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Presence of thyroxine deiodinases in mammary gland: possible modulation of the enzyme-deiodinating activity by somatotropin☆
Domestic Animal Endocrinology 17 (1999) 161–169
Presence of thyroxine deiodinases in mammary gland: possible modulation of the enzyme-deiodinating activity by somatotropin夞 A.B. S´lebodzin´ski*, E. Brzezin´ska-S´lebodzin´ska, E. Styczyn´ska, M. Szejnoga Institute of Animal Reproduction and Food Research, Polish Academic Science, Department of Developmental and Experimental Endocrinology, ul. Grunwaldzka 250, 60-166 Poznan, Poland Received 5 February 1999; accepted 5 February 1999
Abstract Thyroid hormones (TH) and somatotropin (ST) play critical role in lactation. One explanation of their multiple physiological actions is based on the functional interrelationships among ST, TH, and thyroxin deiodinase (5⬘D). This enzyme is present in the mammary tissue, milk cellular components, and whole milk and is responsible for intramammary production of triiodothyronine (T3). In rats in which the 5⬘D isozymes in the mammary gland and in the liver are similarly of type I (5⬘D-I), an enhancement of mammary 5⬘D-I causes a reduction of hepatic 5⬘D-I activities. This opposite rearrangement in the mammary and hepatic deiodinating activities is thought to be a factor of a homeorhetic response characterized by an increased and compartmentalized energy expenditure of the mammary gland. In the cow, the mammary 5⬘D is the type II (5⬘D-II) deiodinase. The 5⬘D-II, owing to its high catalytic efficiency, secures T3 production, making tissues relatively independent from the circulatory levels of TH and from variations in the hepatic 5⬘D-I activity. No significant alterations of 5⬘D-II isozymes were found during a low T3 syndrome. Location of tissue deiodinases in the cow, the 5⬘D-II in the mammary gland, and the 5⬘D-I in the liver make it so that T3 production in these two tissues can be dissociated in time to secure better local requirement for T3 supporting lactation. To date, attempts to evidence that the alterations in iodothyronines blood levels and in tissues’ 5⬘Ds activity during lactation are due to ST action have not received clear experimental support in either cows or rats. © 1999 Elsevier Science Inc. All rights reserved.
夞 This research was supported in part by the State Committee for Scientific Research, Grant No. 5P06D 04810. * Corresponding author. Tel.: ⫹48-61-8689764; fax: ⫹48-61-8689764. E-mail address: [email protected] (A.B. S´lebodzin´ski) 0739-7240/99/$ – see front matter © 1999 Elsevier Science Inc. All rights reserved. PII: S 0 7 3 9 - 7 2 4 0 ( 9 9 ) 0 0 0 3 3 - 8
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Keywords: Somatotropin; Thyroxine deiodinase; Mammary gland
1. Thyroid hormones in mammary secretion Variations in uptake and concentrations of thyroid hormone (TH) among tissues are explained by differences in cellular specific binding power, capillary circulation, and the plasma membrane carrier system [1]. Presence of specific thyroxine (T4) receptors in bovine mammary cytosol has been demonstrated [2], but the mechanism by which TH are transported across the blood–mammary gland barrier is unknown. At first, the TH in milk were thought to originate entirely from circulating hormones. Based on the assumption that transfer of TH from general circulation is their only source in milk, the total amount of T4 and triiodothyronine (T3) “transferred to milk” on a daily basis was estimated by Akasha and Anderson [3]. Reported contents of iodothyronines in milk vary considerably. Amounts of T4 or reverse triiodothyronine (rT3) reported in human milk range from none to very low. In contrast, T3 was reported frequently in easily measurable amounts, but quoted levels differed from 7 to 386 ng of T3/100 mL of milk [7,8]. These contradictory findings were thought to be due to differences in analytical methods, originally developed for TH determination in serum and not suited for TH determination in milk [7]. By means of analytical procedure developed for direct radioimmunoassay of TH in milk [9], it is possible to measure iodothyronines in concentrations in close agreement with that estimated by gas chromatography–mass spectrometry [10]. Compared with the TH concentration in blood, the T4 in milk represents a small fraction (⬇1/30) of that in serum, and T3 in milk approximates levels from 1/3 of that in serum, with a great differences across species. In sheep and in rabbits, T3 in individual milk samples may be twice as high as in serum. Four hours after injection of tracer amounts of (125I)-labeled T4 or T3, milk/serum ratios in lactating rabbits were ⬇0.3 for T4 and from 1.2 to 2.8 for T3 [11]. This indicates that the differences between T4 and T3 milk content might reflect different permeability of the blood–mammary barrier toward T4 and T3. On the other hand, rT3, which is in a very low concentration or is absent in the rabbit milk, passes easily from blood into milk, exceeding up to seven times the blood concentration at the 5th hour after a pharmacological dose of rT3 [9]. Under a majority of circumstances, T3 levels in milk are poorly related to its simple diffusion down a concentration gradient. Except in early lactation, there is no relationship between the T3 concentration in serum and milk in correlated samples from lactating women [12] and animals.
2. Thyroid hormone deiodination in the mammary gland A constant relationship between T3 concentrations in serum and milk is lacking, and T3 levels are often higher in milk than in serum. This, together with the low T3 content in mastitis milk (discussed below), inclined us to assume that iodothyronines are degraded
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within the mammary gland in a process resulting in low or undetectable concentrations of T4 and rT3 in milk. On the contrary, the T3 often in concentrations higher in milk than in blood serum was assumed to reflect a local or intramammary generation of T3 from T4. In 1989, the presence of a TH deiodinating system in the mammary gland tissue of rats and cows and in the milk of sows and cows was revealed independently by three groups of researchers [13–15]. In agreement with the earlier observations and assumption, the differences in iodothyronines concentrations in milk were proved to be associated with the intramammary generation of T3 from T4 [16]. By using different pH optima and the optimal reagent concentrations, it became possible to quantify degradation of T4 to T3 and rT3 in milk [12]. The ability to degrade thyroxine to T3 or to rT3 was thought to be accounted for low or undetectable T4 milk levels. Since rT3 is a preferred substrate for outer ring deiodination, and deiodinating efficiency is several times higher with rT3 over T4 as the substrate [17], concentrations of rT3 may not be available for quantification in an assay. On the other hand, presence of measurable quantities of the T3 in milk is explained by the fact that T3, despite being degraded in milk, is transferred simultaneously into milk from the blood and generated enzymatically from T4 within the mammary gland [12]. Inflammation of the mammary tissues (mastitis) significantly reduces milk T3 content [12]. A decreased T3 concentration and milk 5⬘-deiodinase (5⬘D) activity is a frequent feature of milk sampled from quarters showing inflammation but not of milk from healthy quarters of the same cow. Such a situation seems to reflect individual quarters’ reactivity to exogenous or endogenous factors. This observation is the first indication of a direct relationship between the mammary deiodinase(s) activity and the T3 concentration in milk (A.B. Slebodzinski, unpublished study).
3. Types of deiodinases in the mammary gland and during lactation Following the study on the presence of the mammary 5⬘D activity in the rat [18], further evidence was published by Acceves and Valverde [13], demonstrating that the mammary enzyme corresponds to the type I 5⬘-deiodinase (5⬘D-I), namely to the hepatic 5⬘D-I propylthiouracil (PTU)-sensitive 5⬘-deiodinase. These authors noted decreased circulating levels of T4 and T3, increased rT3, and reduced hepatic 5⬘D-I with simultaneous increased mammary 5⬘-D. On the basis of these findings, they proposed that the opposite rearrangement in the mammary and hepatic 5⬘-deiodinases is a major component of the homeorhetic response, characterized by an increased and compartmentalized energy expenditure of the mammary gland during lactation in the rat [18]. This interpretation is in accordance with the finding that the mammary and the hepatic 5⬘Ds are both of the same type I enzyme. It fits with the notion that thyroid status is the predominant regulator of 5⬘D-I activity in the rat [19]. More recently, the same authors [20] have presented data that the 5⬘D-I is specific to the alveolar epithelium and exists within the rat mammary gland only when the gland is in functional state (lactation) or when the alveolar epithelium is differentiating (puberty or late pregnancy). In the rat, expression of 5⬘D-I mRNA in the mammary gland, liver, kidney, and thyroid gland suggests that the 5⬘D in the lactating mammary gland is encoded by mRNA different
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from the 5⬘D-I activity found in the other tissues [21]. Such a situation implies the possibility of a differential regulation of 5⬘D-I activity in various tissues within the same species. The decrease in hepatic type 5⬘D-I activity during lactation observed in rats [18,22] is likely to be therefore a part of adjustment allowing enhanced activity of the same type 5⬘D-I in peripheral mammary gland, which would increase the local production of T3 to support the high energy expenditure that characterizes lactation. Such a conclusion gained from experiments in lactating rats gives, however, no evidence that similar interrelation between the hepatic and mammary 5⬘monodeiodinases exists in cows, particularly in the view of the fact that the type II and not 5⬘D-I deiodinase is characteristic and is the most abundant deiodinase in the mammary gland in cows. Under conditions that favor different types of thyroxine deiodination, it has been found that, unlike in rats, the 5⬘-monodeiodinase of type II (PTU-resistant 5⬘D-II) predominates in the mammary gland tissue of lactating cows and pigs [12,23]. This type of deiodinase is present in limited number of tissues only (brain, anterior pituitary, brown adipose tissue, placenta, pineal gland, and seminal plasma), where it is involved in production of T3 for local needs (for review see ref. [19]) and most probably plays a significant role in paracrine signaling, whereas the hepatic (and kidney) type 5⬘D-I monodeiodinating activity is a major source of circulating T3 [24]. The type II 5⬘D activity was found in both in the mammary tissue and in paralleled milk samples. In pig milk, deiodinating activity converting T4 to T3 and T4 to rT3, by milk cellular components (the epithelial cells, macrophages, lymphocytes, and granulocytes), was described additionally [12,25]. Response of 5⬘D-II-like activity in milk to well known 5⬘monodeiodinase inhibitors (amiodarone, iopanoic acid, aurothioglucose, and PTU) varies greatly across species, which seems to indicate existing differences in biochemical characteristics of 5⬘D-II in various species. The lowest inhibition of milk deiodinating activity by PTU (⬇10%), was found in cow and human milk, moderate (⬇40 –50%) in the sow and rabbit, and the highest (⬇90%) in rat milk (unpublished results). Most recently, we have found that, in mare’s milk, at least two types of 5⬘-D exist that show some characteristics of type II (⬇50%) [26]. On comparative grounds, existence of both 5⬘-deiodinases (type I and II like) in the same tissue is well known, for instance, in rat pituitary or brain [27]. Different 5⬘Ds also are known to exist in the same tissue but in different species: 5⬘D-I in bovine brown adipose tissue and type II 5⬘D in bovine brown adipose tissue of rodents [28,29]; type 5⬘D-I as the only type in the rat lactating mammary gland [13] and type II 5⬘D as primarily the main type in the cow mammary gland [12]. As generally recognized, type 5⬘D-II, owing to its higher catalytic efficiency than 5⬘D-I, can produce a significant amount of T3 from a considerably smaller T4 pool [30]. In the target tissues, type II 5⬘D secures a high production and prolonged residence time of locally generated T3 [30]. The major consequence of different tissue localizations of both types of deiodinases for T3 economy, as exemplified by studies in rats, is that the 5⬘D-II-deiodinating mechanism accounts for ⬇80% of locally produced T3 in the cerebral cortex whereas the 5⬘D-I-deiodinating mechanism accounts for ⬇20% in the liver [31]. Moreover, the highly efficient T3 production by 5⬘D-II, together with T3 uptake from plasma and T3 disposal rates, allows a homeostatic response to both hypo- and hyper-iodothyroninemias [31]. By analogy to 5⬘D-II activity and significance for the T3 economy in other tissues, the
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presence of the 5⬘D-II in mammary gland of domestic animals implies that the mammary deiodinating system is most probably highly independent from the temporary variations in circulating TH levels and indirectly from the hepatic 5⬘D-I activity. Moreover, by efficient local production of T3, the mammary 5⬘D-II is most likely to be able to respond homeostatically to variations in TH blood levels occurring during so-called low-T3 syndrome, which is characterized by decreased T3, elevated rT3, and usually normal T4 [32]. Such a syndrome was described during early lactation both in rats and cows and has been classified as euthyroid sick syndrome [18,33].
4. Somatotropin and mammary gland deiodinases Growth hormones (GH) long have been recognized as a homeorhetic key factor controlling efficiency of nutrient partitioning [34,35] and their use for galactopoietic response. Although GH-receptor gene expression is present in the mammary gland tissue [36], it is widely accepted that the GH endocrine effect on the mammary cells is primarily indirect through an increased circulating level of IGF-I of hepatic origin [37–39]. The fact that increasing systemic concentrations of IGF-I do not always alter milk yield [40,41] reflects multiplicity of galactopoietic action of growth hormone. The IGFs can be synthesized within the mammary gland; however, the contribution of the milk-borne IGF production generally is considered as low relative to hepatic synthesis. In the rat, in which the IGF-I was proved to be synthesized in the mammary gland, the mRNA for IGF-I increases after treatment with GH [42]. In primary bovine mammary epithelial cells, IGF-I mRNA was not detected. IGF-II is considered to be the major IGF synthesized by bovine mammary epithelial cells [43]. Nevertheless, the hepatic and/or mammary IGF-I and IGF-II both bind with high affinity to the type of mammary IGF receptors that show structural similarities to the type I and type II IGF receptors [44,45]. In the rat, the activity of 5⬘D-I in various tissues was shown to be significantly influenced by growth hormone; however, to our knowledge there is no experimental evidence of the effects of GH on the 5⬘D-I in the mammary gland of lactating rats. However, it has been shown that lactating rats normally display: low serum T4 and T3 paralleling a decreased 5⬘D-I activity in liver and kidney [18,22,46], an inverse relationship between lactational intensity and 5⬘D activity in liver and kidney [47], and a positive relationship between mammary gland 5⬘D and lactation intensity [21]. These data convincingly indicate the importance of the extrathyroidal T4 to T3 converting activity for metabolic adjustment to support lactation. In cattle, administration of recombinant somatotropin (r-bST) results in no or moderate changes in the classic hormone blood levels. Chronic treatment with r-bST (injections 500 mg, every 2 wk), starting on 60 ⫾ 3 days postpartum and continued till the middle of lactation, evokes no changes in baseline of total thyroxine, free T4, T3, prolactin, follicle stimulating and luteinizing hormones, estradiol and progesterone but does change adrenocorticotropic hormone (ACTH) levels. Target tissue responses affected by bST treatment appeared to be ACTH and ovarian progesterone output [48]. In similar studies in lactating cows, average concentrations of T4, T3 and insulin were not changed during bST treatment
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[49]. Observations performed during the middle of lactation (cows given infusion of r-bST; 29 mg/day for 63 days) showed that bST decreased concentrations of T3 by 10% as a result of decrease in the hepatic 5⬘D activity. However, this response was not paralleled by either changes in the T3 milk concentration nor in the mammary gland 5⬘-deiodinase activity [50]. To date, in none of reported experiments in cattle, a shift in serum T4, T3 and rT3 concentrations, resembling the euthyroid sick-like syndrome, occurring naturally during early lactation in cows [33], was evoked with bST treatment. In studies in human beings, recombinant hGH administered as daily injections or continuous infusion to adult patients with GH deficiency caused an increase in serum concentrations of free-T3 and total-T3 and a decrease in free T4 to a similar degree (total T4 being unchanged), independently of the mode of GH administration [51]. Results of combined administration of GH and T3 (T3 in the dose selected to mimic the T3 increase seen during hGH exposure) to healthy adults (for 10-day treatment periods) increased free-T3 levels. From the obtained results, the authors were inclined to conclude that GH and T3 in the physiological range exert distinct but disparate effects on lipids and lipoproteins and do not support the hypothesis that the effects observed during GH administration are exclusively secondary to changes in peripheral T3 levels [52]. Increased activity of 5⬘D in lactating mammary tissue of the cow receiving r-bST has been presented by Capuco et al. [14]. In this study, an acute effect of r-bST (given to six nonpregnant lactating cows; daily injection of 40 mg for 5 days during late lactation) evoked a nearly 2-fold increase in mammary 5⬘D activity. There was no change in serum concentrations of T4 and T3 in bST-treated cows, in agreement with previous data [53]. However, the next report from the same center showed a decrease in serum concentration of T3 and a lack of alterations in the mammary 5⬘D in lactating cows (in the midlactation) receiving infusion of bST [50]. The authors’ conclusion that bST increased the hypothyroid status of the lactating cows and maintained an euthyroid condition in the mammary gland by organspecific changes in 5⬘D activity [50], although interesting, has at present scarce and controversial experimental support. Having similar mammary 5⬘D of type II as the cow, the rabbit seems to be a good model for comparative studies on effects of GH on 5⬘D activity in mammary gland. Our preliminary studies show that r-bST (Sometribove威) administrations to rabbits lower plasma urea and total-T4 concentration in blood; the bST effects on level of T3 and 5⬘Ds activity in milk were so far inconclusive. It may be concluded at this point that, although in farm animals growth hormone acts as a factor controlling partitioning of nutrients and thyroid hormones together with type II 5⬘-deiodinase act as factors controlling maintenance and intensity of lactation, the functional interrelations among the factors underlying their positive role for lactation are still imperfectly understood.
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Presence of thyroxine deiodinases in mammary gland: possible modulation of the enzyme-deiodinating activity by somatotropin夞 A.B. S´lebodzin´ski*, E. Brzezin´ska-S´lebodzin´ska, E. Styczyn´ska, M. Szejnoga Institute of Animal Reproduction and Food Research, Polish Academic Science, Department of Developmental and Experimental Endocrinology, ul. Grunwaldzka 250, 60-166 Poznan, Poland Received 5 February 1999; accepted 5 February 1999
Abstract Thyroid hormones (TH) and somatotropin (ST) play critical role in lactation. One explanation of their multiple physiological actions is based on the functional interrelationships among ST, TH, and thyroxin deiodinase (5⬘D). This enzyme is present in the mammary tissue, milk cellular components, and whole milk and is responsible for intramammary production of triiodothyronine (T3). In rats in which the 5⬘D isozymes in the mammary gland and in the liver are similarly of type I (5⬘D-I), an enhancement of mammary 5⬘D-I causes a reduction of hepatic 5⬘D-I activities. This opposite rearrangement in the mammary and hepatic deiodinating activities is thought to be a factor of a homeorhetic response characterized by an increased and compartmentalized energy expenditure of the mammary gland. In the cow, the mammary 5⬘D is the type II (5⬘D-II) deiodinase. The 5⬘D-II, owing to its high catalytic efficiency, secures T3 production, making tissues relatively independent from the circulatory levels of TH and from variations in the hepatic 5⬘D-I activity. No significant alterations of 5⬘D-II isozymes were found during a low T3 syndrome. Location of tissue deiodinases in the cow, the 5⬘D-II in the mammary gland, and the 5⬘D-I in the liver make it so that T3 production in these two tissues can be dissociated in time to secure better local requirement for T3 supporting lactation. To date, attempts to evidence that the alterations in iodothyronines blood levels and in tissues’ 5⬘Ds activity during lactation are due to ST action have not received clear experimental support in either cows or rats. © 1999 Elsevier Science Inc. All rights reserved.
夞 This research was supported in part by the State Committee for Scientific Research, Grant No. 5P06D 04810. * Corresponding author. Tel.: ⫹48-61-8689764; fax: ⫹48-61-8689764. E-mail address: [email protected] (A.B. S´lebodzin´ski) 0739-7240/99/$ – see front matter © 1999 Elsevier Science Inc. All rights reserved. PII: S 0 7 3 9 - 7 2 4 0 ( 9 9 ) 0 0 0 3 3 - 8
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Keywords: Somatotropin; Thyroxine deiodinase; Mammary gland
1. Thyroid hormones in mammary secretion Variations in uptake and concentrations of thyroid hormone (TH) among tissues are explained by differences in cellular specific binding power, capillary circulation, and the plasma membrane carrier system [1]. Presence of specific thyroxine (T4) receptors in bovine mammary cytosol has been demonstrated [2], but the mechanism by which TH are transported across the blood–mammary gland barrier is unknown. At first, the TH in milk were thought to originate entirely from circulating hormones. Based on the assumption that transfer of TH from general circulation is their only source in milk, the total amount of T4 and triiodothyronine (T3) “transferred to milk” on a daily basis was estimated by Akasha and Anderson [3]. Reported contents of iodothyronines in milk vary considerably. Amounts of T4 or reverse triiodothyronine (rT3) reported in human milk range from none to very low. In contrast, T3 was reported frequently in easily measurable amounts, but quoted levels differed from 7 to 386 ng of T3/100 mL of milk [7,8]. These contradictory findings were thought to be due to differences in analytical methods, originally developed for TH determination in serum and not suited for TH determination in milk [7]. By means of analytical procedure developed for direct radioimmunoassay of TH in milk [9], it is possible to measure iodothyronines in concentrations in close agreement with that estimated by gas chromatography–mass spectrometry [10]. Compared with the TH concentration in blood, the T4 in milk represents a small fraction (⬇1/30) of that in serum, and T3 in milk approximates levels from 1/3 of that in serum, with a great differences across species. In sheep and in rabbits, T3 in individual milk samples may be twice as high as in serum. Four hours after injection of tracer amounts of (125I)-labeled T4 or T3, milk/serum ratios in lactating rabbits were ⬇0.3 for T4 and from 1.2 to 2.8 for T3 [11]. This indicates that the differences between T4 and T3 milk content might reflect different permeability of the blood–mammary barrier toward T4 and T3. On the other hand, rT3, which is in a very low concentration or is absent in the rabbit milk, passes easily from blood into milk, exceeding up to seven times the blood concentration at the 5th hour after a pharmacological dose of rT3 [9]. Under a majority of circumstances, T3 levels in milk are poorly related to its simple diffusion down a concentration gradient. Except in early lactation, there is no relationship between the T3 concentration in serum and milk in correlated samples from lactating women [12] and animals.
2. Thyroid hormone deiodination in the mammary gland A constant relationship between T3 concentrations in serum and milk is lacking, and T3 levels are often higher in milk than in serum. This, together with the low T3 content in mastitis milk (discussed below), inclined us to assume that iodothyronines are degraded
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within the mammary gland in a process resulting in low or undetectable concentrations of T4 and rT3 in milk. On the contrary, the T3 often in concentrations higher in milk than in blood serum was assumed to reflect a local or intramammary generation of T3 from T4. In 1989, the presence of a TH deiodinating system in the mammary gland tissue of rats and cows and in the milk of sows and cows was revealed independently by three groups of researchers [13–15]. In agreement with the earlier observations and assumption, the differences in iodothyronines concentrations in milk were proved to be associated with the intramammary generation of T3 from T4 [16]. By using different pH optima and the optimal reagent concentrations, it became possible to quantify degradation of T4 to T3 and rT3 in milk [12]. The ability to degrade thyroxine to T3 or to rT3 was thought to be accounted for low or undetectable T4 milk levels. Since rT3 is a preferred substrate for outer ring deiodination, and deiodinating efficiency is several times higher with rT3 over T4 as the substrate [17], concentrations of rT3 may not be available for quantification in an assay. On the other hand, presence of measurable quantities of the T3 in milk is explained by the fact that T3, despite being degraded in milk, is transferred simultaneously into milk from the blood and generated enzymatically from T4 within the mammary gland [12]. Inflammation of the mammary tissues (mastitis) significantly reduces milk T3 content [12]. A decreased T3 concentration and milk 5⬘-deiodinase (5⬘D) activity is a frequent feature of milk sampled from quarters showing inflammation but not of milk from healthy quarters of the same cow. Such a situation seems to reflect individual quarters’ reactivity to exogenous or endogenous factors. This observation is the first indication of a direct relationship between the mammary deiodinase(s) activity and the T3 concentration in milk (A.B. Slebodzinski, unpublished study).
3. Types of deiodinases in the mammary gland and during lactation Following the study on the presence of the mammary 5⬘D activity in the rat [18], further evidence was published by Acceves and Valverde [13], demonstrating that the mammary enzyme corresponds to the type I 5⬘-deiodinase (5⬘D-I), namely to the hepatic 5⬘D-I propylthiouracil (PTU)-sensitive 5⬘-deiodinase. These authors noted decreased circulating levels of T4 and T3, increased rT3, and reduced hepatic 5⬘D-I with simultaneous increased mammary 5⬘-D. On the basis of these findings, they proposed that the opposite rearrangement in the mammary and hepatic 5⬘-deiodinases is a major component of the homeorhetic response, characterized by an increased and compartmentalized energy expenditure of the mammary gland during lactation in the rat [18]. This interpretation is in accordance with the finding that the mammary and the hepatic 5⬘Ds are both of the same type I enzyme. It fits with the notion that thyroid status is the predominant regulator of 5⬘D-I activity in the rat [19]. More recently, the same authors [20] have presented data that the 5⬘D-I is specific to the alveolar epithelium and exists within the rat mammary gland only when the gland is in functional state (lactation) or when the alveolar epithelium is differentiating (puberty or late pregnancy). In the rat, expression of 5⬘D-I mRNA in the mammary gland, liver, kidney, and thyroid gland suggests that the 5⬘D in the lactating mammary gland is encoded by mRNA different
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from the 5⬘D-I activity found in the other tissues [21]. Such a situation implies the possibility of a differential regulation of 5⬘D-I activity in various tissues within the same species. The decrease in hepatic type 5⬘D-I activity during lactation observed in rats [18,22] is likely to be therefore a part of adjustment allowing enhanced activity of the same type 5⬘D-I in peripheral mammary gland, which would increase the local production of T3 to support the high energy expenditure that characterizes lactation. Such a conclusion gained from experiments in lactating rats gives, however, no evidence that similar interrelation between the hepatic and mammary 5⬘monodeiodinases exists in cows, particularly in the view of the fact that the type II and not 5⬘D-I deiodinase is characteristic and is the most abundant deiodinase in the mammary gland in cows. Under conditions that favor different types of thyroxine deiodination, it has been found that, unlike in rats, the 5⬘-monodeiodinase of type II (PTU-resistant 5⬘D-II) predominates in the mammary gland tissue of lactating cows and pigs [12,23]. This type of deiodinase is present in limited number of tissues only (brain, anterior pituitary, brown adipose tissue, placenta, pineal gland, and seminal plasma), where it is involved in production of T3 for local needs (for review see ref. [19]) and most probably plays a significant role in paracrine signaling, whereas the hepatic (and kidney) type 5⬘D-I monodeiodinating activity is a major source of circulating T3 [24]. The type II 5⬘D activity was found in both in the mammary tissue and in paralleled milk samples. In pig milk, deiodinating activity converting T4 to T3 and T4 to rT3, by milk cellular components (the epithelial cells, macrophages, lymphocytes, and granulocytes), was described additionally [12,25]. Response of 5⬘D-II-like activity in milk to well known 5⬘monodeiodinase inhibitors (amiodarone, iopanoic acid, aurothioglucose, and PTU) varies greatly across species, which seems to indicate existing differences in biochemical characteristics of 5⬘D-II in various species. The lowest inhibition of milk deiodinating activity by PTU (⬇10%), was found in cow and human milk, moderate (⬇40 –50%) in the sow and rabbit, and the highest (⬇90%) in rat milk (unpublished results). Most recently, we have found that, in mare’s milk, at least two types of 5⬘-D exist that show some characteristics of type II (⬇50%) [26]. On comparative grounds, existence of both 5⬘-deiodinases (type I and II like) in the same tissue is well known, for instance, in rat pituitary or brain [27]. Different 5⬘Ds also are known to exist in the same tissue but in different species: 5⬘D-I in bovine brown adipose tissue and type II 5⬘D in bovine brown adipose tissue of rodents [28,29]; type 5⬘D-I as the only type in the rat lactating mammary gland [13] and type II 5⬘D as primarily the main type in the cow mammary gland [12]. As generally recognized, type 5⬘D-II, owing to its higher catalytic efficiency than 5⬘D-I, can produce a significant amount of T3 from a considerably smaller T4 pool [30]. In the target tissues, type II 5⬘D secures a high production and prolonged residence time of locally generated T3 [30]. The major consequence of different tissue localizations of both types of deiodinases for T3 economy, as exemplified by studies in rats, is that the 5⬘D-II-deiodinating mechanism accounts for ⬇80% of locally produced T3 in the cerebral cortex whereas the 5⬘D-I-deiodinating mechanism accounts for ⬇20% in the liver [31]. Moreover, the highly efficient T3 production by 5⬘D-II, together with T3 uptake from plasma and T3 disposal rates, allows a homeostatic response to both hypo- and hyper-iodothyroninemias [31]. By analogy to 5⬘D-II activity and significance for the T3 economy in other tissues, the
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presence of the 5⬘D-II in mammary gland of domestic animals implies that the mammary deiodinating system is most probably highly independent from the temporary variations in circulating TH levels and indirectly from the hepatic 5⬘D-I activity. Moreover, by efficient local production of T3, the mammary 5⬘D-II is most likely to be able to respond homeostatically to variations in TH blood levels occurring during so-called low-T3 syndrome, which is characterized by decreased T3, elevated rT3, and usually normal T4 [32]. Such a syndrome was described during early lactation both in rats and cows and has been classified as euthyroid sick syndrome [18,33].
4. Somatotropin and mammary gland deiodinases Growth hormones (GH) long have been recognized as a homeorhetic key factor controlling efficiency of nutrient partitioning [34,35] and their use for galactopoietic response. Although GH-receptor gene expression is present in the mammary gland tissue [36], it is widely accepted that the GH endocrine effect on the mammary cells is primarily indirect through an increased circulating level of IGF-I of hepatic origin [37–39]. The fact that increasing systemic concentrations of IGF-I do not always alter milk yield [40,41] reflects multiplicity of galactopoietic action of growth hormone. The IGFs can be synthesized within the mammary gland; however, the contribution of the milk-borne IGF production generally is considered as low relative to hepatic synthesis. In the rat, in which the IGF-I was proved to be synthesized in the mammary gland, the mRNA for IGF-I increases after treatment with GH [42]. In primary bovine mammary epithelial cells, IGF-I mRNA was not detected. IGF-II is considered to be the major IGF synthesized by bovine mammary epithelial cells [43]. Nevertheless, the hepatic and/or mammary IGF-I and IGF-II both bind with high affinity to the type of mammary IGF receptors that show structural similarities to the type I and type II IGF receptors [44,45]. In the rat, the activity of 5⬘D-I in various tissues was shown to be significantly influenced by growth hormone; however, to our knowledge there is no experimental evidence of the effects of GH on the 5⬘D-I in the mammary gland of lactating rats. However, it has been shown that lactating rats normally display: low serum T4 and T3 paralleling a decreased 5⬘D-I activity in liver and kidney [18,22,46], an inverse relationship between lactational intensity and 5⬘D activity in liver and kidney [47], and a positive relationship between mammary gland 5⬘D and lactation intensity [21]. These data convincingly indicate the importance of the extrathyroidal T4 to T3 converting activity for metabolic adjustment to support lactation. In cattle, administration of recombinant somatotropin (r-bST) results in no or moderate changes in the classic hormone blood levels. Chronic treatment with r-bST (injections 500 mg, every 2 wk), starting on 60 ⫾ 3 days postpartum and continued till the middle of lactation, evokes no changes in baseline of total thyroxine, free T4, T3, prolactin, follicle stimulating and luteinizing hormones, estradiol and progesterone but does change adrenocorticotropic hormone (ACTH) levels. Target tissue responses affected by bST treatment appeared to be ACTH and ovarian progesterone output [48]. In similar studies in lactating cows, average concentrations of T4, T3 and insulin were not changed during bST treatment
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[49]. Observations performed during the middle of lactation (cows given infusion of r-bST; 29 mg/day for 63 days) showed that bST decreased concentrations of T3 by 10% as a result of decrease in the hepatic 5⬘D activity. However, this response was not paralleled by either changes in the T3 milk concentration nor in the mammary gland 5⬘-deiodinase activity [50]. To date, in none of reported experiments in cattle, a shift in serum T4, T3 and rT3 concentrations, resembling the euthyroid sick-like syndrome, occurring naturally during early lactation in cows [33], was evoked with bST treatment. In studies in human beings, recombinant hGH administered as daily injections or continuous infusion to adult patients with GH deficiency caused an increase in serum concentrations of free-T3 and total-T3 and a decrease in free T4 to a similar degree (total T4 being unchanged), independently of the mode of GH administration [51]. Results of combined administration of GH and T3 (T3 in the dose selected to mimic the T3 increase seen during hGH exposure) to healthy adults (for 10-day treatment periods) increased free-T3 levels. From the obtained results, the authors were inclined to conclude that GH and T3 in the physiological range exert distinct but disparate effects on lipids and lipoproteins and do not support the hypothesis that the effects observed during GH administration are exclusively secondary to changes in peripheral T3 levels [52]. Increased activity of 5⬘D in lactating mammary tissue of the cow receiving r-bST has been presented by Capuco et al. [14]. In this study, an acute effect of r-bST (given to six nonpregnant lactating cows; daily injection of 40 mg for 5 days during late lactation) evoked a nearly 2-fold increase in mammary 5⬘D activity. There was no change in serum concentrations of T4 and T3 in bST-treated cows, in agreement with previous data [53]. However, the next report from the same center showed a decrease in serum concentration of T3 and a lack of alterations in the mammary 5⬘D in lactating cows (in the midlactation) receiving infusion of bST [50]. The authors’ conclusion that bST increased the hypothyroid status of the lactating cows and maintained an euthyroid condition in the mammary gland by organspecific changes in 5⬘D activity [50], although interesting, has at present scarce and controversial experimental support. Having similar mammary 5⬘D of type II as the cow, the rabbit seems to be a good model for comparative studies on effects of GH on 5⬘D activity in mammary gland. Our preliminary studies show that r-bST (Sometribove威) administrations to rabbits lower plasma urea and total-T4 concentration in blood; the bST effects on level of T3 and 5⬘Ds activity in milk were so far inconclusive. It may be concluded at this point that, although in farm animals growth hormone acts as a factor controlling partitioning of nutrients and thyroid hormones together with type II 5⬘-deiodinase act as factors controlling maintenance and intensity of lactation, the functional interrelations among the factors underlying their positive role for lactation are still imperfectly understood.
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