Glucocorticoid replacement therapy and fibrinolysis in patients with hypopituitarism.

BACKGROUND: Hypopituitarism is associated with increased cardiovascular mortality, and it has been suggested that unphysiological glucocorticoid replacement regimens might contribute to this risk. Traditional glucocorticoid replacement regimens have often led to excessive serum cortisol levels. The hypercortisolaemia of Cushing's syndrome is associated with an increased risk of thromboembolism. OBJECTIVE: To examine whether short-term higher-dose hydrocortisone replacement regimens adversely affect the fibrinolytic system. DESIGN: Crossover study comparing tailored low-dose (LD) glucocorticoid regimen (mean, 17·5 mg hydrocortisone daily), with a traditional high-dose (HD, 30-mg hydrocortisone daily) regimen for 2 weeks. PATIENTS: Ten patients with hypopituitarism and ACTH deficiency - median (range) age, 59 (41-75) years - and 10 age- and sex-matched controls. Nine patients had growth hormone deficiency (five replaced), nine patients had TSH deficiency (nine replaced), eight had gonadotrophin deficiency (five replaced). During the study, other pituitary hormone replacement therapy remained unchanged. Patients with acromegaly and Cushing's syndrome were excluded. MEASUREMENTS: Hourly serum cortisol for 11 h, plasminogen activator inhibitor-1 (PAI-1), tissue plasminogen activator (tPA) and fibrinogen levels after 2 weeks of treatment with both LD and HD regimens. RESULTS: No overall significant differences were found between the three groups using the Kruskal-Wallis test: PAI-1: [median (range)] HD, 25 (5-53) ng/ml; LD, 21 (4-56) ng/ml; controls, 27 (8-51); P = 0·3; tPA: HD, 10 (5-15) ng/ml; LD, 10 (4-13) ng/ml; controls 10 (3-13); P = 0·46; and fibrinogen: HD, 2·5 (1·8-3·5) g/l; LD, 3·0 (2·3-4·4) g/l; controls, 2·6 (1·6-3·2): P = 0·97 In addition, no significant differences between HD and LD using Wilcoxon's paired test; PAI-1 (P = 0·91), tPAag (P = 0·47) and fibrinogen (P = 0·09). CONCLUSIONS: An increased dose of hydrocortisone for 2 weeks creates excessive glucocorticoid exposure, but does not significantly affect fibrinolytic-coagulation parameters.

Interpretation of the short Synacthen test in the presence of low cortisol-binding globulin: two case reports.

CONTEXT: Ten percent of serum total cortisol (TC) is unbound; the remainder is bound to cortisol-binding globulin (CBG) and, to a lesser extent, albumin. CBG concentrations can drop significantly, particularly in critical illness, resulting in a low TC although the free, active, cortisol may be normal or increased. In the context of a low CBG, the diagnosis of pituitary-adrenal insufficiency with measurements of TC is difficult. OBJECTIVE: To remind clinicians of the difficulty in interpreting TC when the CBG is low, the circumstances when CBG concentrations may decrease and that measurement of CBG and calculation of the free cortisol index can help in the assessment of pituitary-adrenal reserve. CASE: We present two patients at risk of primary and secondary adrenal insufficiency with a poor response to 250 microg Synacthen. In both cases we confirmed low CBG concentrations but a normal free cortisol index (FCI), confirming normal pituitary-adrenal reserve. INTERVENTION: In case one, we have been able to avoid long-term steroid replacement therapy. We continue to reduce the steroid dose in case 2 but have been limited by the need for high-dose steroid treatment for exacerbations of the patient's airways disease. CONCLUSION: The use of TC in the assessment of the hypothalamic-pituitary-adrenal (HPA) axis may give rise to misleading results if the CBG concentration is low. The FCI may be a better marker of pituitary-adrenal reserve in these subjects. Clinicians should be cautious when interpreting abnormal cortisol results and we emphasize the importance of good clinical assessment.

Graves' disease and coexisting struma ovarii: struma expression of thyrotropin receptors and the presence of thyrotropin receptor stimulating antibodies.

Struma ovarii is a rare cause of hyperthyroidism and particularly rare in patients with coexisting Graves' disease. We describe a 28-year-old female who presented with symptoms and signs of hyperthyroidism (free thyroxine [FT(4)] 39 pmol/L, thyrotropin [TSH] < 0.05 mU/L) and associated ophthalmopathy, consistent with Graves' disease. The patient relapsed twice: once after initial successful management with carbimazole and subsequently after subtotal thyroidectomy. Radioisotope scanning showed focal uptake bilaterally in the neck and believing this was the source of thyroid hormone excess, carbimazole was restarted. A left ovarian mass was found on ultrasound during the investigation of unrelated nephrotic syndrome resulting from focal segmental glomerulosclerosis. A 555-g struma ovarii was removed surgically. Hypothyroidism developed postoperatively (FT(4) 9.7 pmol/L, TSH 36 mU/L). Circulating TSH receptor stimulating antibodies were positive and immunohistochemical studies confirm the presence of TSH receptors on the struma ovarii. The demonstration of TSH receptors on the struma ovarii increases previous speculation that struma ovarii growth and function may be augmented by the circulating TSH receptor stimulating antibodies of Graves' disease.

Failure to normalize parathyroid hormone during treatment of vitamin D deficiency in Asian patients.

OBJECTIVE: Vitamin D deficiency and osteomalacia remain commonplace within the Asian community in Bradford. The treatment of vitamin D deficiency and osteomalacia is cheap and effective, but there are few data on long-term outcomes. Studies have suggested that a minority of patients fail to normalize parathyroid hormone (PTH) levels during therapy with vitamin D. This study aimed to determine what proportion of Asian patients with vitamin D deficiency and secondary hyperparathyroidism normalize PTH levels following therapy with oral vitamin D and to examine reasons for failure to normalize PTH. DESIGN: This study examined the impact of an oral regimen of vitamin D 800 i.u. (20 micrograms) and calcium 1000 mg daily, on PTH levels within an endocrinology outpatient clinic. patients 51 (4M:47F) Asian patients, median age 39 years (range 16-77 years) with vitamin D deficiency (25-hydroxyvitamin D < 25 nmol/l) and secondary hyperparathyroidism (PTH > 5.7 pmol/l). MEASUREMENTS: All patients had at least one follow-up measurement of PTH and calcium during treatment. A subgroup of patients gave consent for examination of GP-prescribing records to indirectly asses adherence to therapy. RESULTS: PTH normalized in only 28/51 (55%) patients (group N) and failed to normalize in 23/51 (45%) patients (group F). Baseline patient characteristics including: age, basal serum 25-hydroxyvitamin D (25OHD), basal serum PTH, basal serum calcium and post treatment serum calcium, were similar in groups N and F. Mild hypercalcaemia occurred in only two (3.9%) patients. The proportion of prescriptions collected by patients in group N was 75 (17-100)% and in group F was 17 (0-100)%, P < 0.0001. CONCLUSIONS: This study has demonstrated that long-term oral treatment with vitamin D and calcium, fails to normalize PTH in a significant proportion of patients with vitamin D deficiency and osteomalacia. This is most likely related to lack of adherence to long-term treatment. Improved ways of treating this condition need to be explored.

Routine biochemistry in suspected vitamin D deficiency.

Vitamin D deficiency, which continues to be widespread amongst persons of Asian descent in the UK, is often detected from abnormal results on routine biochemistry. The aim of this study was to assess the frequency of abnormal results from routine baseline tests of serum calcium, phosphate, and alkaline phosphatase in patients who subsequently proved to have vitamin D deficiency and secondary hyperparathyroidism. A retrospective examination was undertaken to assess these baseline indices in a cohort of 84 such patients seen in Bradford-5 male; 80 of Asian descent; median age 46 years (range 16-82); serum 25-hydroxyvitamin D<10 microg/L; parathyroid hormone >54 ng/L. Calcium was normal in 55 patients (66%), phosphate in 68 (81%) and alkaline phosphatase in 24 (29%). In only 5 patients were all three indices outside the normal range. The median parathyroid hormone concentration was significantly greater in patients with abnormal routine biochemistry (145 [range 55-1662] ng/L) than in patients with normal routine biochemistry (88 [59-322] ng/L) but the median 25-hydroxyvitamin D levels did not differ (3.1 [1.3-9.9] and 3.0 [1.5-7.3] microg/L). Routine biochemistry was normal in 20% of cases. If routine biochemistry is relied upon to detect vitamin D deficiency and osteomalacia, a substantial minority of cases will be missed.