For some years, research in the field of growth endocrinology has been mainly focused on growth hormone (GH). However, it appears that GH does not always control growth rate. For instance, it does not clearly influence intra-uterine growth: moreover, although the results of GRF or GH administration appear convincing in rats, pigs or heifers, this is not the case in chickens and lambs. In addition, GH does not always clearly stimulate somatomedin production, particularly diring food restriction and fetal life, and in hypothyroid animals or sex-linked dwarf chickens. In such situations, this phenomenon is associated with a reduced T3 production, suggesting a significant influence of thyroid function on GH action, and more generally, on body growth. In fact, numerous data demonstrate that thyroid hormone is strongly involved in the regulation of body growth. In species with low maturity at birth, such as the rat. T4 and T3 affect postnatal growth eleven days earlier than the appearance of GH influence. In contrast to GH, thyroid hormone significantly influences fetal growth in sheep. Moreover, the body growth rate is clearly stimulated by T3 in dwarf animals. In addition to its complex metabolic effects involved in the general mechanisms of body growth, thyroid hormone stimulates the production of growth factors, particularly EGF and NGF. Moreover, it affects GH and somatomedin production and also their tissue activity. All these results strongly suggest that it would be difficult to study GH regulation and physiological effects without taking thyroid function into account.

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Thyroid hormone and growth: relationships with growth hormone effects and regulation

Polychlorinated biphenyls (PCB) are industrial chemicals linked to developmental deficits that may be caused in part by disrupting thyroid hormone (TH) action by either reducing serum TH or interacting directly with the TH receptor (TR). Individual PCB congeners can activate the TR in vitro when the metabolic enzyme cytochrome P4501A1 (CYP1A1) is induced, suggesting that specific PCB metabolites act as TR agonists. To test this hypothesis in vivo, we compared two combinations of PCB congeners that either activate the TR (PCB 105 and 118) or not (PCB 138 and 153) in the presence or absence of a PCB congener (PCB 126) that induces CYP1A1 in vitro. Aroclor 1254 was used as a positive control, and a group treated with propylthiouracil was included to characterize the effects of low serum TH. We monitored the effects on TH signaling in several peripheral tissues by measuring the mRNA expression of well-known TH-response genes in these tissues. Aroclor 1254 and its component PCB 105/118/126 reduced total T4 to the same extent as that of propylthiouracil but increased the expression of some TH target genes in liver. This effect was strongly correlated with CYP1A1 expression supporting the hypothesis that metabolism is necessary. Effects were gene and tissue specific, indicating that tissue-specific metabolism is an important component of PCB disruption of TH action and that PCB metabolites interact in complex ways with the TR. These are essential mechanisms to consider when evaluating the health risks of contaminant exposures, for both PCB and other polycyclic compounds known to interact with nuclear hormone receptors.

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Individual Polychlorinated Biphenyl (PCB) Congeners Produce Tissue- and Gene-Specific Effects on Thyroid Hormone Signaling during Development

The contents of immunoreactive somatostatin (IR-SRIF) and β-endorphin (IR-β-EP) in 12 brain regions were examined in rats exposed neonatally to propylthiouracil (PTU) through the mother's milk. Since the dose of PTU used in this study is lower than the usual dose employed to induce hypothyroidism, a milder form of neonatal hypothyroidism resulted. This conclusion is supported by the only mild subnormal growth of rats to adulthood and serum T4 and T3 concentrations in the normal range. Adult rats treated with PTU neonatally had significantly higher IR-SRIF contents in several brain regions compared to controls, whereas IR-β-EP levels were not significantly different (significant increase only in the thalamus) in most regions. The results indicate that even mild hypothyroidism during early postnatal development causes permanent impairment of brain function, which manifests itself in part by an altered brain content of IR-SRIF.

Immunoreactive somatostatin and. beta. -endorphin content in the brain of mature rats after neonatal exposure to propylthiouracil

There is now a large literature to support the view that thyroid hormones have little role in fetal growth and development (1–5). Athyroid human newborns have few if any signs of their chemical hypothyroidism, and length, weight and head circumference at birth are normal for gestation age. Moreover, IQ and neurological function parameters are normal in the vast majority of hypothyroid newborns detected by chemical screening and treated in the early neonatal period (6,7). Selected intrauterine effects of thyroid hormone deficiency have been recognized. Serum TSH concentrations are regularly elevated at birth in hypothyroid infants indicating active negative feedback control of pituitary TSH secretion by thyroid hormone in utero (2–5,8). Also, newborn thermogenesis may be mildly impaired, and the fall in body temperature in the athyroid human infant may be more marked than in a normal, euthyroid neonate (2–4). Thermogenesis in the newborn is largely a function of brown adipose tissue (BAT), and recent evidence in the sheep suggests that norepinephrine-stimulated oxygen consumption in newborn BAT is obtunded by hypothyroidism (9,10).

Maturation of Thyroid Hormone Actions

The effects of thyroid hormone deficiency on serum levels and liver messenger RNA (mRNA) expression of insulin-like growth factors (IGFs) were studied in neonatal (until 20 days of life), weaned (22–37 days), and adult (72–87 days) rats, short periods (5, 10, and 15 days) after thyroidectomy (T). Serum levels and liver mRNA expression of IGF-I, plasma and pituitary GH, plasma insulin, and glycemia were measured in all populations; and serum levels and liver mRNA expression of IGF-II were measured only in the neonatal populations. Surprisingly, plasma insulin and GH and serum and liver mRNA expression of IGF-I were found elevated in T neonatal rats, and they decreased in weaned and adult rats and in neonatal rats rendered hypothyroid by mercapto-1-methylimidazole (MMI) treatment (MMI-hypothyroid). T and MMI-treatment of neonatal rats disturbed the normal pattern of progressive decrease of IGF-II with age. A positive correlation between insulin and IGF-I and a poor correlation between GH and IGF-I were foun...

Mechanism of hypothyroidism action on insulin-like growth factor-I and -II from neonatal to adult rats: insulin mediates thyroid hormone effects in the neonatal period.

The developmental profiles of hypothalamic somatostatin and pituitary and serum growth hormone (GH) concentrations were examined in rats exposed chronically to a low iodine diet or propylthiouracil. Hypothalamic somatostatin and pituitary and serum GH concentrations were similar during development in control and low-iodine-diet animals. Propylthiouracil-induced hypothyroidism, however, was associated with reduced hypothalamic somatostatin and pituitary and serum GH concentrations, the latter being undetectable after 6 days. These data indicate that hypothalamic control of GH secretion is unaltered in low-iodine-diet rats who maintain an euthyroid status by preferential triiodothyronine (T3) production. The marked derangements observed in the hypothyroid animals indicate that thyroid hormones are critical for the postnatal maturation of the GH regulatory mechanism.

Hypothalamic somatostatin and pituitary and serum growth hormone concentrations during postnatal development in rats exposed chronically to propylthiouracil or a low iodine diet.

Dussault Jh

Papers

Hypothalamic somatostatin and pituitary and serum growth hormone concentrations during postnatal development in rats exposed chronically to propylthiouracil or a low iodine diet.