Diagnosis Of Growth Hormone Deficiency In Adults Research Articles

Diagnosis of adult GH deficiency

On the basis of overwhelming evidence that adults with growth-hormone (GH) deficiency have impaired health that improves with GH replacement,1 many countries have already approved such treatment for these patients. The features of adult GH deficiency are recognisable but are not distinctive, so clinical suspicion must be confirmed by iochemical tests. Confirmation is particularly important in an era of health-expenditure rationing because GH is expensive and costs approximately £2500 per person per year.

Diagnostic efficiency of serum IGF-I, IGF-binding protein-3 (IGFBP-3), IGF-I/IGFBP-3 molar ratio and urinary GH measurements in the diagnosis of adult GH deficiency: importance of an appropriate reference population.

To analyse the diagnostic role of serum IGF-I, IGF-binding protein-3 (IGFBP-3), IGF-I/IGFBP-3 molar ratio and urinary GH (uGH) excretion in adult GH deficiency (GHD). Twenty-seven adults (age range: 18-71 years) with severe GHD, defined by a peak GH response to an insulin tolerance test below 3microg/l in patients with at least one additional pituitary hypofunction. Reference values were established from a selected age- and body mass index-matched population (154 healthy adults grouped in four age groups). IGF-I and IGFBP-3 were measured by RIA (Nichols) and results expressed as standard deviation (s.d.) scores from our reference population and assay normative data (s.d. score Nichols). uGH was measured by IRMA. Within the control group, IGF-I, IGFBP-3, IGF-I/IGFBP-3 ratio standardisation regarding our control population and IGF-I with respect to the assay normative data resulted in disappearance of age-related differences. However, IGFBP-3 s.d. score Nichols resulted in mean values between +1.4 and +2.5 s.d. score. Greatest diagnostic efficiency was for IGF-I standardised with respect to our controls (97.2%), followed by s.d. score IGFBP-3 (92.9%). s.d. score IGF/IGFBP-3 ratio and uGH showed poor diagnostic efficiency. Any combination of at least two abnormal parameters raised specificity to 100%. IGF-I standardised with respect to assay reference (s.d. score Nichols) showed similar diagnostic value (95.0%) whereas IGFBP-3 showed low sensitivity (33. 3%). Within the GHD patients, those with three or more additional deficiencies had lower s.d. score IGF-I than those with only two or one. We underline the importance of an appropriate reference population for correct interpretation of GH secretion markers. Considering our results, specificity obtained with two simultaneous abnormal parameters when referred to an adequate reference population may add valuable information to alternative GH stimulation tests to confirm adult GHD.

The study of spontaneous GH secretion after 36-h fasting distinguishes between GH-deficient and normal adults.

Within an appropriate clinical context, GH deficiency (GHD) in adults can only be diagnosed biochemically by provocative testing. The evaluation of IGF-I, IGFBP-3 and even of spontaneous GH secretion do not establish the diagnosis of adult GHD. In fact, remarkable overlaps between normal and GHD adults have been reported for all these parameters. On the other hand, it is well known that even short-term fasting stimulates GH secretion in normal subjects. The aim of our study was to determine the effects of 36 h fasting on 8-h diurnal GH, insulin and glucose levels as well as on basal IGF-I, IGFBP-3, acid-labile subunit (ALS), IGFBP-1, GHBP and free fatty acid (FFA) levels. We studied 9 GHD adults (GHD, 8 males, 1 female; age, mean +/- SEM: 37.6 +/- 2.3 years, body mass index (BMI): 24.5 +/- 1.0 kg/m2) and 20 age-matched normal subjects (NS) as controls (13 males, 7 females; age: 28.9 +/- 0.6 years, BMI: 21.6 +/- 0.4 kg/m2). In all subjects we studied the effects of 36 h fasting on 8-h daytime GH, insulin and glucose levels (assay every 30 min from 0800 h to 1600 h) as well as on basal IGF-I, IGFBP-3, ALS, IGFBP-1, GHBP and FFA levels. Before fasting, basal mean IGF-I, IGFBP-3 and ALS levels in GHD were lower (P < 0. 0001) than in NS. IGFBP-1, GHBP and FFA levels were similar in both groups. Before fasting mean GH concentration (mGHc) in GHD was lower (P < 0.05) than in NS (0.4 +/- 0.2 vs. 2.2 +/- 0.6 mu/l) but with a clear overlap between the 2 groups (range 0.4-0.8 vs. 0.4-6.8 mu/l). After fasting, both in GHD and NS basal IGF-I, IGFBP-3, ALS and GHBP levels did not change significantly. On the other hand, in both GHD and in NS IGFBP-1 was increased (P < 0.0001) to a similar extent, while FFA increased in NS more (P < 0.01) than in GHD. Fasting significantly increased mGHc in NS (12.0 +/- 1.2 mu/l, P < 0.0001) but not in GHD (0.6 +/- 0.2 mu/l). After fasting, no overlap was present between GHD and NS (0.4-1.6 vs. 2.4-20.8 mu/l, respectively). Mean glucose and insulin concentrations over 8 h in GHD and NS in basal conditions were similar and were reduced to the same extent in both groups. Our findings demonstrate that after short-term fasting, the study of spontaneous GH secretion distinguishes between GH-deficient adults and normal subjects; this phenomenon occurs before significant changes in IGF-I and IGFBP-3 levels. These results suggest that the assessment of spontaneous GH secretion could be useful for the diagnosis of adult GH deficiency only after short-term fasting.

Usefulness of IGF-I assay for the diagnosis of GH deficiency in adults.

IGF-I is the best marker of GH secretory status but it also depends on the nutritional status and peripheral hormones such as insulin, glucocorticoids, thyroid hormones and gonadal steroids. Though monitoring IGF-I levels is the best way for evaluating appropriate GH replacement, the usefulness of IGF-I assay in the diagnosis of adult GH deficiency (GHD) is still matter of debate. To clarify this point in a large population of GHD adults (no. = 135, 61 women and 74 men; age, mean +/- SE: 43.8 +/- 1.4 yr, range 20-80 yr) we studied IGF-I levels, their reproducibility and association to peak GH response to GHRH + arginine (GHRH + ARG) test and insulin tolerance test (ITT). The results in GHD were compared with those in a large population of normal subjects (no. = 336, 233 women and 103 men, aged 20-80 yr). Mean IGF-I levels in GHD (77.8 +/- 4.9 micrograms/l) were clearly lower (p < 0.001) than those in normal subjects (170.2 +/- 4.7 micrograms/l). In Childhood Onset GHD (CO-GHD; no. = 40; age, mean +/- SE: 27.8 +/- 1.5 yr) IGF-I levels were lower than those in Adult Onset GHD (AO-GHD; no. = 95, age, mean +/- SE: 50.7 +/- 1.4 yr) (56.6 +/- 9.7 vs 87.1 +/- 5.4 micrograms/l, p < 0.0003). In both GHD and normal subjects IGF-I levels showed good, reproducibility (r = 0.92, p < 0.00001 and r = 0.62, p < 0.00001, respectively). In GHD, but not in normal subjects, IGF-I levels were positively associated to peak GH responses to GHRH + ARG (r = 0.57, p < 0.00001); on the other hand, the GH peak after ITT was not associated to IGF-I in GHD. In normal subjects, but not in GHD, IGF-I levels were negatively associated to age (r = -0.60, p < 0.00001). Considering individual IGF-I levels there was a clear overlap between GHD and normal subjects. However, this overlap was strongly dependent on age. In fact, in the third and fourth decade of life 83.6% of GHD had IGF-I levels below the 3rd centile of normal values; on the other hand, in the fifth-sixth decade and in ageing 47% and only 12% of GHD, respectively, had IGF-I levels low for age. In conclusion, our results demonstrate that IGF-I levels represent a reproducible marker of GH status and are reduced more in CO-GHD than in AO-GHD adults. An overlap exists between GHD and normal subjects, however this is small up to the 4th decade of life. Thus, though normal IGF-I levels do not rule out the existence of GHD, up to 40 yr low IGF-I levels strongly point to GHD if malnutrition and liver disease have been ruled out.

Diagnosis of adult GH deficiency (GHD): Predictive value of serum IGF-I and number of pituitary hormone deficits

Diagnosis of adult GH deficiency (GHD): Predictive value of serum IGF-I and number of pituitary hormone deficits

Urinary Growth Hormone (GH), Insulin-Like Growth Factor I (IGF-I), and IGF-Binding Protein-3 Measurements in the Diagnosis of Adult GH Deficiency

Urinary Growth Hormone (GH), Insulin-Like Growth Factor I (IGF-I), and IGF-Binding Protein-3 Measurements in the Diagnosis of Adult GH Deficiency

The growth Hormone ResearchSociety consensus guidelines for the diagnosis and treatment of adult GH deficiency

The Growth Hormone Research Society (GRS) convened a workshop in Port Stephens, Australia in April 1997 to establish consensus guidelines for the diagnosis and treatment of adults with GH deficiency (GHD). Scientists with expertise in the field, representatives from industry involved in the manufacture of GH and representatives from health authorities from a number of countries participated in the workshop. The workshop considered the following questions: (1) How should adult GHD be defined? (2) Who should be tested for adult GHD? (3) How should the diagnosis of adult GHD be established? (4) How should GH and insulin-like growth factor-I (IGF-I) assays be standardized? (5) Who should be treated for adult GHD? (6) What dose of GH should be used for treatment of adult GHD? (7) How should treatment of adult GHD be monitored? (8) What are the contraindications to treatment of adult GHD? (9) What safety issues need to be considered? (10) How long should treatment of adult GHD be continued? The consensus guidelines developed at this workshop and the rationale for some of these recommendations will be reviewed in this paper.

High-affinity growth hormone binding protein, insulin-like growth factor I and insulin-like growth factor binding protein 3 in adults with growth hormone deficiency.

The high-affinity growth hormone binding protein (GHBP) circulates in human blood and represents the extracellular domain of the growth hormone (GH) receptor. The effects of GH deficiency on GHBP in adults are not clear. The aim of this study was to evaluate serum GHBP levels in adults with GH deficiency and to assess whether GHBP measurement may contribute to the diagnosis of adult GH deficiency, based on a two-step model. We measured insulin-like growth factor I (IGF-I), IGF binding protein 3 (IGFBP-3) and GHBP levels in serum samples of 36 patients with adult-onset GH deficiency. The GHBP levels were measured by FPLC size-exclusion chromatography; IGF-I and IGFBP-3 levels were measured by RIA. Serum GHBP levels were elevated above the upper limit of the 95% confidence interval in 26 patients, whereas IGF-I and IGFBP-3 levels were low in 10 patients and in 16 patients, respectively. The combination of low serum IGF-I and low IGFBP-3 levels was found in 10 patients. In nine patients, serum IGF-I levels were low, with elevated GHBP levels. Low serum IGF-I, low IGFBP-3 and elevated GHBP levels were found in five patients. Only four out of 36 patients had serum IGF-I, IGFBP-3 and GHBP levels that were within the 95% confidence interval of the control values. We conclude that adults with acquired GH deficiency have elevated GHBP levels in comparison to healthy subjects. We suggest that measurement of GHBP levels might contribute to the diagnosis of adult GH deficiency, though further research is required to study the additional value of GHBP measurements.

Assessment of GH status in adults with GH deficiency using serum growth hormone, serum insulin-like growth factor-I and urinary growth hormone excretion.

The benefits of treating adults with GH deficiency are now well recognized although the criteria for deciding which patients to treat are still not clear. At present the 'gold standard' is the insulin stress test (IST) which is unpleasant and potentially dangerous, particularly in patients with hypopituitarism. The aim of this study was to determine whether alternative methods of assessing GH status are reliable in predicting GH deficiency. Forty-four patients with unequivocal GH deficiency (peak IST < 2 mU/l) and 17 with partial deficiency (peak IST 2-10 mU/l) were studied. Each patient was assessed clinically with respect to the number of other pituitary axes affected and biochemically with an estimate of urinary GH excretion (uGH) and serum IGF-I. These markers were then related to GH status as defined by insulin stress testing. Insulin stress tests were performed using 0.1 units/kg i.v. and accepted with a blood glucose < 2 mmol/l. Serum GH and IGF-I were measured by radioimmunoassay whilst uGH was estimated by an immunoradiometric assay using commercially available reagents. uGH was estimated from the mean of two overnight urine collections which consisted of all urine passed from last voiding through to the first morning sample. The presence of unequivocal GH deficiency (peak IST < 2 mU/l) was predictable if 2 or more other pituitary axes were affected (90%). uGH declined significantly with the level of peak IST response (P < 0.001) and almost so with the number of other deficient hypothalamic-pituitary axes affected (P = 0.057). Thus, uGH accurately reflected GH status and showed good separation from normal controls in patients less than 40 years (specificity 79%) and between 40 and 60 years (specificity 67%). Above this age the method is less specific (36%). Patients excreted significantly less GH than controls in all three age groups (P < 0.01). Subnormal levels of IGF-I were strongly predictive of unequivocal GH deficiency (91% with subnormal IGF-I have a peak IST GH < 2 mU/l) although a normal value does not reliably exclude the diagnosis. A diagnosis of adult GH deficiency can be reliably made without the need for an insulin stress test by using a combination of low urinary GH excretion, subnormal IGF-I levels and clinical assessment with regard to the number of other pituitary axes affected.