The effect of fasting on thyroidal T4-5' monodeiodinating activity in mice

Complete fasting induces a significant decrease of serum T3 and a fall in TSH in rodents and man. To evaluate the effect of starvation on thyroidal T4 5'monodeiodinating activity, in vitro conversion of T4 to T3 by thyroid and liver homogenate from one to three days fasted mice was compared with homogenates from control mice on animal chow. 5'monodeiodinating activity was significantly lower in thyroid homogenates of fasted mice than in those of chow-fed control [100 +/- 5.0 and 92 +/- 5.0 pmol T3.(mg protein)-1.h-1 at 48 and 72 h fasting, respectively, vs 132 +/- 5.0 pmol T3.(mg protein)-1.h-1 of fed control, p less than 0.01]. A similar decrease in thyroidal 5'monodeiodinating activity was seen in the liver. The decrease in thyroidal 5'monodeiodinating activity induced by fasting was not reversed by the supplementation of homogenates with the thiol-protecting agent, dithiothreitol (0.2-4.0 mmol/l). Physiological replacement of T4, 0.58 nmol.(100 g)-1.day-1, did not alter the effect of starvation in either the thyroid or liver. TSH (0.02 IU/day) injection, on the other hand, stimulated 5'monodeiodinating activity in homogenates of thyroids from 3-days fasted mice which was no different from TSH-treated fed control. It is postulated that starvation-induced decrease in thyroidal T4 to T3 converting activity may play a role, together with decreased hepatic 5'monodeiodinating activity, in fasting-induced low serum T3 in mice.     

Characterization of human iodothyronine sulfotransferases

Sulfation is an important pathway of thyroid hormone metabolism that facilitates the degradation of the hormone by the type I iodothyronine deiodinase, but little is known about which human sulfotransferase isoenzymes are involved. We have investigated the sulfation of the prohormone T4, the active hormone T3, and the metabolites rT3 and 3,3'-diiodothyronine (3,3'-T2) by human liver and kidney cytosol as well as by recombinant human SULT1A1 and SULT1A3, previously known as phenol-preferring and monoamine-preferring phenol sulfotransferase, respectively. In all cases, the substrate preference was 3,3'-T2 > rT3 > T3 > T4. The apparent Km values of 3,3'-T2 and T3 [at 50 micromol/L 3'-phosphoadenosine-5'-phosphosulfate (PAPS)] were 1.02 and 54.9 micromol/L for liver cytosol, 0.64 and 27.8 micromol/L for kidney cytosol, 0.14 and 29.1 micromol/L for SULT1A1, and 33 and 112 micromol/L for SULT1A3, respectively. The apparent Km of PAPS (at 0.1 micromol/L 3,3'-T2) was 6.0 micromol/L for liver cytosol, 9.0 micromol/L for kidney cytosol, 0.65 micromol/L for SULT1A1, and 2.7 micromol/L for SULT1A3. The sulfation of 3,3'-T2 was inhibited by the other iodothyronines in a concentration-dependent manner. The inhibition profiles of the 3,3'-T2 sulfotransferase activities of liver and kidney cytosol obtained by addition of 10 micromol/L of the various analogs were better correlated with the inhibition profile of SULT1A1 than with that of SULT1A3. These results indicate similar substrate specificities for iodothyronine sulfation by native human liver and kidney sulfotransferases and recombinant SULT1A1 and SULT1A3. Of the latter, SULT1A1 clearly shows the highest affinity for both iodothyronines and PAPS, but it remains to be established whether it is the prominent isoenzyme for sulfation of thyroid hormone in human liver and kidney.     

Characterization of iodothyronine sulfotransferase activity in the cytosol of Rana catesbeiana tadpole tissues

We have investigated the sulfation of thyroid hormones (THs) in the cytosol from Rana catesbeiana tadpole tissues. Sulfation of 3,3′,5-triiodothyronine (T₃) by the liver cytosol, which was dependent on protein amount, incubation time, and temperature, suggested the presence of TH sulfotransferases (SULTs) in the liver. The apparent Michaelis-Menten constant (K_m) of the liver cytosol was 0.22 μM for T₃, and the apparent maximum velocity (V_max) of the liver cytosol was 7.65 pmol/min/mg protein for T₃. Iodothyronine sulfating activity in the liver cytosol was increased in tadpoles at premetamorphic (stages IX-X) and metamorphic climax (stage XX) stages, and in adult frogs. The substrate preference of iodothyronine sulfation for the liver cytosol from tadpoles (stage X) was: 3,3′,5′-triiodothyronine > T₃ > 3,3′,5,5′-tetraiodothyroacetic acid > 3,3′,5-triiodothyroacetic acid, T₄, 3-iodothyronine > 3,5-diiodothyronine. Several halogenated phenols were potent inhibitors (IC₅₀ = 0.15-0.21 μM). The substrate preference for T₃ was gradually lost by the onset of metamorphic climax stages. These enzymatic characteristics of iodothyronine sulfation in the liver cytosol from tadpoles resembled those of mammalian phenol SULTs, except that the tadpole cytosol had a higher affinity (one or two orders of magnitude) for T₃ than mammalian SULTs. These results suggested that an enzyme homologous to mammalian phenol SULT (SULT1) may be involved in TH metabolism in tadpoles.     

Effects of glutathione on iodothyronine 5'-deiodinase activity

At nanomolar substrate levels, physiological concentrations (less than or equal to 5 mM) of glutathione (GSH) activate a low Km iodothyronine 5'-deiodinase (I-5'D) activity in renal and hepatic microsomes, but not the low Km (type II) I-5'D in the pituitary, cerebral cortex, or brown adipose tissue. The latter enzyme as well as the type I enzyme activity at micromolar substrate concentrations required higher (greater than 10 mM) concentrations of GSH. However, GSH appeared to interact with the type I and type II enzymes even at subactivation levels, since it inhibited the activation of these enzymes by dithiothreitol (DTT). Activation of the renal and hepatic low Km I-5'D by GSH resembled that by DTT in 1) the similarity of Km values for both T4 (20 nM) and rT3 (2 nM), 2) the catalytic mechanism (ordered sequential with the iodothyronine as the second substrate), 3) the values for activation energies, and 4) sensitivity to inhibition by propylthiouracil. However, the low Km I-5'D activated by GSH was about 10-fold more sensitive to inhibition by iopanoate than when activated by DTT. The responsiveness of the low Km I-5'D's in renal and hepatic microsomes to physiological concentrations of GSH suggests their participation in the metabolism of iodothyronines in vivo.     

Investigations on iodothyronine deiodinase activity in the maturing rat brain

5-Monodeiodination of T4 and T3 and 5'-monodeiodination of T4 and rT3 were studied in brain homogenates of male Sprague-Dawley rats, aged 1-60 days. Portions of the homogenates were incubated with the substrates at 37 C for 30 min. The reaction products were estimated by specific RIAs. All of the four reactions were dependent upon time, temperature, pH, and upon the concentrations of substrate, thiol, and tissue protein. Maximal reactions were obtained between 40 and 160 mM dithioerythritol. T4 5'-deiodination proceeded optimally at pH 7.4 and 0.4 microM substrate, the other reactions at pH 8.5 and 10 microM substrate. The four reactions were inactivated by heat (56 C, 30 min) and inhibited by 10(-5) M iopanoic acid. Only rT3 5'-deiodination was inhibited by 3 X 10(-4) M propylthiouracil (greater than 95%). In cerebellum, basal ganglia, brainstem, and hypothalamus both T4 and T3 5-deiodinase activity were very high in perinatal rats [up to 5.56 pmol/(min X mg protein) in hypothalamus], and decreased rapidly with age. In cortex and olfactory bulb these enzyme activities were low after birth, followed by an increase during the growth spurt [up to 632 fmol/(min X mg protein) in olfactory bulb]. T4 and rT3 5'-deiodinase activity in all brain regions studied were at their lowest in perinatal rats. During and after the growth spurt an increase was observed [up to 457 fmol/(min X mg protein) in cerebellum]. The reciprocal course of 5- and 5'-deiodination between birth and growth spurt in most of the brain regions studied might lead to a reduced intracellular thyromimetic activity during the perinatal period.     

Characterization of iodothyronine sulfatase activities in human and rat liver and placenta

In conditions associated with high serum iodothyronine sulfate concentrations, e.g. during fetal development, desulfation of these conjugates may be important in the regulation of thyroid hormone homeostasis. However, little is known about which sulfatases are involved in this process. Therefore, we investigated the hydrolysis of iodothyronine sulfates by homogenates of V79 cells expressing the human arylsulfatases A (ARSA), B (ARSB), or C (ARSC; steroid sulfatase), as well as tissue fractions of human and rat liver and placenta. We found that only the microsomal fraction from liver and placenta hydrolyzed iodothyronine sulfates. Among the recombinant enzymes only the endoplasmic reticulum-associated ARSC showed activity toward iodothyronine sulfates; the soluble lysosomal ARSA and ARSB were inactive. Recombinant ARSC as well as human placenta microsomes hydrolyzed iodothyronine sulfates with a substrate preference for 3,3'-diiodothyronine sulfate (3,3'-T(2)S) approximately T(3) sulfate (T(3)S) > rT(3)S approximately T(4)S, whereas human and rat liver microsomes showed a preference for 3,3'-T(2)S > T(3)S > rT(3)S approximately T(4)S. ARSC and the tissue microsomal sulfatases were all characterized by high apparent K(m) values (>50 microM) for 3,3'-T(2)S and T(3)S. Iodothyronine sulfatase activity determined using 3,3'-T(2)S as a substrate was much higher in human liver microsomes than in human placenta microsomes, although ARSC is expressed at higher levels in human placenta than in human liver. The ratio of estrone sulfate to T(2)S hydrolysis in human liver microsomes (0.2) differed largely from that in ARSC homogenate (80) and human placenta microsomes (150). These results suggest that ARSC accounts for the relatively low iodothyronine sulfatase activity of human placenta, and that additional arylsulfatase(s) contributes to the high iodothyronine sulfatase activity in human liver. Further research is needed to identify these iodothyronine sulfatases, and to study the physiological importance of the reversible sulfation of iodothyronines in thyroid hormone metabolism.     

The ontogeny of iodothyronine 5'-monodeiodinase activity in Rana catesbeiana tadpoles

Generation of T3 from T4 in vivo cannot be demonstrated in tadpoles until just before metamorphic climax (MC). Possible explanations include the absence of the necessary 5'-monodeiodinase (5'D) process, and/or the presence of an active T3 and T4 5-deiodinase (5D) system before MC. In the present study, 5'D activity was determined in the 12,000 x g supernatent fraction of tissue homogenates prepared from tadpoles in premetamorphosis (PM) and MC (induced by immersion in 2 x 10(-8) M T4) by measuring the 125I-formed from [125I] rT3 or [125I]T4 in the presence of 20 mM dithiothreitol. Eadie-Hofstee plots of data were used to determine maximum velocity and Km. During PM, 5'D activity was undetectable in liver, tail, heart, and kidney, minimal in brain and gut, and could be quantitated only in skin. During MC, 5'D activity was undetectable in liver, heart, and kidney, but was present in tail tissue and was increased more than 5-fold in skin and gut. The increased activity was due to a change in maximum velocity, with no change in Km. In its properties, the tadpole 5'D system was comparable to the type II system found in some mammalian tissues. Thus, it exhibited Km values for T4 and rT3 in the nanomolar range, the preferred substrate was T4, and activity was unaffected by propylthiouracil in the presence of 10 mM dithiothreitol. Under comparable incubation conditions, T3 5D activity was detected in most tissues during PM; the highest activity was found in liver, gut, and kidney. 5D activity was barely detectable in MC. From these studies it is suggested that accumulation of T3 generated from T4 in the tadpole is minimal before MD due to the predominance of 5D activity. During MC, accumulation of T3 is possible because of the substantial increase in 5'D activity together with a marked drop in 5D activity. The principle T3-generating organs appear to be gut, skin, and tail tissue.     

硒对碘过量仔鼠脑5'-和5-脱碘酶活性的干预作用

目的研究小鼠摄入高碘对仔鼠脑5＇-和5-脱碘酶活性的影响及硒的干预作用。方法将60只Balb／c断乳小鼠按体重随机分为4个不同的饮水组：正常对照组、高碘组（3000μg／L I）、单独补硒组（200μg／L Se）、高碘加硒组（3000μg／LI＋200μg／L Se），喂养4个月时，雌雄交配。测定14和28日龄仔鼠血清TSH、TT4、TT3和rT3水平，及0、14和28日龄仔鼠大脑5＇-和5-脱碘酶活性。结果14日龄仔鼠血清TT4水平高碘组显著低于对照组和高碘加硒组，而TSH水平高碘组显著高于对照组和高碘加硒组，28日龄仔鼠血清TT4、TT3和TSH水平各组间差异无统计学意义（P〉0．05）。0和14日龄仔鼠脑5＇-脱碘酶活性高碘组显著高于对照组（P〈0．05），高碘补硒组显著低于高碘组。0和14日龄仔鼠脑5-脱碘酶活性高碘组显著低于对照组（P〈0．05），而高碘加硒组显著高于高碘组。结论补硒能缓解高碘所致仔鼠脑5＇-和5-脱碘酶活性的改变。     

Characterization of elevated plasma alkaline phosphatase activity in genetically obese mice

Alkaline phosphatase activity in obese mice ($\text{C57BL}\text{6J}\text{ob}\text{ob}$) was significantly increased from 18 to 63 weeks of age when compared to that of their lean controls ($\text{C57BL}\text{6J}\text{+/?}$). In 5 week old animals, the earliest age examined, the circulating activity of alkaline phosphatase was similar in both obese mice and their lean counterparts. To characterize the circulating alkaline phosphatase activity in the obese mouse and its lean counterpart, the response of the enzyme to fasting, various inhibitors, heat inactivation, and urea denaturation was examined and compared. L-homoarginine and L-p-bromotetramisole inhibited to a large extent the circulating activity of alkaline phosphatase in both obese mice and their lean controls in the fed state, while L-phenylalanine had essentially no effect. Even though the response of alkaline phosphatase in plasma to several inhibitors was similar, the rate of denaturation by urea of enzyme activity in plasma was significantly slower in obese mice than in their lean controls in the fed state. While the rate of inactivation of alkaline phosphatase activity in plasma for the initial two minutes at 56°C was similar in obese mice and their lean counterparts, the subsequent rate of heat inactivation was significantly slower in the plasma from obese mice. Thus, both obese and lean mice in the fed state have a circulating activity of alkaline phosphatase in plasma with a greater contribution from a skeletal isoenzyme and a lesser one of intestinal origin. Even though the contribution of the bone isoenzyme could not be completely differentiated from that of liver, the circulating alkaline phosphatase activity in the obese mouse has a component of greater stability to both urea denaturation and heat inactivation, presumably hepatic in origin.     

Imidazenil and diazepam increase locomotor activity in mice exposed to protracted social isolation

In cortex and hippocampus, protracted (>4 weeks) social isolation of adult male mice alters the subunit expression of GABA type A receptors (GABA(A)-Rs) as follows: (i) the mRNAs encoding GABA(A)-R alpha1, alpha2, and gamma2 subunits are decreased by approximately 50%, whereas those encoding alpha4 and alpha5 subunits are increased by approximately 100%; (ii) similarly, the synaptic membrane expression of the alpha1 subunit protein is down-regulated, and that of the alpha5 subunit protein is up-regulated; and (iii) the binding of [(3)H]flumazenil to hippocampal synaptic membranes is decreased. Behaviorally, socially isolated (SI) mice are resistant to the sedative effects of the positive allosteric GABA(A)-R modulators diazepam (DZP) and zolpidem. This resistance seems to be attributable to the decrease of alpha1-containing GABA(A)-Rs. Paradoxically, DZP, which, unlike zolpidem, acts at alpha5-containing GABA(A)-Rs, increases the locomotor activity of SI mice. Imidazenil, which fails to modulate alpha1-, alpha4-, and alpha6-containing GABA(A)-Rs but is a selective positive allosteric modulator of alpha5-containing GABA(A)-Rs, also increases locomotor activity in SI mice. Importantly, SI mice responded to muscimol, 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3(2H)-one, and allopregnanolone similar to group-housed mice. These data suggest that a switch (a decrease in alpha1/alpha2 and gamma2 and an increase in alpha4 and alpha5 subunits) in the composition of the heteropentameric GABA(A)-R subunit assembly without a change in total GABA(A)-R number occurs during social isolation. Thus, the repertoire of DZP and imidazenil actions in SI mice appears to be elicited by the allosteric modulation of GABA(A)-Rs overexpressing alpha5 subunits. Benzodiazepine response mediated by alpha1-containing GABA(A)-Rs is expected to be silent or reduced.     

Catecholamine stimulation of iodothyronine 5'-deiodinase activity in rat dispersed brown adipocytes

We describe an in vitro system for evaluating the direct effects of catecholamines on the activity of the type II iodothyronine 5'-deiodinase in dispersed rat brown adipocytes. Incubation with norepinephrine or phenylephrine for 3-4 h causes up to a 5-fold increase in deiodinase activity in these cells. As found in vivo studies, the norepinephrine stimulation is blocked by coincubation with the alpha 1-adrenergic antagonist prazosin. The beta-adrenergic antagonist alprenolol either has no effect or increases stimulation by norepinephrine. These results suggest that beta-adrenergic agonists inhibit the activation or synthesis of the deiodinase in these cells.     

Hearing loss and retarded cochlear development in mice lacking type 2 iodothyronine deiodinase

The later stages of cochlear differentiation and the developmental onset of hearing require thyroid hormone. Although thyroid hormone receptors (TRs) are a prerequisite for this process, it is likely that other factors modify TR activity during cochlear development. The mouse cochlea expresses type 2 deiodinase (D2), an enzyme that converts thyroxine, the main form of thyroid hormone in the circulation, into 3,5,3'-triiodothyronine (T3) the major ligand for TRs. Here, we show that D2-deficient mice have circulating thyroid hormone levels that would normally be adequate to allow hearing to develop but they exhibit an auditory phenotype similar to that caused by systemic hypothyroidism or TR deletions. D2-deficient mice have defective auditory function, retarded differentiation of the cochlear inner sulcus and sensory epithelium, and deformity of the tectorial membrane. The similarity of this phenotype to that caused by TR deletions suggests that D2 controls the T3 signal that activates TRs in the cochlea. Thus, D2 is essential for hearing, and the results suggest that this hormone-activating enzyme confers on the cochlea the ability to stimulate its own T3 response at a critical developmental period.     

Regulation of tissue iodothyronine deiodinase activity in a model of prolonged critical illness.

BACKGROUND: The low plasma triiodothyronine (T3) observed during prolonged critical illness can be explained in part by suppressed hepatic deiodinase type I (D1) and increased D3 activity. Infusion of thyrotropin-releasing hormone (TRH) can restore D1 and D3 activity in critically ill rabbits, but it remains unknown whether this is a direct effect of TRH or the TRH-induced rise in circulating thyroxine (T4) and T3. METHODS: To answer this specific question, burn-injured rabbits randomly received a 4-day treatment with saline, T4, T3, T4+T3, or TRH, started on day 4 of the illness. Plasma iodothyronine concentrations, D1 and D3 activity, and T3-responsive gene expression were quantified in liver and kidney. RESULTS: Infusion of T4, T3, or TRH increased circulating T3 levels and hepatic D1 activity. Co-infusion of T3 with T4 enhanced T4 to T3 conversion as demonstrated by lower T4, higher T3, and lower reverse T3 (rT3) levels and tended to further increase hepatic D1 activity. Hepatic D1 activity correlated positively with circulating T3 and the T3/rT3 ratio, but not with T4, rT3, or thyroid-stimulating hormone. CONCLUSIONS: During prolonged critical illness, D1 activity is primarily regulated via changes in circulating T3, suggesting that the low plasma T3 concentrations may be important in sustaining low D1 activity in this condition.     

Characterization of outer ring iodothyronine deiodinases in tissues of the saltwater crocodile (Crocodylus porosus)

The distribution and characterization of outer ring deiodination (ORD) using reverse triiodothyronine (rT3) and thyroxine (T4) as substrates is reported in microsomes of liver, kidney, lung, heart, gut, and brain tissues from juvenile saltwater crocodiles (Crocodylus porosus). In lung and heart only small amounts of rT3 ORD and T4 ORD were detected, while in brain only a small amount of T4 ORD was detected. More detailed characterization studies could be performed on liver, kidney, and gut microsomes. Reverse T3 outer ring deiodination (rT3 ORD) was the predominant activity in liver and kidney microsomes. The properties of crocodile liver and kidney rT3 ORD, such as preference for rT3 as substrate, a dithiothreitol (DTT) requirement of 10 mM, inhibition by propylthiouracil (PTU), and Michaelis-Menten (Km) constant in the micromolar range, correspond to the properties previously reported for a type I deiodinase. The temperature optimum for rT3 ORD was between 30 and 35 degrees. There was also rT3 ORD activity in gut microsomes, along with what appeared to be a type II-like, low-Km deiodinase with a substrate preference for T4. There was also a small amount of T4 ORD activity in liver and kidney microsomes. Liver T4 ORD, like a type II deiodinase, had a preference for T4 as substrate at low substrate concentrations and a DTT requirement of 15 mM and was insensitive to PTU. However, at high substrate concentrations the predominant activity was of the type I deiodinase nature. T4 ORD in liver had an optimal incubation temperature of 30 to 35 degrees. Gut microsomal T4 ORD was also type II-like at low substrate concentrations and type I-like at high substrate concentrations. Gut T4 ORD had an optimal incubation temperature of 25 to 30 degrees and a DTT requirement of 20 mM DTT. Kidney microsomal T4 ORD had the same optimal temperature and DTT requirement as that in gut microsomes; however, there was no competition by low substrate concentrations. These results suggest that ORD in juvenile saltwater crocodile kidney is most likely exclusively catalyzed by a type I-like deiodinase. Liver and gut ORD, in contrast, is catalyzed by two enzymes, with a predominance of a type I-like deiodinase in liver and a type II-like deiodinase in gut. Low-Km T3 IRD activity could not be detected in any tissues of the juvenile saltwater crocodile.     

Graves' immunoglobulin G stimulates iodothyronine 5'-deiodinating activity in FRTL-5 rat thyroid cells

To elucidate the effect of Graves' immunoglobulin G (IgG) on iodothyronine deiodination in the thyroid, we examined the characteristics of iodothyronine 5'-deiodinating (I-5'-D) activity in FRTL-5 rat thyroid cells and the effect of Graves' IgG on its activity. FRTL-5 cells were sonicated and incubated with 0.5 mumol/L rT3 with a tracer amount of [125I]rT3 in 0.1 mol/L phosphate buffer containing 1 mmol/L EDTA and 0.5 mmol/L dithiothreitol. The released 125I- was separated by Dowex-50WX2 column and counted. The amount of I- released was tissue, incubation time, temperature, and pH dependent, strongly suggesting that the reaction is enzymatic. The activity was completely inhibited by propylthiouracil. The Km value for rT3 was approximately 0.32 microM when analyzed by Lineweaver-Burk plot. TSH, dibutyl cAMP, and Graves' IgG induced I-5'-D activity in a dose-dependent manner. However, cycloheximide (5 mumol/L) abolished the stimulating effects of these agents on I-5'-D activity. These results suggest that TSH, dibutyl cAMP, and Graves' IgG induced I-5'-D activity through the synthesis of new enzyme protein. A significant positive correlation between thyroid-stimulating antibody activity assayed by measuring cAMP production using FRTL-5 cells and I-5'-D activity induced by the Graves' IgG in 10 patients with untreated Graves' disease was observed (r = 0.79; P less than 0.01). The present findings suggest that type I iodothyronine 5'-deiodinase exists in FRTL-5 rat thyroid cells and that Graves' IgG as well as TSH stimulate the activity at least in part by activating adenylate cyclase.     

Granulopoietic increase by BCG in mice.

Repeated doses of the non-specific immunostimulant BCG were injected intraperitoneally, followed by serial measurement of serum colony stimulating factor (CSF), and CFU-C number and percent synthesizing DNA. Following primary challenge with BCG, CSF remained at low levels until day 7, rose to a peak by day 10, and remained elevated through 14 days. Secondary challenge resulted in a bi-phasic CSF response with a small peak on day 1 and a larger one by day 7. Following secondary challenge, the percent of CFU-C in 'S' phase doubled in 24 hours; CFU-C significantly increased in number by 48 hours. The studies suggest that the marrow toxicity of cycle active cytotoxic drugs might be altered by non-specific immunostimulants such as BCG.     

碘化甲腺原氨酸脱碘酶的研究进展

甲状腺激素是哺乳动物生长发育的重要调节激素,碘化甲腺原氨酸脱碘酶是调控甲状腺激素的主要蛋白酶。其可分为3种类型,有相似的结构,但功能各异,在不同的组织器官,如大脑、子宫、胎盘和肝脏等发挥着不同的生理作用。甲状腺疾病、非甲状腺疾病病态综合征及糖尿病等内分泌疾病,以及一些药物的使用等均能影响其活性。