• GH sensitivity of GH-deficient adults is dependent on gender but not timing of onset.

      Columb, Breeda; Smethurst, Linda E; Mukherjee, Annice; Jostel, Andreas; Shalet, Stephen M; Murray, Robert D; Department of Endocrinology, Christie Hospital NHS Trust, Manchester, UK. (2009-02)
      BACKGROUND: Females secrete 2-3 -fold greater amounts of GH compared with males despite maintaining similar IGF-I levels. IGF-I generation tests in healthy subjects suggest this discordancy results from relative resistance to GH in females. In GHD females the presumed relative insensitivity to GH is reflected by a lower basal IGF-I and the need for higher GH maintenance doses during replacement. Adults with severe GHD of childhood-onset (CO) have lower basal IGF-I SDS and require higher GH maintenance doses compared with adult-onset (AO) patients with GHD of equal severity. We hypothesised CO-GHD adults to be less sensitive to GH than AO-GHD patients. METHODOLOGY: In a single site study we analysed the incremental change in IGF-I (DeltaIGF-I) in 116 GHD adults following initiation of GH replacement. The data were corrected to provide DeltaIGF-I/mg GH because of slight variances in initial GH dose. RESULTS: Following GH replacement DeltaIGF-I was 230 +/- 245 and 356 +/- 278 ng/ml/mg GH in females and males, respectively (P = 0.01). In CO and AO patients DeltaIGF-I was 282 +/- 206 and 294 +/- 292 ng/ml/mg GH, respectively (P = 0.83). Further analysis after stratification by both gender and timing of onset of GHD showed DeltaIGF-I was 226 +/- 164, 324 +/- 228, 231 +/- 268, and 373 +/- 304 ng/ml/mg GH in the CO females, CO males, AO females, and AO males, respectively (AO males vs. AO females, P = 0.03; CO males vs. CO females, P = 0.17; AO males vs. CO males, P > 0.05; AO females vs. CO females, P > 0.05). Multiple linear regression with DeltaIGF-I as the dependent variable and age, gender, BMI, baseline IGF-I level, and timing of onset as independent variables showed DeltaIGF-I to be dependent on gender alone (R = 0.28, P = 0.004). Age (P = 0.44), BMI (P = 0.54), baseline IGF-I level (P = 0.63) and timing of onset (P = 0.61) had no effect on DeltaIGF-I. CONCLUSION: We have shown gender to have a significant impact on GH sensitivity in GHD adults, which, at least in part, explains differences in maintenance dosages during replacement. None of the additional variables impacted significantly on GH sensitivity. The lower basal IGF-I SDS and higher GH replacement requirement reported in CO compared with AO patients cannot be explained by differences in sensitivity to GH.
    • The use of thyroid function tests in the diagnosis of hypopituitarism: definition and evaluation of the TSH Index.

      Jostel, Andreas; Ryder, W David J; Shalet, Stephen M; Christie Hospital, Department of Endocrinology, Manchester, United Kingdom. (2009-02-18)
      SUMMARY Background: TSH secretion in hypopituitary patients may be decreased due to TSH deficiency, but it remains also under feedback inhibition by fT4. We propose a TSH Index (TSHI) as 'fT4-adjusted TSH', that corrects for any physiological TSH suppression, in order to provide a true estimate of pituitary thyrotrope function and any pathological pituitary suppression. Methods: 9519 TFTs (Bayer Immuno-1(R)) in 4064 patients of our institution were examined, including 444 patients investigated for hypopituitarism. Based on the physiological log-linear relationship between fT4 and TSH, we estimated the amount of feedback-induced change in logTSH per change in fT4, which allowed the extrapolation of logTSH to a fixed fT4 of 0, defining the TSH Index. TSH Indices were compared with other measures of pituitary function. Results: Feedback inhibition was estimated to cause a 0.1345 decrease in logTSH[mU/L] per 1pmol/L increase in fT4 concentration, i.e. TSHI=logTSH+0.1345xfT4. Patients with lower peak stimulated GH and cortisol concentrations had significantly lower TSHI (p<0.0001). TSH Indices measured before pituitary stimulation tests predicted highly significantly the risk of test failure (p=0.0002). 21.9% of all potential fT4-TSH combinations within the current reference ranges were identified as abnormal on the basis of the TSHI. Conclusion: The TSH Index provides an accurate estimate of the severity of pituitary dysfunction in hypopituitary patients based on simple TFTs. It predicts the probability of pituitary stimulation test failure, and extends the diagnosis of TSH deficiency into areas of the normal TFT reference ranges.