Ken H. Darzy

Modified-Release Hydrocortisone to Provide Circadian Cortisol Profiles

CONTEXT Cortisol has a distinct circadian rhythm regulated by the brains central pacemaker. Loss of this rhythm is associated with metabolic abnormalities, fatigue, and poor quality of life. Conventional glucocorticoid replacement cannot replicate this rhythm. OBJECTIVES Our objectives were to define key variables of physiological cortisol rhythm, and by pharmacokinetic modeling test whether modified-release hydrocortisone (MR-HC) can provide circadian cortisol profiles. SETTING The study was performed at a Clinical Research Facility. DESIGN AND METHODS Using data from a cross-sectional study in healthy reference subjects (n = 33), we defined parameters for the cortisol rhythm. We then tested MR-HC against immediate-release hydrocortisone in healthy volunteers (n = 28) in an open-label, randomized, single-dose, cross-over study. We compared profiles with physiological cortisol levels, and modeled an optimal treatment regimen. RESULTS The key variables in the physiological cortisol profile included: peak 15.5 microg/dl (95% reference range 11.7-20.6), acrophase 0832 h (95% confidence interval 0759-0905), nadir less than 2 microg/dl (95% reference range 1.5-2.5), time of nadir 0018 h (95% confidence interval 2339-0058), and quiescent phase (below the mesor) 1943-0531 h. MR-HC 15 mg demonstrated delayed and sustained release with a mean (sem) maximum observed concentration of 16.6 (1.4) microg/dl at 7.41 (0.57) h after drug. Bioavailability of MR-HC 5, 10, and 15 mg was 100, 79, and 86% that of immediate-release hydrocortisone. Modeling suggested that MR-HC 15-20 mg at 2300 h and 10 mg at 0700 h could reproduce physiological cortisol levels. CONCLUSION By defining circadian rhythms and using modern formulation technology, it is possible to allow a more physiological circadian replacement of cortisol.

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.

Hypopituitarism following Radiotherapy Revisited.

Neuroendocrine disturbances in anterior pituitary hormone secretion are common following radiation damage to the hypothalamic-pituitary (H-P) axis, the severity and frequency of which correlate with the total radiation dose delivered to the H-P axis and the length of follow-up. The somatotropic axis is the most vulnerable to radiation damage and GH deficiency remains the most frequently seen endocrinopathy. Compensatory hyperstimulation of a partially damaged somatotropic axis may restore normality of spontaneous GH secretion in the context of reduced but normal stimulated responses in adults. At its extreme, endogenous hyperstimulation may limit further stimulation by insulin-induced hypoglycaemia resulting in subnormal GH responses despite the normality of spontaneous GH secretion. In children, failure of the hyper-stimulated partially damaged H-P axis to meet the increased demands for GH during growth and puberty may explain what has previously been described as radiation-induced GH neurosecretory dysfunction and, unlike in adults, the insulin tolerance test remains the gold standard for assessing H-P functional reserve. With low radiation doses (<30 Gy) GH deficiency usually occurs in isolation in about 30% of patients, while with radiation doses of 30-50 Gy, the incidence of GH deficiency can reach 50-100% and long-term gonadotropin, TSH and ACTH deficiencies occur in 20-30, 3-9 and 3-6% of patients, respectively. With higher dose cranial irradiation (>60 Gy) or following conventional irradiation for pituitary tumours (30-50 Gy), multiple hormonal deficiencies occur in 30-60% after 10 years of follow-up. Precocious puberty can occur after radiation doses of <30 Gy in girls only, and in both sexes equally with a radiation dose of 30-50 Gy. Hyperprolactinaemia, due to hypothalamic damage is mostly seen in young women after high dose cranial irradiation and is usually subclinical. H-P dysfunction is progressive and irreversible and can have an adverse impact on growth, body image, sexual function and quality of life. Regular testing is advised to ensure timely diagnosis and early hormone replacement therapy.

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.

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.

Circadian Secretion Pattern of Copeptin, the C-Terminal Vasopressin Precursor Fragment

Copeptin, the C-terminal peptide of provasopressin, is stoichiometrically released with arginine vasopressin (AVP). In contrast to AVP, it is stable ex vivo (1) and reflects the AVP system, as shown in diabetes insipidus or the syndrome of inappropriate antidiuretic hormone secretion(2). Copeptin is a reliable marker of severe stress, with increased concentrations found in cases of critical illness, sepsis, hemorrhagic shock, and stroke(2). The serum copeptin concentration is profoundly and immediately stimulated after myocardial infarction(3). The absence of such stimulation within the first hours after the onset of symptoms has recently been proposed as an important negative predictor for excluding the likelihood of infarction in patients with unspecific chest pain(3). Any further use of the peptide as a marker critically depends on clear cutoffs between health and disease. To better characterize the diagnostic accuracy of …

Cranially irradiated adult cancer survivors may have normal spontaneous GH secretion in the presence of discordant peak GH responses to stimulation tests (compensated GH deficiency)

Context  We have previously demonstrated that spontaneous (physiological) GH secretion was entirely normal in cranially irradiated patients who had normal individual peak GH responses to the insulin tolerance test (ITT) but reduced maximal somatotroph reserve as indicated by substantially reduced group GH responses to the GHRH + arginine stimulation test (AST). The normality of spontaneous GH secretion was attributed to a compensatory increase in hypothalamic stimulatory input within a partially damaged hypothalamic–pituitary (h–p) axis. It is unknown, however, if such compensatory stimulation can also maintain normality of GH secretion in those who fail the ITT but pass the GHRH + AST.

Evolving therapeutic strategies for acromegaly

Acromegaly is an uncommon endocrine disorder characterized by pathologically elevated growth hormone (GH) and insulin-like growth factor-I (IGF-I) levels. In more than 99% of cases acromegaly is caused by a GH-secreting pituitary adenoma. If untreated, life expectancy is reduced by an average of 10 years (1) and the increased mortality rate is due to cardiovascular, cerebrovascular, respiratory and malignant disease (2). The object of therapy is 2fold, restore normal life expectancy and reduce the morbidity associated with the disease. There are now several epidemiological reports which indicate that if GH levels can be reduced to less than 5 mU/l life expectancy is normalized (2). The achievement of a GH level less than 5 mU/l, however, does not imply removal of every single GH-secreting tumor cell, i.e. cure, but rather that “epidemiological safe” GH levels (“cure”) have been attained. Thus, it is not uncommon to see the combination of a pathologically elevated IGF-I level in the presence of a mean GH level less than 5 mU/l. The mortality and life expectancy data are almost all derived from GH studies although there is one oft-quoted report suggesting that IGF-I levels have to be normalized before life expectancy is normalized (3); however the latter report does not actually contain IGF-I data! Nonetheless a significant proportion of patients with a mean GH level less than 5 mU/l and a raised IGF-I level may be affected adversely by disease morbidity. Traditionally, primary therapy for acromegaly has been pituitary surgery followed by pituitary irradiation in those in whom the disease remained active post-operatively. The advent of modern medical therapy began with bromocriptine and now is represented by a more powerful dopamine agonist (DA) drug, cabergoline, somatostatin (SS) analogue depot preparations