The Placental Transfer of Propylthiouracil, Methimazole and Carbimazole

Marchant, B.; Brownlie, B. E. W.; Hart, D. M.; Horton, P. W.; Alexander, W. D.

doi:10.1210/jcem-45-6-1187

Cited by 163 publications

(51 citation statements)

References 17 publications

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“…Pregnant and lactating rats were therefore treated with the goitrogen methimazole (MMI). MMI can cross the placenta (Calvo et al 1990(Calvo et al , 1992Marchant et al 1977;Mortimer et al 1997;Sack et al 1995) and is safely used to suppress plasma-TH levels both in animals and humans (Becks and Burrow 1991;Lind 1997). The neuronal and morphogenetic development of the inner ear, as well as the auditory function, was analyzed in adult offspring of untreated (control) and MMI-treated dams.…”

Section: Introductionmentioning

confidence: 99%

Thyroid Hormone Deficiency Before the Onset of Hearing Causes Irreversible Damage to Peripheral and Central Auditory Systems

Knipper

Zinn

Maier

et al. 2000

Journal of Neurophysiology

171

156

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Thyroid hormone deficiency before the onset of hearing causes irreversible damage to peripheral and central auditory systems. J. Neurophysiol. 83: 3101-3112, 2000. Both a genetic or acquired neonatal thyroid hormone (TH) deficiency may result in a profound mental disability that is often accompanied by deafness. The existence of various TH-sensitive periods during inner ear development and general success of delayed, corrective TH treatment was investigated by treating pregnant and lactating rats with the goitrogen methimazole (MMI). We observed that for the establishment of normal hearing ability, maternal TH, before fetal thyroid gland function on estrus days 17-18, is obviously not required. Within a crucial time between the onset of fetal thyroid gland function and the onset of hearing at postnatal day 12 (P12), any postponement in the rise of TH-plasma levels, as can be brought about by treating lactating mothers with MMI, leads to permanent hearing defects of the adult offspring. The severity of hearing defects that were measured in 3-to 9-mo-old offspring could be increased with each additional day of TH deficiency during this critical period. Unexpectedly, the active cochlear process, assayed by distortion product otoacoustic emissions (DPOAE) measurements, and speed of auditory brain stem responses, which both until now were not thought to be controlled by TH, proved to be TH-dependent processes that were damaged by a delay of TH supply within this critical time. In contrast, no significant differences in the gross morphology and innervation of the organ of Corti or myelin gene expression in the auditory system, detected as myelin basic protein (MBP) and proteolipid protein (PLP) mRNA using Northern blot approach, were observed when TH supply was delayed for few days. These classical TH-dependent processes, however, were damaged when TH supply was delayed for several weeks. These surprising results may suggest the existence of different TH-dependent processes in the auditory system: those that respond to corrective TH supply (e.g., innervation and morphogenesis of the organ of Corti) and those that do not, but require T3 activity during a very tight time window (e.g., active cochlear process, central processes).

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Section: Introductionmentioning

confidence: 99%

Thyroid Hormone Deficiency Before the Onset of Hearing Causes Irreversible Damage to Peripheral and Central Auditory Systems

Knipper

Zinn

Maier

et al. 2000

Journal of Neurophysiology

171

156

View full text Add to dashboard Cite

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“…15,16 Another reason for the preference of propylthiouracil over methimazole is that a small study reported limited transplacental passage of propylthiouracil compared with methimazole. 17 This finding was refuted by a later study. 18 The risk of fetal hypothyroidism was not different between women with Graves disease taking propylthiouracil and those taking methimazole.…”

Section: Antithyroid Drugs During Pregnancymentioning

confidence: 89%

Hyperthyroidism during Pregnancy

1978

N Engl J Med

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“…It is also possible that intracellular concentrations of PTU in vivo were too low to produce enzyme inhibition. However, since PTU crosses the placenta (18), it seems likely that some PTU does enter the thin layer of trophoblastic cells that separates the fetal and maternal circulations.…”

Section: Discussionmentioning

confidence: 99%

“…However, the present studies show that information can be obtained that is in many ways more physiologically and clinically relevant than that obtained in disrupted cell and organ preparations or in cultured cells. PTU is administered to pregnant women with hyperthyroidism and is known to traverse the placenta and to reach the fetal circulation (18). IA is generally not administered to pregnant women, but recent studies have suggested that this class of compounds may be useful in treating Graves' Disease (19).…”

Section: Discussionmentioning

confidence: 99%

Inner-ring deiodination of 3,5,3'-triiodothyronine in the in situ perfused guinea pig placenta.

Castro¹,

Braverman²,

Alex³

et al. 1985

J. Clin. Invest.

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IntroductionBroken cell preparations of rat and human placentas contain an inner (tyrosyl)-ring iodothyronine deiodinase enzyme with greatest activity when the substrate is 3,5,3'-triiodothyronine (T3). This report describes the deiodination of T3 in the intact placenta and the effect of sodium iopanoate (IA) and propylthiouracil (PTU) on T3 deiodination. Under nembutal anesthesia, the placenta of60-65-d-old pregnant guinea pigs was surgically exposed, a single umbilical artery and the umbilical vein were cannulated, and the fetus was removed. In a temperature-controlled chamber (37°C), the fetal side of the placenta was perfused through the umbilical artery at a rate of 1 ml/min with 3% bovine serum albumin Krebs-Henseleit buffer containing 0.14 nM outer ring labeled 1'"IJT3. Placenta effluent fractions were collected at timed intervals from the umbilical vein canulla throughout a 120-min perfusion period. The contents of the perfusion buffer and the various effluent fractions were analyzed for their iodothyronine content by high pressure liquid chromatography. In five experiments, the percent composition of '25I-labeled iodothyronines in the perfusion buffer and placenta effluent was 95.3±1.0 (mean±SE) and 70.2±2.1 for T3 (P < 0.01), 2.5±0.7 and 20.1±1.8 for 3,3'-T2 (P < 0.01), and 0 and 8.2±0.9 for 3'-Ti. The placenta receives a large percentage of the fetal cardiac output (1), and, as we and others have reported (2-7), contains enzymes that deiodinate thyroid hormones. These observations support the possibility that the placenta is an important site for fetal thyroid hormone metabolism. Deiodination of the iodothyronines can occur in the phenolic (5' or outer) or in the tyrosyl (5 or inner) rings. These deiodinative pathways play a major role in the metabolism of thyroxine (T4),' generating the metabolically active iodothyronine, 3,5,3'-triiodothyronine (T3), and the metabolically inactive iodothyronine, 3,3',5'-triiodothyronine (rT3). Deiodination is also the principal pathway for the metabolism of T3, which results in the formation of the inactive diiodothyronines, 3,3'-T2 and 3,5-T2, as well as the inactive monoiodothyronines, 3'-T, and 3-T1. Thus, placental deiodination is potentially an important mechanism for the modulation of fetal thyroid hormone action. While detailed studies of deiodination have been performed in placenta homogenates and subcellular fractions (6,8), there is little information on iodothyronine deiodination in the intact placenta (9).In this study, we discovered the metabolic fate of T3 when perfused through the fetal side ofthe guinea pig placenta in situ. Since previous studies employing placenta homogenates have shown an inhibitory effect ofpropylthiouracil (PTU) and sodium iopanoate (IA) on T4 deiodination (8), the effect of these drugs on T3 metabolism in the intact placenta was evaluated.

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The Placental Transfer of Propylthiouracil, Methimazole and Carbimazole

Cited by 163 publications

References 17 publications

Thyroid Hormone Deficiency Before the Onset of Hearing Causes Irreversible Damage to Peripheral and Central Auditory Systems

Thyroid Hormone Deficiency Before the Onset of Hearing Causes Irreversible Damage to Peripheral and Central Auditory Systems

Hyperthyroidism during Pregnancy

Inner-ring deiodination of 3,5,3'-triiodothyronine in the in situ perfused guinea pig placenta.

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