Levothyroxine treatment generates an abnormal uterine contractility patterns in an in vitro animal model

Abstract

ObjectiveAbnormal uterine contraction patterns were recently demonstrated in uterine strips from pregnant women treated with Levothyroxine (T4). These abnormalities were correlated with an increased risk of C-section delivery and associated surgical complications. To date, no study has investigated whether uterine contractility is modified by hypothyroidism or T4 treatment. Herein, we analyze the physiological role of T4 on uterine contractions.Study designFemale non-pregnant Sprague–Dawley rats (N = 22) were used and divided into four groups: 1) control, 2) hypothyroidism, 3) hypothyroidism treated with low T4 doses (20 μg/kg/day) and 4) with high T4 doses (100 μg/kg/day). Hypothyroidism was induced by an iodine-deficient diet. Isometric tension measurements were performed in vitro on myometrium tissues in isolated organ baths. Contractile activity parameters were quantified (amplitude, duration, frequency and area under the curve) using pharmacological tools to assess their effect.ResultsScreening of thyroid function confirmed a hypothyroid state for all rats under iodine-free diet to which T4 was subsequently administered to counterbalance hypothyroidism. Results demonstrate that hypothyroidism significantly decreased contractile duration (−17%) and increased contractile frequency (+26%), while high doses of T4 increased duration (+200%) and decreased frequency (−51%). These results thus mimic the pattern of abnormal contractions previously observed in uterine tissue from T4-treated hypothyroid pregnant women.ConclusionOur data suggest that changes in myometrial reactivity are induced by T4 treatment. Thus, in conjunction with our previous observations on human myometrial strips, management of hypothyroidism should be improved to reduce the rate of C-sections in this group of patients.

The impact of levothyroxine exposure on delivery outcome in hypothyroid pregnant women (PETAL study): A five-year retrospective cohort study

“…[21][22][23] Therefore, a prolonged uterine quiescent phase in late pregnancy could be hypothesized as a cause of fetal breech presentation, in addition to an inefficient uterine contraction pattern induced by a high thyroxine concentration state, resulting in an increase of overall CD rate. 4,12,21,[24][25][26] However, our study cannot support this hypothesis as the prescribed dosage, the women's adherence to levothyroxine therapy and their thyroid function could not be assessed for all patients due to missing data. More studies are then needed to explore the effect of inappropriately treated hypothyroidism on delivery outcome.…”

“…Based on the results our team previously demonstrated in fundamental research, we could presume a possible additional effect of levothyroxine due to overtreatment in hypothyroid pregnant women of our population. 11,12 Some clinical studies also documented an increased risk of CD and labor induction with hyperthyroidism, where women are exposed to high thyroxine serum concentrations due to a pathological overstimulation of thyroid hormone production. [21][22][23] Therefore, a prolonged uterine quiescent phase in late pregnancy could be hypothesized as a cause of fetal breech presentation, in addition to an inefficient uterine contraction pattern induced by a high thyroxine concentration state, resulting in an increase of overall CD rate.…”

“… 11 We conducted a second study where the same altered contraction pattern was observed in hypothyroid female rats that were supposedly over-supplemented with levothyroxine, although their thyroid function was not verified. 12 Therefore, exposure to an inappropriate dosage of levothyroxine may possibly affect the uterine contraction efficiency in peripartum.…”

Myoinositol Causes Myometrial Contractions in Isolated Non-Pregnant Rat Myometrium

“…It is observed that glibenclamide and metformin, drugs used in diabetes and PCOS, does not change the amplitude and frequency of spontaneous uterine contractions (23). It was found in another rat study that T4 treatment changes myometrial activity (24). After the observation of increased frequency of uterine contraction during ovarian stimulation cycles compared with the corresponding phase of natural menstruel cycles in a number of studies, a new pharmaterapeutic target arised and investigation of drugs reducing the contractility of uterus increased and conflicting results are found (25,26).…”

Uterotonic Effects of Aqueous and Methanolic Extracts of Lannea acida in Wistar Rats: An In Vitro Study

“…In fact, as term approaches, the quiescent uterus becomes activated byestrogens.This leads to increased expression of various contraction-associated proteins (CAPs) such as prostaglandin and oxytocin receptors [2]. Also, an increase in gap junction formation between adjacent myometrial cells allows electrical synchrony within the myometrium and ensures effective coordination of contractions [3]. During labor process, the frequency and intensity of myometrial smooth muscle contractions are essential contributing factors to normal delivery [4].…”