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Dimitri Novitzky and David K C Cooper

Acute critically ill patients experience a rapid decline in plasma free thyroid hormone levels (free triiodothyronine (FT3) and free levothyroxine (FT4)), with a marked elevation of reverse T3, recognized as the euthyroid sick syndrome (ESS) or low-T3 syndrome. The ESS is also often associated with depressed myocardial function, sometimes referred to as the ‘stunned myocardium’. Its clinical effects may vary from minimal hemodynamic impairment to cardiogenic shock. Medical management may range from aspirin alone to placement of a left ventricular assist device. With adequate supportive therapy, recovery usually occurs within days or weeks. The effect of T3/T4 therapy has been studied in three conditions in which the ESS and myocardial functional depression have been documented – i) transient regional myocardial ischemia and reperfusion, ii) transient global myocardial ischemia in patients undergoing cardiac surgery on cardiopulmonary bypass, and iii) transient inadequate global myocardial perfusion in brain-dead potential organ donors. Under all three conditions, myocardial ischemia leads to rapid loss of high-energy phosphates, accumulation of myocardial tissue lactate, and probably loss of homeostasis of cytosolic calcium, which may further increase cell injury. There is an inability to generate ATP through the Krebs cycle, which reduces the high-energy phosphate pool essential for all cell ATPases. Under all three conditions, following administration of T3/T4, the myocardial dysfunction was rapidly reversed. We, therefore, cautiously advocate the use of thyroid hormonal therapy to any patient with the ESS and/or a stunned myocardium.

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K. J. COOPER, C. P. FAWCETT and S. M. McCANN

Results of experiments using steroid injections or implants have indicated that pituitary gonadotrophin secretion is not only modified by a change in perfusion rate of the releasing factors (RF) of luteinizing hormone (LH) and follicle-stimulating hormone, but that steroid feedback directly at the pituitary level may be involved in the cyclic regulation of gonadotrophin secretion (Ramirez, Abrams & McCann, 1964; Harris & Campbell, 1966; Arimura & Schally, 1971). Consequently, it has been suggested that pituitary responsiveness to LH-RF might change during the oestrous cycle as a result of variation in steroid secretion (Antunes-Rodrigues, Dhariwal & McCann, 1966). This experiment investigates this possibility.

Female Sprague—Dawley rats weighing 220–250 g and maintained under a lighting régime of 14 h light: 10 h darkness at a temperature of 21 ± 2 °C were used. Only animals showing at least two consecutive 4-day oestrous cycles were studied. LH-RF-evoked stimulation of LH release was examined

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S A Lanham, A L Fowden, C Roberts, C Cooper, R O C Oreffo and A J Forhead

Thyroid hormones are important for normal bone growth and development in postnatal life. However, little is known about the role of thyroid hormones in the control of bone development in the fetus. Using computed tomography and mechanical testing, the structure and strength of metatarsal bones were measured in sheep fetuses in which thyroid hormone levels were altered by thyroidectomy or adrenalectomy. In intact fetuses, plasma concentrations of total calcium and the degradation products of C-terminal telopeptides of type I collagen increased between 100 and 144 days of gestation (term 145±2 days), in association with various indices of bone growth and development. Thyroid hormone deficiency induced by thyroidectomy at 105–110 days of gestation caused growth retardation of the fetus and significant changes in metatarsal bone structure and strength when analyzed at both 130 and 144 days of gestation. In hypothyroid fetuses, trabecular bone was stronger with thicker, more closely spaced trabeculae, despite lower bone mineral density. Plasma osteocalcin was reduced by fetal thyroidectomy. Removal of the fetal adrenal gland at 115–120 days of gestation, and prevention of the prepartum rises in cortisol and triiodothyronine, had no effect on bodyweight, limb lengths, metatarsal bone structure or strength, or circulating markers of bone metabolism in the fetuses studied near term. This study demonstrates that hypothyroidism in utero has significant effects on the structure and strength of bone, with different consequences for cortical and trabecular bone.

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A. D. CARE, L. L. ANDERSON, C. W. COOPER, S. L. OXENREIDER and M. PHILLIPPO

The surgically isolated thyroid gland in the pig has been shown to secrete thyrocalcitonin (TC) when perfused with an artificial medium, hypercalcaemic with respect to ionized calcium concentration (Care & Gitelman, 1968). Therefore, hypophysial hormones must not be essential for the release of at least some TC stimulated by hypercalcaemia. The present work was designed to evaluate quantitatively the effect of previous hypophysectomy on the rate of secretion of TC in response to a given degree of hypercalcaemia.

In preliminary experiments, a pair of litter-mate male piglets, 19 days old, was selected and one was hypophysectomized by an adaptation of the method of Liggins, Kennedy & Holm (1967). At autopsy, hypophysectomy was confirmed by visual examination of the sella turcica. Nine days after operation, the thyroid was isolated in situ and perfused with hypercalcaemic blood (6·7 m-equiv.Ca/1.) for 2 hr. according to the method of Care (1965). The thyroid of

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R. M. Sharpe, I. A. Swanston, I. Cooper, C. G. Tsonis and A. S. McNeilly

ABSTRACT

Immunoreactive inhibin was measured in testicular interstitial fluid (IF) from rats during sexual maturation or after impairment of spermatogenesis induced by ethane dimethanesulphonate (EDS), unilateral cryptorchidism or local heating (43 °C, 30 min) of the testes, to ascertain its usefulness as a marker of changing Sertoli cell function. Cultures of isolated seminiferous tubules were also studied. Inhibin was measured by a radioimmunoassay directed towards the first 26 amino acids of the N-terminus of the α-subunit, and the results confirmed for selected pools of IF by in-vitro bioassay using dispersed ovine pituitary cells.

During puberty, IF levels of immunoactive inhibin fell by more than 90% (P<0·001) between 30 and 60 days of age, a decrease paralleled by the levels of androgen-binding protein (ABP), another Sertoli cell product secreted into IF. These changes also paralleled, but preceded, the fall (60%; P<0·001) in serum levels of FSH between 40 and 70 days, while the serum and IF levels of testosterone increased more than two-fold over this period. When adult rats were injected with EDS to destroy the Leydig cells, testosterone levels in IF and serum were undetectable at 3 and 7 days after treatment, were just detectable at 14 days and thereafter returned slowly towards normal by 42 days. The initial androgen withdrawal following EDS treatment caused a progressive reduction in testicular weight up to 21 days and this was accompanied by a significant increase in the serum levels of FSH and a two- to threefold increase in the IF levels of immunoactive inhibin (and also of ABP). Serum FSH and IF levels of immunoactive inhibin returned to within the normal range by 42 days when testosterone levels had normalized. In contrast, in two other experimental situations in which a marked decrease in testicular weight coupled with an increase in IF levels of ABP occurs, different results for the IF levels of immunoactive inhibin were obtained. Thus, in rats exposed to local heating of the testes, IF levels of immunoactive inhibin remained unchanged from control values at 21–40 days after treatment, a finding confirmed by bioassay results. In rats made unilaterally cryptorchid for 10 months, levels of immunoactive inhibin in IF were reduced by 60% (P<0·01) in the abdominal compared with the contralateral scrotal testis.

These results suggest that (1) IF levels of immunoactive inhibin do not always change in parallel to the levels of ABP and may be a useful marker of changing Sertoli cell function, and (2) in at least two situations (puberty and after EDS treatment), there may be a positive relationship between the serum levels of FSH and the IF levels of immunoactive inhibin. This positive relationship was confirmed by in-vitro findings in which FSH and dibutyryl cyclic AMP (but not testosterone) were shown to stimulate immunoactive inhibin production by isolated rat seminiferous tubules during culture for 2–6 days.

J. Endocr. (1988) 119, 315–326

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R. M. BUCKLE, A. D. CARE, C. W. COOPER and H. J. GITELMAN

SUMMARY

The influence of plasma magnesium concentration on parathyroid gland function has been evaluated by perfusion at a constant rate of an isolated parathyroid gland in five goats and one sheep with whole blood of varying magnesium content. The concentration of magnesium in fresh whole blood was adjusted either by dialysis or by the addition of magnesium chloride before the perfusion. In each experiment, the concentration of calcium was maintained constant or was slightly altered to oppose the possible influence of magnesium on the rate of release of parathyroid hormone. Parathyroid hormone concentration in parathyroid venous plasma was estimated by a specific radioimmunoassay.

In each experimental animal we observed that the concentration of parathyroid hormone in the effluent plasma diminished when the concentration of magnesium was raised or increased when the concentration of magnesium was lowered. These observations demonstrate a specific influence of magnesium on the rate of release of parathyroid hormone.

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Joachim Wistuba, Jens Mittag, C Marc Luetjens, Trevor G Cooper, Ching-Hei Yeung, Eberhard Nieschlag and Karl Bauer

Severe forms of congenital hypothyroidism lead to serious clinical symptoms if thyroid hormone replacement therapy is not instituted immediately after birth. In this study, Pax8−/− mice that are born without a thyroid gland were used as an animal model to study the consequences of congenital hypothyroidism. As expected, adequate treatment of these animals with thyroxine restored the general deficits of congenital hypothyroidism; however, Pax8-deficient male mice were infertile. We report here that in these mice, the efferent ducts and epididymides are either absent or the efferent ducts exhibit a reduced lumen and extensive connective tissue, which appears to impair testicular drainage and subsequently leads to complete absence of spermatozoa from the epididymis. The results suggest that, starting with the onset of pubertal testicular fluid secretion, a backpressure is created in the testis by the absence of efferent ducts or constriction of their tubule lumen when present. This subsequently leads to secondary disorganization of the seminiferous epithelium that increases with age, resulting in mixed atrophy of the testis in the adult. Serum testosterone levels as well as mRNA expression of anterior pituitary hormones are in the normal range, indicating that the observed infertility is not due to hormonal imbalance, but rather to a developmental defect of the efferent ducts. The demonstration of Pax8 expression in the epithelia of the epididymis and the efferent ducts suggests a direct morphogenic role of Pax8 in the development of these organs. It remains to be elucidated whether congenital hypothyroid male patients with mutations in the Pax8 gene are similarly affected.

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Ricardo J Samms, Michelle Murphy, Maxine J Fowler, Scott Cooper, Paul Emmerson, Tamer Coskun, Andrew C Adams, Alexei Kharitonenkov, Francis J P Ebling and Kostas Tsintzas

The aim of this study was to investigate the mechanisms by which fibroblast growth factor 21 (FGF21) affects hepatic integration of carbohydrate and fat metabolism in Siberian hamsters, a natural model of adiposity. Twelve aged matched adult male Siberian hamsters maintained in their long-day fat state since birth were randomly assigned to one of two treatment groups and were continuously infused with either vehicle (saline; n=6) or recombinant human FGF21 protein (1 mg/kg per day; n=6) for 14 days. FGF21 administration caused a 40% suppression (P<0.05) of hepatic pyruvate dehydrogenase complex (PDC), the rate-limiting step in glucose oxidation, a 34% decrease (P<0.05) in hepatic acetylcarnitine accumulation, an index of reduced PDC flux, a 35% increase (P<0.05) in long-chain acylcarnitine content (an index of flux through β-oxidation) and a 47% reduction (P<0.05) in hepatic lipid content. These effects were underpinned by increased protein abundance of PD kinase-4 (PDK4, a negative regulator of PDC), the phosphorylated (inhibited) form of acetyl-CoA carboxylase (ACC, a negative regulator of delivery of fatty acids into the mitochondria) and the transcriptional co-regulators of energy metabolism peroxisome proliferator activated receptor gamma co-activator alpha (PGC1α) and sirtuin-1. These findings provide novel mechanistic basis to support the notion that FGF21 exerts profound metabolic benefits in the liver by modulating nutrient flux through both carbohydrate (mediated by a PDK4-mediated suppression of PDC activity) and fat (mediated by deactivation of ACC) metabolism, and therefore may be an attractive target for protection from increased hepatic lipid content and insulin resistance that frequently accompany obesity and diabetes.