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Untreated maternal hypothyroidism (hypoT) has serious consequences in offspring development that may result from the effect on lactation of maternal metabolism dysfunction. We studied the effects of prolonged propylthiouracyl (PTU)-induced hypoT (0.1% PTU in drinking water starting 8 days before mating until day 21 of pregnancy or for 30 days in virgin rats) on liver and mammary lipid metabolism and serum lipid concentrations. In virgins, hypoT reduced hepatic mRNAs associated with triglyceride (TG) and cholesterol synthesis (including fatty acid synthase and 3-hydroxy-3-methylglutaryl coenzyme A reductase), and induced lobuloalveolar mammary development. Thyroid hormones influence all major metabolic pathways. Their most obvious and well-known action is an increase in basal energy expenditure through actions on protein, carbohydrate, and lipid metabolism. With specific regard to liver lipid metabolism, thyroid hormones stimulate fatty acid and cholesterol synthesis (1, 2), increase mobilization of plasma cholesterol and triglycerides (TGs) (3, 4), and stimulate fatty acid and cholesterol degradation (5, 6). Disturbances in thyroid function are commonly associated with alterations in plasma lipid levels. Experimental hypothyroidism (hypoT) induced by propylthiouracyl (PTU) treatment is characterized by the accumulation of plasma LDL cholesterol, and decreased VLDL and plasma TGs (7), generally reflecting reduced binding activity of the hepatic LDL receptor (LDLR), which can be normalized after substitution therapy with thyroid hormone (3,8).Pregnancy is a state of dynamic changes in metabolism and nutrient utilization. The insulin-resistant condition and the increase in plasma estrogen levels occurring during late pregnancy are the main factors responsible for the development of a state of maternal hypertriglyceridemia that has been extensively studied in humans and rats (9)(10)(11). This condition benefits the progeny in two ways. First, it supplies essential fatty acids that are critical to normal fetal development and that circulate primarily esterified and associated with lipoproteins. A linear correlation between maternal and fetal plasma TGs has been described that has an important implication in newborn weight (12, 13). Second, it contributes to milk synthesis in preparation for lactation, providing circulating TG in the form of lipoprotein to the mammary gland (MG) for milk lipid synthesis (9).It has been demonstrated that the induction of hypothyroidism in dairy cows suppresses milk production during the treatment period (14). On the other hand, ad-

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HypoT produces a drastic decrease in milk TGs; the main cause for this seems to be the decreases in liver TG synthesis and in circulating TGs, which, along with reduced mammary uptake of fatty acids caused by decreased LPL expression and possibly diminished mammary lipogenesis, result in an impaired mammary output of TGs to the milk. Thus, the impaired growth of the litters of HypoT mothers can be largely attributed to the low milk quality along with the impaired milk ejection.

The aim of this study was to examine, using semiquantitative reverse transcriptase-polymerase chain reaction (RT-PCR) the changes in mRNA expression of the two estrogen receptor (ER) subtypes, ERalpha and ERbeta, prolactin receptor long and short form, and progesterone (Pg) receptor (PgR), in liver and mammary gland during gestation, early lactation, and weaning in both hyperthyroid (HT) and normal rats. Pregnancy increased long prolactin receptors (PRL-R(L)) and ERalpha mRNAs in liver and PRL-R(I) in mammary gland. Lactation decreased PRL-R(L) in liver and ERbeta and PgR in mammary gland. HT decreased PRL-R(L), at the end of pregnancy (G21), ERalpha (in G21 and L1) in liver and PRL-R(L) in L1 as well as short prolactin receptors (PRL-R(S)) (G7, L1) and ERbeta (G7, G14, L4) in mammary gland. In conclusion, our data indicated that (1) PRL-R1 and ERalpha expression levels are differentially regulated in the liver, and PgR and ERbeta in mammary gland during pregnancy and lactation (2) ERbeta is variably expressed depending on the state of thyroid hormones, however the ERalpha gene expression remained constant in mammary gland. (3) PRL-R1 mRNA expression is highly induced in the mammary gland during late pregnancy and abruptly declines on the first day of lactation for the HT rats.

This study investigated the influence of chronic hyperthyroidism on mammary function in lactating rats and the effects on their pups. Thyroxine-treated (10 microg per 100 g body weight per day; hyperthyroid (HT)) or vehicle-treated rats were mated 2 weeks after the start of treatment and killed with their litters on days 7, 14 and 21 of lactation. Serum concentrations of triiodothyronine (T(3)) and tetraiodothyronine (T(4)) increased in thyroxine-treated rats. In HT mothers, serum prolactin decreased on day 7 and day 14 of lactation, whereas insulin-like growth factor I (IGF-I) and progesterone concentrations decreased, and corticosterone increased on day 7 of lactation. In HT pups, T(4) concentration increased on day 7 and day 14 of lactation, whereas T(3) increased only on day 14 of lactation, and growth hormone increased on day 7 of lactation. Mammary prolactin binding sites did not vary, but there was an increase in the binding sites in the liver on day 14 of lactation in thyroxine-treated rats. In an acute suckling experiment, thyroxine-treated rats released less oxytocin, growth hormone and prolactin and excreted less milk than did control rats. Mammary casein, lactose and total lipid concentrations in thyroxine-treated rats were similar to those of control rats on day 14 of lactation. Histological studies of the mammary glands showed an increased proportion of alveoli showing reduced or no lumina and cells with condensed nuclei on day 14 and day 21 of lactation; the TdT-mediated dUTP nick-end labelling (TUNEL) test revealed an increase in apoptosis in alveolar cells on day 21 of lactation in thyroxine-treated rats. Expression of SGP-2, a gene expressed during mammary involution, increased in thyroxine-treated rats on day 14 and day 21 of lactation, whereas expression of insulin-like growth factor binding protein 5, a proapoptotic signal, was unchanged. Bcl-2, which promotes survival of mammary gland epithelial cells was unchanged, whereas expression of IGF-I, which also promotes survival of mammary gland epithelial cells, increased on day 21 of lactation in thyroxine-treated rats. These results indicate that thyroxine treatment produces some milk stasis as a result of impairments in suckling induced release of oxytocin that may initiate the first stage of mammary involution, increasing apoptosis in a gland that is otherwise actively producing and secreting milk.

The effect of acute and chronic hyperthyroidism was studied in serum and liver lipids in rats. Wistar adult female rats were separated into three groups. The first group, injected with saline solution was used as control (Co), while the second and third were injected daily with tetraiodothyronine (T4) 10 microg/100 g body weight; the second group (HT-I) for one week and the third group (HT-II) for five weeks. In HT-I, serum T4 level was higher than in HT-II. Triiodothyronine (T3) concentration increased in HT-I and HT-II. The serum triglyceride concentration increased in HT-II in relation to HT-I and Co groups. Serum total cholesterol, HDL-cholesterol and bile acids did not vary among the three groups. LDL cholesterol fraction was lower in HT-I and HT-II than in Co group. In the liver, total and free cholesterol (FC) concentrations decreased in HT-I, but both increased in HT-II, in relation to Co. Esterified cholesterol did not change among the three groups. Liver triglyceride (TG) mass decreased in HT-I and HT-II in relation to Co, but it was higher in HT-II than in HT-I. Hepatic fatty-acid synthase (FAS) and acetyl-CoA carboxylase (ACC) activities increased in HT-I and HT-II in relation to Co and there were no differences between HT-I and HT-II. The incorporation of [3H]-H2O into esterified cholesterol did not differ significantly among the groups, while its incorporation into FC decreased and into TG increased in HT-I and HT-II, in relation to Co. The effect of T4 on the amount and turnover of lipids is affected by the time of hormone administration, but the increase of FAS and ACC activities was the same for both times studied.

Two per thousand pregnant women have hyperthyroidism (HT), and although the symptoms are attenuated during pregnancy, they rebound after delivery, affecting infant development. To examine the effects of hyperthyroidism on lactation, we studied lipid metabolism in maternal mammary glands and livers of hyperthyroid rats and their pups. Thyroxine (10 microg/100 g body weight/d) or vehicle-treated rats were made pregnant 2 wk after commencement of treatment and sacrificed on days 7, 14, and 21 of lactation with the litters. Circulating triiodothyronine and tetraiodothyronine concentrations in the HT mothers were increased on all days. Hepatic esterified cholesterol (EC) and free cholesterol (FC) and triglyceride (TG) concentrations were diminished on days 14 and 21. Lipid synthesis, measured by incorporation of [3H]H2O into EC, FC, and TG, fatty acid synthase, and acetyl CoA carboxylase activities increased at day 14, while incorporation into FC and EC decreased at days 7 and 21, respectively. Mammary FC and TG concentrations were diminished at day 14; incorporation of [3H]H2O into TG decreased at days 7 and 21, and incorporation of [3H]H2O into FC increased at day 14. In the HT pups, growth rate was diminished, tetraiodothyronine concentration rose at days 7 and 14 of lactation, and triiodothyronine increased only at day 14. Liver TG concentrations increased at day 7 and fell at day 14, while FC increased at day 14 and only acetyl CoA carboxylase activity fell at day 14. Thus, hyperthyroidism changed maternal liver and mammary lipid metabolism, with decreased lipid concentration in spite of increased liver rate of synthesis and decreases in mammary synthesis. These changes, along with the mild hyperthyroidism of the litters, may have contributed to their reduced growth rate.