOGHD) occurs in patients with a known pituitary pathology or in those who have previously received full conventional pituitary hormone replacement therapy. [1] The AOGHD patients have abnormal body composition (BC) with reduced lean body mass, increased fat mass, reduced strength and exercise capacity, impaired psychological wellbeing, reduced bone mineral density (BMD) and increased cardiovascular risk factors. With Growth Hormone (GH) treatment there is normalization of the above parameters. [2],[3] The present study was undertaken to characterize the AOGHD syndrome in patients with hypothalamopituitary diseases in a tertiary institute in Mumbai, as there is no published Indian data on this subject till date.
Thirty-four patients (aged 33-60 years) with suspected AOGHD attending Endocrine Clinic from 2001-2004,who were on replacement doses for hormonal deficiencies (except growth hormone) for at least six months before entry into the study were evaluated prospectively after obtaining informed consent. The study was approved by the local ethics committee. Patients with malignant lesion, secretory pituitary tumors or other systemic disorders were excluded. The subjects included those who had undergone surgery or radiotherapy and the histopathological diagnosis included non-functioning pituitary adenoma [n=28 (16M/12F)], craniopharyngioma [n=4 (2M/2F)], meningioma (n=1F) and optic schwanomma (n=1F). Thirty subjects who demonstrated a maximal serum growth hormone (GH) concentration of 3ng/ml or less by an immunoradiometric assay (IRMA) after the insulin tolerance test (ITT) were diagnosed to have GH deficiency (GHD) [4] and were analyzed. They were grouped as Group 1 (15 Males) and Group 2 (15 females) and were analyzed separately. The female patients were subdivided in two groups as Group 2a: females with onset of GHD after 45years of age (n=8) and Group 2b: females with onset of GHD before 45 years of age (n=7). The age of onset of GHD was taken as age at which surgery for the central lesion was carried out. Thirty healthy controls, age, sex and body mass Index (BMI) matched with patients with no systemic disorders and on no medications were studied for similar parameters except for the ITT Test after their consent. Laboratory analyses: Blood was collected after an overnight fast for biochemistry, serum lipid profile and hormonal evaluation; levels of serum insulin (RIA), serum insulin like growth factor-1 (IGF1) [IRMA-acid-alcohol extraction] and serum insulin like growth factor binding factor-3 (IGFBP3) [IRMA] were estimated by kit from DSL Inc, Webster, Tx. Insulin sensitivity was estimated, in the basal state, by use of the homeostasis model assessment (HOMA). The GH level was measured by IRMA kit -1900(DSL Inc, Webster, Tx) with standards calibrated to WHO first international standard (code 80/505:22k Da rhGH). Body composition and bone mineral density: Dual energy X-ray absorptiometry (Hologic model QDR-4500) measurements included total hip, left femoral neck and lumbar spine. The short term in vivo precision (coefficients of variation %) in our unit was as follows: lumbar spine, 1.09%; femoral neck, 3.29%; and total hip, 1.26%. Echocardiography: Cardiovascular function was assessed by two-dimensional, Mmode and Doppler echocardiography by a cardiologist blinded to study according to the standardization of the American Society of Echocardiography for left ventricular (LV) systolic and diastolic function and LV mass Index. Carotid sonography: Intima-media thickness (IMT) was measured 1.5cm proximal to the carotid artery bifurcation, by high-resolution mode B ultrasound (mean of three measurements taken). Quality of life (QoL) assessment: Adult growth hormone deficiency-specific quality of life (QoL-AGHDA): This questionnaire [5] consists of 25 questions with yes or no answers, relevant to the issues brought by GHD; lack of assertiveness, concentration, memory and energy; increased anxiety and depression; and difficulties in social interactions. A yes answer indicates that the patient perceives the problem. The sum of the number of yes answers is used as a measure of QoL, with a high score denoting an impaired QoL. Statistics: Results are reported as the mean±SD. Comparisons were performed using two-tailed student's test (SPSS Software version 10.0) and P <0.05 was considered significant.
Baseline characteristics were similar between patients and controls except for increased waist-hip ratio (WHR) and lower IGF 1 and IGFBP3 in patients [Table - 1]. Body composition (DXA): In patients, Fat mass (FM) (%), truncal FM (%) was higher and lean body mass (LBM) (%), truncal LBM (%) was lower than controls [Table - 2]. Bone mineral density: The BMD was similar in Group 1 w.r.t controls. In female patients, BMD was significantly less than controls. Group 2a had BMD similar to controls, while Group 2b had significantly lower BMD [Table - 3]. Glucose homeostasis: There was no statistically significant difference between the mean sugars, insulin while HOMA IR [males 2.88±4.55 (patient) vs. 2.21±1.7(control), P value: 0.599(CI diff:−1.44 to3.1); females 3.63±4.2(patient) vs. 1.93±1.14(control), P value: 0.348(CI diff: −0.48 to 4.0)] tended to be higher in patients as compared to controls. The HOMA IR was 34% and 57% higher in male and female patients respectively than controls. Lipid profile: Lipid parameters were similar in patients (MandF) and controls (data not shown). However, the lipid profile was abnormal {Triglycerides (TG)[mg/dl]:170.55±72.5(patient) vs. 101.24±31.0 (control); P -0.038 (CI diff: 1.76 to 86.51) and very low density lipoprotein cholesterol(VLDL)[mg/dl]: 33.54±14.9 (patient) vs. 20.25±6.18 (control); P- 0.05(CI diff: 1.86 to 21.7)}in Group 2b. Echocardiography: Morphology, LV systolic and diastolic functions were similar in male patients and controls. In femalesthe Isovolumic relaxation time (IVRT) wassignificantly more than controls {108.7msec±20.1 (patient) vs. Controls 87.0msec±19.4 (controls); P = 0.006*(CI diff:10.4 to 36.9)} Carotid IMT: The mean IMT in the right internal carotid {[male1.004±0.174: (patients) vs. 0.780±0.21 (control) P value:0. 04* (CI diff:0.13 to 0.42)]; [females: 0.946±0.154 (patient) vs. 0.662±0.206 (control) P value: 0.000*(95% CI of difference:0. 14-0.40)} and left internal carotid [male 1.008±0.243: (patients) vs. 0.791±0.23 (control) P value: 0.019* (CI diff:0.10 to 0.44)]; [females: 0.947±0.153 (patient) vs. 0.689±0.199 (control) P value: 0.000* (95% CI diff:0.12-0.38) }was significantly increased in comparison with the controls. QoL: The AGHDA score {[male: 12.40±6.80 (patients) vs. 6.67±2.16 (control) P value: 0.004*(CI diff: 2.42 to 9.1)]; [females: 12.47±5.04 (patient) vs. 4.33±2.19 (control) P value: 0.000* (95% CI of difference: 4.65-6.4)} was significantly higher in male and female patients as compared to the controls.
To the best of our knowledge, this is the first study providing data about AOGHD patients in the Asian Indian population. Our patients with AOGHD showed altered BC with excess truncal fat mass similar to that reported in the literature. [6],[7],[8] Asian Indians have a unique body composition with greater waist circumference, excess truncal body fat and insulin resistance (IR) for a given BMI and thus have greater central obesity when compared with the Caucasians. [9],[10],[11] The IR denoted by HOMA IR tended to be high in our patient cohort, which is in agreement with the literature [12],[13],[14],[15] and could be accounted by the central obesity due to AOGHD. In males and females (age >45 years) the lipid profile showed no difference. The lipid abnormalities (high TG, VLDL) were seen in only Group 2b (F <45 years) as reported earlier. [16],[17] Our findings of similar LDL [18],[19] and HDL levels are in keeping with the published literature. [19] Although abnormalities induced by inappropriate replacement of glucocorticoid and thyroxine (T4) [20] could contribute to dyslipidemia, patients in our study received replacement in the conventional manner and were proven to be euthyroid. Earlier studies have shown evidence of cardiac dysfunction (diastolic and systolic) more convincingly with dynamic tests (stress echocardiography, radionuclide angiography, etc) especially with exercise [21],[22] though some studies have shown functional impairment at rest also. Cardiac parameters in our male patients were within the normal range which is in accordance with a previous study. [23] Interestingly, female patients had diastolic dysfunction at rest as in other studies. [21],[24] The mean IMT in male and female patients of both carotids was significantly increased in comparison with the controls. Increased IMT, with more atheromatous plaques in the carotid and the femoral arteries, has been reported in GHD, compared with control subjects. [25],[26] These findings suggest increased cardiovascular risk in our cohort of AOGHD patients. Various factors affect BMD in hypopituitary patients namely the age, severity, duration of GHD, inadequacy or overreplacement of the associated hormonal deficiencies and altered body composition. [10] In Group 1 and 2a there was no significant difference in BMD at various sites in comparison to the controls as shown in the literature. [27],[28],[29],[30] Our control population had osteopenia though they were healthy individuals and non-smokers. It is known that BMD at all sites in Indian population has been reported to be 5-15% lower than that in Caucasians, [31] which has been related to genetic reasons, smaller skeletal size of Indians and calcium and vitamin D malnutrition. Recent data indicates a high prevalence of vitamin D deficiency in urban Indians [32] though this is not assessed in the present study. In Group 2b BMD was significantly less in patients compared with controls. Due to very few patients below the age of 45 years we could not evaluate for similar changes in the male group. Our study highlights the age at onset of GHD as one of the important factors for the BMD changes though genetic and nutritional factors may also add to the derangement of metabolic health of our AOGHD patients. Patients had significant impairment of QoL. Low QoL in hypopituitary adults at diagnosis [5] and its improvement after GH therapy have been demonstrated in earlier studies. [33] The individuals with the lowest QoL had the most improvement after GH treatment. There are certain limitations to the study, namely cross-sectional design and lower number of patients in each subgroup. Ideally, AOGHD patients should have been compared with patients with hypothalamopituitary disease having normal GH level, which would have unequivocally proven the results to be due to GHD. It would be interesting to start GH therapy in all the patients and quantify the response in all the various parameters according to the age of onset of GHD. To summarize, male patients and females more than 45years with AOGHD syndrome have central obesity, increased cardiovascular risk (increased IMT) and poor quality of life while BMD was not affected. Younger AOGHD female patients less than 45 years of age have most of the features of classical AOGHD syndrome and would be the group to benefit maximally with rhGH treatment which is important in a resource constraint situation.
We would like to acknowledge help of Scientific Officers Mrs. Anjana Karvat and Mr. Harshavardhan Powar.
[Table - 1], [Table - 2], [Table - 3]
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