methimazole and Deafness

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).

Topics: Animals; Auditory Threshold; Cochlea; Deafness; Drug Administration Schedule; Evoked Potentials, Auditory, Brain Stem; Female; Fetus; Gene Expression; Hypothyroidism; Immunohistochemistry; Maternal-Fetal Exchange; Methimazole; Myelin Basic Protein; Myelin Proteolipid Protein; Organ of Corti; Otoacoustic Emissions, Spontaneous; Pregnancy; Rats; Rats, Wistar; Reaction Time; RNA, Messenger; Thyroid Hormones

The aim of the study was to trace subtle changes in the membranous labyrinth after experimental hypothyroidism that, at least in part, could explain how a reversed hearing impairment can occur, as is often clinically encountered in hypothyroid patients after thyroid substitution therapy. Adult Sprague-Dawley rats were made hypothyroid during six weeks by the use of methimazole in their drinking water. Their inner ears were investigated morphologically at the end of this period. The tectorial membrane is the first structure of the inner ear to show morphologic changes in hypothyroidism. Changes in the normal position and structure constantly were found. A thickening of the basilar membrane was indicated in many, but not all, specimens and in some control animals and may be coincidental. The initial morphologic changes are likely to be reversible after substitution therapy.

Topics: Animals; Cochlea; Deafness; Hypothyroidism; Methimazole; Organ of Corti; Rats; Rats, Inbred Strains; Tectorial Membrane; Time Factors