Free triiodothyronine has a distinct circadian rhythm that is delayed but parallels thyrotropin levels.

CONTEXT: TSH is known to have a circadian rhythm, but the relationship between this and any rhythm in T(4) and T(3) has not been clearly demonstrated. OBJECTIVE: With a view to optimizing thyroid hormone replacement therapy, we have used modern assays for free T(4) (FT4) and free T(3) (FT3) to investigate circadian rhythmicity. SETTING: The study was performed at a university hospital. DESIGN AND SUBJECTS: This was a cross-sectional study in 33 healthy individuals with 24-h blood sampling (TSH in 33 and FT4 and FT3 in 29 individuals) and cosinor analysis. RESULTS: Of the individuals, 100% showed a sinusoidal signal in TSH, for FT4 76%, and for FT3 86% (P < 0.05). For FT4 and FT3, the amplitude was low. For TSH the acrophase occurred at a clock time of 0240 h, and for FT3 approximately 90 minutes later at 0404 h. The group cosinor model predicts that TSH hormone levels remain above the mesor between 2020 and 0820 h, and for FT3 from 2200-1000 h. Cross correlation of FT3 with TSH showed that the peak correlation occurred with a delay of 0.5-2.5 h. When time-adjusted profiles of TSH and FT3 were compared, there was a strong correlation between FT3 and TSH levels (rho = 0.80; P < 0.0001). In contrast, cross correlation revealed no temporal relationship between FT4 and TSH. CONCLUSIONS: FT3 shows a circadian rhythm with a periodicity that lags behind TSH, suggesting that the periodic rhythm of FT3 is due to the proportion of T(3) derived from the thyroid. Optimizing thyroid hormone replacement may need to take these rhythms into account.

Modified-release hydrocortisone for circadian therapy: a proof-of-principle study in dexamethasone-suppressed normal volunteers.

BACKGROUND: All existing long-term glucocorticoid replacement therapy is suboptimal as the normal nocturnal rise and waking morning peak of serum cortisol is not reproduced. AIM: To test whether it is possible to reproduce the normal overnight rise and morning peak in serum cortisol using an oral delayed and sustained release preparation of hydrocortisone (Cortisol(ds)). SUBJECTS AND METHODS: Six healthy normal male volunteers attended on two occasions, in a single-dose, open-label, nonrandomized study. Endogenous cortisol secretion was suppressed by administration of dexamethasone. Cortisol(ds) (formulation A or B) was administered at 2200 h on day 1. Blood samples for measurement of cortisol were taken from 2200 h every 30 min until 0700 h, then hourly until 2200 h on day 2. Fifteen body mass index (BMI)-matched control subjects had serum cortisol levels measured at 20-min intervals for 24 h. Serum cortisol profiles and pharmacokinetics after Cortisol(ds) were compared with those in controls. RESULTS: Formulations A and B were associated with delayed drug release (by 2 h and 4 h, respectively), with median peak cortisol concentrations at 4.5 h (0245 h) and 10 h (0800 h), respectively, thereby reproducing the normal early morning rise in serum cortisol. Total cortisol exposure was not different from controls. CONCLUSIONS: For the first time we have shown that it is possible to mimic the normal circadian rhythm of circulating cortisol with an oral modified-release formulation of hydrocortisone, providing the basis for development of physiological circadian replacement therapy in patients with adrenal insufficiency.

Hypopituitarism after cranial irradiation.

Radiation-induced damage to the hypothalamic-pituitary (h-p) axis is associated with a wide spectrum of subtle and frank abnormalities in anterior pituitary hormones secretion. While the rapidity of onset of these abnormalities is primarily radiation dose-dependent, their frequency and severity also depend on the length of follow-up. The GH axis is the most vulnerable to radiation damage, and GH deficiency is usually the only neuro-endocrine abnormality following irradiation of the h-p axis with doses <30 Gy. With higher radiation doses (30-50 Gy), the frequency of GH insufficiency can be as high as 50-100% and that of TSH and ACTH around 3-6%. Abnormalities in gonadotrophin secretion are dose-dependent; precocious puberty can occur after radiation dose <30 Gy in girls only, and in both sexes equally with a radiation dose of 30-50 Gy. Gonadotrophin deficiency occurs infrequently, and is usually a long-term complication following a minimum radiation dose of 30 Gy. Hyperprolactinemia has been described in both sexes and all ages, but is mostly seen in young women after intensive irradiation and is usually subclinical. A much higher incidence of gonadotrophin, ACTH and TSH deficiencies, (30-60% after 10 yr) occurs after more intensive irradiation (>70 Gy) used for nasopharyngeal carcinomas and tumors of the skull base, and following conventional irradiation (30-50 Gy) for pituitary tumors. Radiation-induced anterior pituitary hormone deficiencies are irreversible and progressive. Regular testing is mandatory to ensure timely diagnosis and early hormone replacement therapy, to improve linear growth and prevent short stature in children cured from cancer, to preserve sexual function, prevent ill health and osteoporosis, and improve the quality of life.

Radiation-induced growth hormone deficiency.

Deficiency of one or more anterior pituitary hormones may follow treatment with external irradiation when the hypothalamic-pituitary axis falls within the fields of irradiation. Hypopituitarism occurs in patients who receive radiation therapy for pituitary tumours, nasopharyngeal cancer and primary brain tumours, as well as in children who undergo prophylactic cranial irradiation for acute lymphoblastic leukaemia, or total body irradiation for a variety of tumours and other diseases. The degree of pituitary hormonal deficit is related to the radiation dose received by the hypothalamic-pituitary axis. Thus, after lower radiation doses isolated growth hormone deficiency ensues, whilst higher doses may produce hypopituitarism. The timing of onset of the radiation-induced pituitary hormone deficit is also dose-dependent. The main site of radiation damage is the hypothalamus rather than the pituitary, although the latter may be affected directly.

The usefulness of the combined growth hormone (GH)-releasing hormone and arginine stimulation test in the diagnosis of radiation-induced GH deficiency is dependent on the post-irradiation time interval.

The diagnostic usefulness of the insulin tolerance test (ITT) in patients with radiation-induced GH deficiency (GHD) is well established, whereas that of the combined GHRH plus arginine stimulation test (AST) is unproven. Both tests were undertaken in 49 adult survivors (aged 16-53.7 yr), who were previously irradiated for non-pituitary brain tumors or leukemia, and 33 age-, gender-, and BMI-matched controls. The aims of the study were to examine the impact of the time interval after irradiation on the pattern of GH responsiveness to the two provocative tests and to establish the role of the GHRH + AST in the diagnosis of radiation-induced GHD. The median (range) peak GH responses to either test were significantly lower (P < 0.0001) in the patients [GHRH + AST, 19.9 (range, 2.7-103.5) microg/liter; ITT, 5 (0.2-34.8) microg/liter] than in normals [GHRH + AST, 55 (5.7-173.5) microg/liter; ITT, 23.8 (4.2-80) microg/liter]. In patients and normal controls, the median peak GH response to the GHRH + AST was significantly greater (P < 0.0001) than the response to the ITT. However, the ratio of the peak GH response to the GHRH + AST over that achieved with the ITT (discordancy ratio) was significantly higher (P = 0.007) in the patients (median, 3.45; range, 0.8-53.5) compared with normals (median, 2; range, 0.34-18.6), consistent with dominant hypothalamic damage and relatively preserved somatotroph responsiveness. The peak GH response to the ITT fell significantly within 5 yr of irradiation with little further change over the subsequent 10 yr. In contrast, the peak GH response to the GHRH + AST barely changed within 5 yr of irradiation but subsequently declined significantly over the next 10 yr. Thus, the evolution of change in GH responsiveness to the two different stimuli over time was markedly different, resulting in a significantly raised discordancy ratio of 6 within the first 5 postirradiation years, which then normalized over the next 10 yr. The peak GH responses to the GHRH + AST and the discordancy ratio were negatively correlated with the time interval after irradiation (r = -0.40, P = 0.0037; and r = -0.4, P = 0.0046, respectively). On a practical clinical level, the discordancy between the GH test results was important; 50% of those classified as severely GHD patients by the ITT were judged normal or only GH insufficient by the GHRH + AST. In conclusion, these findings suggest that hypothalamic dysfunction occurs early and somatotroph dysfunction occurs late, following radiation damage to the hypothalamic-pituitary axis. This time dependency of somatotroph dysfunction may reflect either secondary somatotroph atrophy due to hypothalamic GHRH deficiency or delayed direct radiation-induced damage to the pituitary gland. The high false negative diagnosis rate for severe GHD makes the GHRH + AST an unreliable test in clinical practice when GH status is explored in the early years after cranial irradiation with the intention to treat.

Low-dose GH replacement improves the adverse lipid profile associated with the adult GH deficiency syndrome.

OBJECTIVE: Adult growth hormone deficiency (AGHD) is associated with an adverse lipid profile. The majority of previous studies of GH replacement have used supraphysiological doses and reported favourable changes in the lipid profile. Whether this beneficial effect is the result of pharmacological GH therapy, or occurs in response to low-dose GH replacement aimed at normalization of the serum IGF-I, has not been fully elucidated. STUDY DESIGN: We studied 67 patients with GH deficiency using a low-dose individualized GH replacement regimen. GH was commenced at a dose of 0.27 mg/day and the GH dose titrated until the serum IGF-I was normalized. Serum lipids were assessed at baseline, 12 and 24 months. RESULTS: A reduction in total cholesterol (TC) was observed at 12 (6.01 vs. 5.77 mmol, P = 0.04) and 24 months (6.01 vs. 5.56, P = 0.09). The reduction in LDLC failed to reach significance at 12 months (3.97 vs. 3.8, P = 0.09), but was significant at 24 months (3.97 vs. 3.50, P = 0.02). Levels of HDLC did not change significantly at 12 or 24 months. Significant improvements in the TC/HDLC ratio were observed at both 12 (5.68 vs. 5.29, P = 0.01) and 24 months (5.68 vs. 4.86, P = 0.007). A significant fall in triglycerides (TG) was present at 12 months (2.07 vs. 1.83, P = 0.01), and was maintained at 24 months, but was no longer significant (2.07 vs. 1.89, P = 0.28). At 12 months there was no correlation between improvements in lipid parameters and either the change in IGF-I SD score or the GH dose. Using multivariate analysis the change in TC, LDLC and the TC/HDLC ratio with 12 months GH replacement were determined by the baseline TC, LDLC and TC/HDLC levels (R2 = 0.18, P = 0.004; R2 = 0.20, P = 0.006; and R2 = 0.33, P < 0.0001), respectively. CONCLUSIONS: Low-dose individualized GH replacement aimed at normalization of the serum IGF-I is associated with significant improvements in TC, LDLC, TGs and the TC/HDLC ratio. The greatest improvements are observed in patients with the most adverse lipid profiles at baseline. Improvements are independent of changes in the IGF-I SDS and GH dose.

GH-deficient survivors of childhood cancer: GH replacement during adult life.

Childhood survivors of cancer are prone to a number of adverse sequelae related to the therapeutic interventions undertaken to achieve remission. The endocrine system is frequently affected; hypothalamo-pituitary dysfunction, in particular GH deficiency, is common after cranial irradiation. It is unclear to what extent GH deficiency contributes to the abnormalities observed in adult survivors of childhood cancer, and whether GH replacement reverses these anomalies. We compared 27 GH-deficient survivors of childhood cancer with 27 adult age- and sex-matched controls and went on to replace GH in the patient group to determine whether GH resulted in improvements of the baseline abnormalities. The GH-deficient survivors of childhood cancer had an adverse lipid profile (total cholesterol, 5.4 vs. 4.6 mM, P = 0.004; high-density lipoprotein cholesterol, 1.05 vs. 1.6 mM, P < 0.001; and triglycerides, 1.3 vs. 1.0 mM, P < 0.001) and were osteopenic (lumbar spine z-score, -1.53 vs. -0.31 SD score, P < 0.001; femoral neck z-score, -1.23 vs. -0.27 SD score, P = 0.02); additionally, the female subgroup had an increased percentage body fat (43.6 vs. 32.8%, P = 0.016). In keeping with the selection criterion, quality of life in the patient cohort, relative to the healthy controls, was severely impaired [adult GH-deficiency assessment (AGHDA), 15.5 (range, 8-25) vs. 1 (range, 0-19), P < 0.0001; psychological general well-being schedule, 67.5 (range, 18-86) vs. 89.0 (range, 51-104), P < 0.0001]. After 12 months of GH replacement, small (but significant) improvements were observed in body composition in the male subgroup (waist-hip ratio, 0.871 vs. 0.863, P < 0.05); and in the female cohort, total cholesterol (6.0 vs. 5.2 mM, P = 0.01) and triglyceride (2.1 vs. 1.4 mM, P = 0.01) levels fell. Bone mineral density improved in only one of the four sites studied (ultradistal radius, -1.21 vs. -1.09, P = 0.048) after a median duration of GH therapy of 18 months. Quality of life improved dramatically by 3 months (AGHDA, 15.5 vs. 10.0, P < 0.001), and the improvement was maintained at 12 months (AGHDA, 15.5 vs. 9.0, P < 0.001). Importantly, there was no clinical suggestion of tumor recurrence during the 12 months of GH replacement. The minor improvements observed in body composition, the lipid profile, and bone mineral density in GH-deficient adult survivors of childhood cancer after 12-18 months of physiological GH replacement suggest that GH deficiency may not be the major etiological factor in their pathogenesis; the converse seems to be true for the quality of life status of these individuals. We propose that, as in patients with hypopituitarism caused by pituitary disease, the main indication for GH replacement in GH-deficient survivors of childhood cancer should be severe impairment of quality of life.