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A J Forhead and A L Fowden

The thyroid hormones, thyroxine (T4) and triiodothyronine (T3), are essential for normal growth and development of the fetus. Their bioavailability in utero depends on development of the fetal hypothalamic–pituitary–thyroid gland axis and the abundance of thyroid hormone transporters and deiodinases that influence tissue levels of bioactive hormone. Fetal T4 and T3 concentrations are also affected by gestational age, nutritional and endocrine conditions in utero, and placental permeability to maternal thyroid hormones, which varies among species with placental morphology. Thyroid hormones are required for the general accretion of fetal mass and to trigger discrete developmental events in the fetal brain and somatic tissues from early in gestation. They also promote terminal differentiation of fetal tissues closer to term and are important in mediating the prepartum maturational effects of the glucocorticoids that ensure neonatal viability. Thyroid hormones act directly through anabolic effects on fetal metabolism and the stimulation of fetal oxygen consumption. They also act indirectly by controlling the bioavailability and effectiveness of other hormones and growth factors that influence fetal development such as the catecholamines and insulin-like growth factors (IGFs). By regulating tissue accretion and differentiation near term, fetal thyroid hormones ensure activation of physiological processes essential for survival at birth such as pulmonary gas exchange, thermogenesis, hepatic glucogenesis, and cardiac adaptations. This review examines the developmental control of fetal T4 and T3 bioavailability and discusses the role of these hormones in fetal growth and development with particular emphasis on maturation of somatic tissues critical for survival immediately at birth.

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K L Franko, A J Forhead and A L Fowden

Glucocorticoid administration during pregnancy programmes cardiovascular and metabolic functions in the adult offspring. Often, the control procedures are stressful per se and raise maternal glucocorticoid concentrations. This study compared the effects of maternal injection with dexamethasone (dex, 200 μg/kg) or saline with no treatment from 15 to 20 days of rat pregnancy on offspring growth and glucose metabolism. Near term, maternal corticosterone concentrations were higher in the saline-treated dams and lower in the dex-treated dams relative to untreated animals. In both male and female offspring, growth rate was measured for 14 weeks, and glucose tolerance was assessed between 12 and 13 weeks together with body fat content and plasma concentrations of insulin, leptin, and corticosterone between 14 and 15 weeks. Offspring liver was collected at different ages and was analyzed for glycogen content and gluconeogenic enzyme activity. Compared with untreated animals, both dex and saline treatments altered postnatal growth although adult body weight was unaffected. The two treatments had different effects on adult insulin concentrations and on hepatic glycogen content and gluconeogenic enzyme activities both pre- and postnatally. Relative to untreated animals, adult glucose tolerance was improved by maternal saline injection in males but not in females, while it was impaired in female offspring but not in male offspring of the dex-treated dams. Adult glucose tolerance was related to male body fat content but not to female body fat content. Dex and saline treatments of pregnant rats have differential sex-linked effects on the growth and glucose metabolism of their offspring, which indicates that the programming actions of natural and synthetic glucocorticoids may differ.

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D Smart, A J Forhead, R F Smith and H Dobson

Abstract

The present study was designed to investigate whether transport, a mild environmental stressor, could affect the oestradiol-induced LH surge in postpartum ewes and, if so, the mechanism involved. Welsh Mountain ewes, with lambs removed at parturition (day 0) and hand-milked 12 and 48 h later, were given 50 μg oestradiol benzoate intramuscularly at various times postpartum. Blood samples were taken via an indwelling jugular venous catheter every 2 h from 8 to 24 h after oestradiol injection. All results are given as means ± s.d. On day 1 oestradiol was unable to induce an LH surge in any ewe. Transport (10–14 h after oestradiol) delayed the onset of the oestradiol-induced LH surge on day 14 (17·5 ±1·7 vs 14·4±2·0 h, n=5 each; P<0·05), but not on day 28 (14·9 ±2·0 vs 14·0 ±2·4 h, n=5 out of 7). Transport had no effect on the amplitude of the surge on either day. Naloxone treatment (1 mg/kg per 2 h) was unable to prevent the delay caused by transport (18·0±1·1 vs 17·5 ± 1·7 h, n=8 each), and did not affect the amplitude of the surge (28·4±5·3 vs 28·1 ±2·3 ng/ml, n=8 each). The duration of the LH surges were not assessed. On day 7, transport from 16 to 20 h after oestradiol delayed the LH surge (22·8 ±2·0 vs 18·0 ± 2·8 h, n=8 each; P<0·05) and reduced the surge amplitude (19·7 ±1·7 vs 22·8 ±2·8 ng/ml; P<0·05), whilst transport from 10 to 14 h did not. Transport (16 to 20 h) had no effect on surge duration (6·25 ±0·7 vs 6·75 ± 1·0 h). In conclusion, transport inhibited the oestradiol-induced LH release in the early postpartum ewe by a non-opioidergic mechanism, but only if the stressor occurred within 2–3 h of the expected onset of the surge.

Journal of Endocrinology (1994) 142, 447–451

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A L Fowden, D S Gardner, J C Ousey, D A Giussani and A J Forhead

At birth, the endocrine pancreas becomes more directly involved in the control of glycaemia than in utero. However, compared with other tissues, relatively little is known about the maturational changes that occur in the fetal endocrine pancreas in preparation for extrauterine life. This study examined the pancreatic β-cell response to exogenous administration of glucose and arginine in fetal horses with respect to their gestational age and concentration of cortisol, the hormone responsible for prepartum maturation of other fetal tissues. Glucose administration had no effect on fetal insulin secretion between 175 and 230 days of gestation but evoked a rapid insulin response in fetuses closer to term (290–327 days). In late gestation, the β-cell response was more rapid and greater in magnitude in fetuses with basal cortisol levels higher than 15 ng/ml than in those with lower cortisol values at the time of glucose administration. The fetal β-cell response to arginine was unaffected by the rise in fetal plasma cortisol towards term. These findings show that there are maturational changes in pancreatic β-cell function in fetal horses as cortisol levels rise close to term. Primarily, these prepartum maturational changes were in the mechanisms of glucose-stimulated insulin secretion, which would enable the β cells to regulate glycaemia at the higher glucose levels observed postnatally.

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A L Fowden, J Szemere, P Hughes, R S Gilmour and A J Forhead

Abstract

Using indwelling crown–rump length (CRL)-measuring devices, the growth rate of sheep fetuses was monitored during late gestation and after experimental manipulation of fetal plasma cortisol by exogenous infusion and fetal adrenalectomy. In intact control fetuses, the increment in CRL declined progressively during the last 20–25 days of gestation: mean ± s.e.m. values fell from 5·5 ± 0·4 mm/day (n=12) at 21–25 days before delivery to 2·5 ± 0·3 mm/day (n=12) in the last 5 days before birth (P<0·01). These changes closely parallelled the normal prepartum increase in fetal plasma cortisol which rose from 19·3 ±3·3 nmol/l (n=10) at 21–25 days before birth to 177·4 ± 19·0 nmol/l (n=10) in the final 5 days before delivery (P<0·01). When this cortisol surge was prevented by fetal adrenalectomy, there was no decrease in CRL increment towards normal term: mean CRL increment in the 5 days before normal term (4·8 ± 0·6 mm/day, n=5) was similar to that observed at 21–25 days before term (4·7 ± 0·4 mm/day, n=5). At delivery at term, the body weight (4·116 ± 0·280 kg, n=5) and CRL (51·9 ± 1·7 cm, n=5) of the adrenalectomized fetuses were significantly greater than the corresponding values in their sham-operated controls (2·877 ± 0·070 kg and 47·1 ±1·6 cm, n=6, respectively). In contrast with the sham-operated controls, plasma glucose and insulin levels in the adrenal-ectomized fetuses decreased towards term. Infusion of cortisol into the preterm fetus for 5 days increased fetal plasma cortisol to term levels and decreased the CRL increment to a value (1·8 ± 0·5 mm/day, n=8) which was similar to that observed in untreated controls during the last 5 days before spontaneous delivery at term (2·1 ± 0·3 mm/day, n=6). There were no significant alterations in the fetal arterial concentrations of plasma glucose or insulin in response to fetal cortisol infusion. When all the data were combined irrespective of treatment or proximity to delivery, the fetal plasma concentrations of cortisol (P<0·001) and glucose (P<0·04), but not insulin (P>0·05), had a significant effect on the fetal CRL increment measured over 5-day periods during the last 25–30 days of gestation. These findings show that cortisol inhibits growth of the axial skeleton in the sheep fetus during late gestation. They also indicate that the prepartum cortisol surge may be responsible for the normal decline in fetal growth rate observed towards term in this species.

Journal of Endocrinology (1996) 151, 97–105

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K L Franko, D A Giussani, A J Forhead and A L Fowden

Fetal glucocorticoids have an important role in the pre-partum maturation of physiological systems essential for neonatal survival such as glucogenesis. Consequently, in clinical practice, synthetic glucocorticoids, like dexamethasone, are given routinely to pregnant women threatened with pre-term delivery to improve the viability of their infants. However, little is known about the effects of maternal dexamethasone treatment on the glucogenic capacity of either the fetus or mother. This study investigated the effects of dexamethasone treatment using a clinically relevant dose and regime on glycogen deposition and the activities of glucose-6-phosphatase (G6Pase) and phosphoenolpyruvate carboxykinase (PEPCK) in the liver and kidney of pregnant ewes and their fetuses, and of non-pregnant ewes. Dexamethasone administration increased the glycogen content of both the fetal and adult liver within 36 h of beginning treatment. It also increased G6Pase activity in the liver and kidney of the fetuses but not of their mothers or the non-pregnant ewes. Neither hepatic nor renal PEPCK activity was affected by dexamethasone in any group of animals. These changes in glycogen content and G6Pase activity were accompanied by rises in the plasma glucose and insulin concentrations and by a fall in the plasma cortisol level in the fetus and both groups of adult animals. In addition, dexamethasone treatment raised fetal plasma tri-iodothyronine (T3) concentrations and reduced maternal levels of plasma T3 and thyroxine, but had no effect on thyroid hormone concentrations in the non-pregnant ewes. These findings show that maternal dexamethasone treatment increases the glucogenic capacity of both the mother and fetus and has major implications for glucose availability both before and after birth.

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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.