Hashimoto’s thyroiditis impairs embryo implantation by compromising endometrial morphology and receptivity markers in euthyroid mice

Abstract

BackgroundAlthough thyroid dysfunction caused by Hashimoto’s thyroiditis (HT) is believed to be related to implantation failure due to the underdevelopment of the receptive uterus, it is unknown whether HT itself, even in the euthyroid state, impairs embryo implantation associated with endometrial receptivity defects. To address whether HT itself can affect endometrial receptivity accompanied by implantation alterations, a euthyroid HT model was established in mice.MethodsFemale NOD mice were immunized twice with thyroglobulin and adjuvant to induce the experimental HT model. Four weeks after the second treatment, the mice were normally mated, and pregnant ones were sacrificed in implantation window for thyroid-related parameter and steroid hormones measurements by electrochemiluminescence immunoassay and enzyme-linked immunosorbent assay and implantation site number calculation by uptake of Chicago Blue dye. In addition, certain morphological features of endometrial receptivity were observed by hematoxylin-eosin staining and scanning electron microscopy, and the expression of other receptivity markers were analyzed by immunohistochemistry, RT-qPCR or Western Blot.ResultsHT mice displayed intrathyroidal monocyte infiltration and elevated serum thyroid autoantibody levels without thyroid dysfunction, defined as euthyroid HT in humans. Euthyroid HT resulted in implantation failure, fewer pinopodes, retarded pinopode maturation, and inhibited expression of receptivity markers: estrogen receptor α (ERα), integrin β3, leukemia inhibitory factor (LIF), and cell adhesion molecule-1 (ICAM-1). Interestingly, despite this compromised endometrial receptivity response, no statistical differences in serum estradiol or progesterone level between groups were found.ConclusionsThese findings are the first to indicate that HT induces a nonreceptive endometrial milieu in the euthyroid state, which may underlie the detrimental effects of HT itself on embryo implantation.

Effect of antithyroid antibodies on women with recurrent miscarriage: A meta‐analysis

“…The study of Merhan Dorostghoal 65 demonstrate that the endometrial ER‐α expression may lead to defects in uterine receptivity and contribute to unexplained infertility. Furthermore, Zhangbi Wu 66 indicated that TPO‐Ab induces a non‐receptive endometrial milieu in the euthyroid state, which may underlie the detrimental effects of Hashimoto's thyroiditis (HT) itself on embryo implantation. More research is needed to identify the role of thyroid autoantibodies on implantation.…”

Positive Impact of Levothyroxine Treatment on Pregnancy Outcome in Euthyroid Women with Thyroid Autoimmunity Affected by Recurrent Miscarriage

“…The association between TAI and miscarriage remains a matter of debate: it has been suggested that women with TAI have a more generalized autoimmune activity [ 5 , 6 ], leading to an increased fetal loss. Recent data suggest that euthyroid women are affected by TAI-impaired embryo implantation through induction of endometrial receptivity defects [ 7 ]. However, few studies have demonstrated the efficacy of therapies which modulate the immune function in preventing miscarriage [ 8 ].…”

MANAGEMENT OF ENDOCRINE DISEASE: Thyroid and female infertility: more questions than answers?!

“…The prevalence of thyroid dysfunction, the absolute number and percentage of T-cells, T-helper (Th) cells, B-cells and natural killer (NK) cells were not different between women with and without TAI (32,33). Since no difference in serum oestradiol or progesterone levels were observed between groups, these findings could indicate that TAI induces a non-receptive endometrial milieu that may underlie the detrimental effects on embryo implantation (34). However, in most clinical studies similar implantation rates were noted between women with -and without TAI, although with more first-trimester miscarriages in women with TAI (15,35).…”