Disorders of thyroid hormone functions and influences upon reproductive hormone production of adult female cynomolgus monkey (Macaca fascicularis) chronically forced-fed daily with methimazole and its recovery afters drug withdrawal

Abstract

The aims of this study are ( i ) to establish the various degrees of hypothyroidism in adult female cynomolgus monkeys by forced-fed with methimazole (MMI), ( ii ) to investigate the influence of these states of hypothyroidism upon serum level of thyroid hormones, TBG, TSH, PRL, E₂, and P,( iii ) to compare these hormonal patterns between the pregnant monkey Previously treated with MMI and normal pregnant monkeys. MMI in the dose of 10 mg/day for 4 - 2U weeks was capable of inducing hypothyroidism. The drug was reduced to 5 and 2.50 mg/day in order to exhibit less degree of inhibition and thereby the severity of hypothyroidism. These dosages of MMI were used for maintain severe and mild hypothyroidism for 63 - 140 and 80 - 231 days, respectively. Severe and mild states of serum fT4 levels declined to 0.03 - 0.45 ng/d1 and 0.60 - 1.10 ng/d1. Corresponding decrease of T3 and T4 were evident along with lower fT4 levels. On the other hand, TSH increased prominently during the severe state (> 35 mIU/L) and then dropped to 4 - 19 mIU/L during the mild state. Compensatory phenomena were noticed during the period between severe and mild states. Only one animal showed two periods of severe states. During the progressive hypothyroidism, clinical symptoms such as edematous eye lids, amenorrhea, galactorrhea, anorexia and lethargy were also observed. The PRL levels elevated in concurrent with the raised TSH levels during severe hypothyroidism. Increment of TBG levels during this state was noted duemainly to lower T3 and T4 levels. Both levels of E₂ and P declined with irregular bleeding cycles interspersed with amenorrhea. In mild state, serum PRL levels reduced concomitantly with lower TSH levels. The greater E₂ and P during the follicular and luteal phases with resumption of menstrual bleeding cycles were found. Some normal cycles showed detectable LH pesk in mid cycle with classical higher E₂ and P patterns during the follicular and luteal phases, respectively. After drug withdrawal, the levels of T3, T4 and fT4 started to rise progressively toward the control values whereas the TSH levels diminished gradually toward the control values. Both PRL and TBG levels decreased to normal. Pregnancy occurred during the first post- treatment cycle monkey no. 63. Comparing these hormonal patterns including TBG throughout entired gestation of monkey no. 63 and normal pregnant animals, most of them were similar. However, the PRL levels of no. 63 remained fairly high before and during the pregnancy and seemed to be greater than those in normal pregnancy while the pattern of TSH levels tended to be low and contrasted to those in normal pregnancy.