Evaluation of the adequacy of levothyroxine replacement therapy in patients with central hypothyroidism.

As there are few data on the evaluation of the adequacy of levothyroxine (L-T4) therapy in patients with central hypothyroidism (CH), a prospective study was performed to assess the accuracy of various parameters in the follow-up of 37 CH patients. Total and free thyroid hormones, TSH, and a series of clinical and biochemical indexes of peripheral thyroid hormone action have been evaluated off and on L-T4 therapy. Samples were taken before the daily administration of L-T4. In all patients off therapy, clinical hypothyroidism and low levels of free T4 (FT4) were observed, whereas values of FT3, total T4, and total T3 were below the normal range in 73%, 57%, and 19% of cases, respectively. Most of the indexes of thyroid hormone action were significantly modified after L-T4 withdrawal and exhibited significant correlation with free thyroid hormone levels. During L-T4 replacement therapy, 32 patients had circulating levels of FT4 and FT3 and indexes within the normal range with a mean L-T4 daily dose of 1.5 +/- 0.3 microg/kg BW. Despite normal serum FT4, 3 patients had borderline high values of FT3 and a clear elevation of serum-soluble interleukin-2 receptor concentrations, suggesting overtreatment. Low or borderline low FT4/FT3 levels indicated undertreatment in 2 patients. The clinical parameters lack the required specificity for the diagnosis or follow-up of CH patients. The L-T4 daily dose should be established, taking into account the weight, the age, and the presence of other hormone deficiencies or pharmacological treatment of CH patients. In conclusion, our results indicate that the diagnosis of CH is reached at best by measuring TSH and FT4 concentrations. In the evaluation of the adequacy of L-T4 replacement therapy, both FT4 and FT3 serum levels together with some biochemical indexes of thyroid hormone action are all necessary to a more accurate disclosure of over- or undertreated patients.

Urinary free deoxypyridinoline levels during childhood.

Free urinary deoxypyridinoline (DPD) levels, corrected for the urinary concentration of creatinine (nmol/mmol), were determined in 144 healthy children (76 males and 68 females, mean age +/- SE: 9.1 +/- 0.2 yr, age range: 5.1-14.0 yr) in order to detect the possible age-related changes of this reliable index of bone resorption activity and the relationship between free DPD, gender and pubertal development. Multiple regression analysis revealed that most of the variation in DPD levels was explained by chronological age (coefficient: 2.89, p < 0.02), whereas sex and pubertal stage did not add significance to the variance. Urinary DPD levels were similar in males (24.7 +/- 1.8 nmol/mmol urinary creatinine) and females (24.2 +/- 2.0 nmol/mmol urinary creatinine) and significantly higher (p < 0.02) in pubertal (Tanner stage II-V: 28.6 +/- 2.8 nmol/mmol urinary creatinine) than in prepubertal children (22.4 +/- 1.4 nmol/mmol urinary creatinine), both in males and in females. The pattern of DPD levels was clearly different between females and males, the maximum increase being evident at Tanner stage II-III (mid-puberty) in females and at Tanner stage IV-V (mid-late puberty in males. The increase of DPD paralleled the elevation of urinary GH (pmol/mmol urinary creatinine), a non-invasive and acceptable index of physiological GH secretion, observed during the pubertal growth spurt. The progressive increase of urinary GH in older children was not followed by a further stimulation of bone resorption. Although the relationships between urinary, GH and DPD need to be better investigated, it seems plausible to hypothesize that the determination of urinary free DPD, as a marker of GH action on bone, might have some potential in the follow-up of growth promoting treatments, such as GH.

Evaluation of markers of bone and collagen turnover in patients with active and preclinical Cushing's syndrome and in patients with adrenal incidentaloma.

Although steroid-induced negative effects on bone and collagen have been well described in corticosteroid-treated patients, few studies have extensively evaluated bone and collagen turnover in patients with endogenous Cushing's syndrome. In this work serum bone-Gla protein (BGP), C-terminal cross-linked telopeptide of type I collagen (ICTP) and N-terminal propeptide of type III procollagen (PIIINP) levels were determined in patients with active (n = 12) and preclinical (n = 6) Cushing's syndrome, adrenal incidentalomas (n = 35) and in healthy controls (n = 28). In patients with overt Cushing's syndrome, serum BGP (0.9+/-0.2 ng/ml), ICTP (2.7+/-0.2 ng/ml) and PIIINP (1.9+/-0.2 ng/ml) levels were significantly lower (P < 0.0001) than in controls (5.5+/-0.2, 3.9+/-0.2 and 3.2+/-0.2 ng/ml respectively). In preclinical Cushing's syndrome, serum BGP (2.5+/-0.8 ng/ml), ICTP (2.2+/-0.1 ng/ml) and PIIINP (2.2+/-0.2 ng/ml) levels were significantly lower than in normal subjects (P < 0.0001, P < 0.0001 and P < 0.02 respectively), being similar to those recorded in overt Cushing's syndrome. In patients with adrenal incidentaloma, serum BGP (4.2+/-0.5 ng/ml) and ICTP (2.9+/-0.2 ng/ml) levels were significantly lower than those found in controls (P < 0.05 and P < 0.001 respectively), while serum PIIINP levels (3.6+/-0.2 ng/ml) did not differ from those of normals. In particular, 9/35 patients with adrenal incidentaloma had markedly depressed BGP levels (<2.0 ng/ml; mean 0.8+/-0.1 ng/ml): all patients of this subgroup showed an exaggerated 17-hydroxyprogesterone increase after ACTH administration. In the same patients, serum ICTP (3.0+/-0.4 ng/ml) and PIIINP (3.6+/-0.2 ng/ml) levels did not differ from those found in the incidentaloma group. In conclusion, our study indicates that bone and collagen turnover are markedly affected in patients with overt and preclinical Cushing's syndrome. Although patients with adrenal incidentaloma do not show any signs or symptoms of overt hypercortisolism, the presence of reduced BGP and ICTP levels might be considered a further index of an 'abnormal' pattern of steroid secretion in some of them. As a consequence, the presence of early alterations in markers of bone turnover might be useful for selecting those patients who need more accurate follow-up of the adrenal mass.

Body composition analysis by dual energy x-ray absorptiometry and anthropometry in adults with childhood-onset growth hormone (GH) deficiency before and after six months of recombinant GH therapy.

Measurements of total body fat (BF) and fat free mass (FFM) obtained by anthropometry, using the Durnin and Womersley (DW) equations, and by total body dual energy x-ray absorptiometry (DXA) were compared in 8 adults with childhood-onset GH deficiency (GHD) and in 9 healthy subjects. The sensitivity of these two methods in detecting the changes in body composition produced by six months of GH therapy in patients with GHD was also compared. Anthropometric determination of percent BF was calculated from the sum of biceps, triceps, subscapular and suprailiac skinfolds, using the appropriate DW and Siri equations for body density and percent fat estimation. FFM was calculated by subtracting BF from body mass (BM). BF and FFM were also determined by DXA (QDR 1000/W, Hologic Inc). The data obtained from the GHD patients were compared with those recorded in a control group of healthy males, matched for sex, age and physical activity. Body composition obtained by anthropometry: before GH treatment, significant differences existed between patients and controls in terms of BM (mean +/- SD: 45.8 +/- 10.0 vs 71.7 +/- 6.6 kg), percent BF (21.0 +/- 3.2 vs 17.1 +/- 3.7%) and FFM (36.0 +/- 6.5 vs 59.3 +/- 3.7 kg), while body mass index (BMI, kg/m2) values were similar in the two groups. Six months of GH therapy did not change BM and BMI, but caused a significant reduction of percent BF (from 21.0 +/- 3.2 to 18.6 +/- 4.0%) and a rise of FFM (from 36.0 +/- 6.5 to 38.0 +/- 6.7 kg). After treatment, no significant differences were found between percent BF values of patients and controls. Body composition obtained by DXA: BF (22.0 +/- 3.9%) and FFM (37.2 +/- 8.0 kg) of patients significantly differed from those of controls (16.8 +/- 3.7% and 59.8 +/- 3.7 kg) before treatment; after GH treatment, percent BF values (17.7 +/- 4.9%) of patients were similar to those of controls. Anthropometry vs DXA: high correlation (p < 0.001-0.0001, R2 = 0.784-0.988) was found between the percent BF and FFM determined by anthropometry and by DXA for both patients, before and after treatment, and controls. It is noteworthy that, for both BF and FFM, most values were evenly distributed along the identity line, showing no systematic overestimation or underestimation by anthropometry. The relation between DXA and anthropometry was maintained even after GH treatment. These results indicate that body fat and FFM assessment by anthropometry are comparable to those by DXA. GH-induced changes in body composition in hypopituitary adults are detected with the same level of accuracy by the two techniques. The reliability, practicality and low cost of anthropometry favour its use for the assessment of body composition even in GHD patients.

Lack of effects of circulating thyroid hormone levels on serum leptin concentrations.

Leptin is the protein product of the ob gene, secreted by adipocytes. It has been suggested that it may play an important role in regulating appetite and energy expenditure. The aim of this study was to evaluate a possible interaction of thyroid hormones with the leptin system. We studied 114 adult patients (65 females and 49 males): 36 were affected with primary hypothyroidism (PH), 38 with central hypothyroidism (CH) and 40 with thyrotoxicosis (TT). Patients with CH were studied both before and after 6 months of L-thyroxine replacement therapy. Body mass index (BMI; kg/m2), thyroid function and fasting serum leptin were assessed in all patients. Since BMI has been proved to be the major influencing variable of circulating leptin levels, data were expressed as standard deviation score (SDS) calculated from 393 male and 561 female controls matched for age and BMI. No difference in SDS was recorded between males and females whatever the levels of circulating thyroid hormones. In males, no significant difference was recorded among the SDSs of PH (-0.36 +/- 1.2), TT (-0.35 +/- 1.2) and CH (0.01 +/- 1.4) patients. Females with PH had an SDSs significantly lower than TT females (-0.77 +/- 1.0 vs -0.06 +/- 1.2; P < 0.02), while no significant differences between CH (-0.34 +/- 0.7) and TT females or between CH and PH females were observed. SDS in CH patients after 6 months of L-thyroxine therapy significantly varied only in females (0.25 +/- 1.4). In conclusion, circulating thyroid hormones do not appear to play any relevant role in leptin synthesis and secretion. However, as females with either overt hypo- or hyper-thyroidism or central hypothyroidism after L-thyroxine therapy show differences in their SDSs, a subtle interaction between sex steroids and thyroid status in modulating leptin secretion, at least in women, may occur.