Discussion
The WHO worldwide estimation suggests that infertility currently affects up to 50–80 million women, with a variable incidence that may rise to about 50% of all women [10]. Infertility in women can occur due to several factors that include ovulatory dysfunction, tubal, cervical and/or uterine factors, as well as endometriosis. However, in 20–30% of cases, infertility remains unexplained [10].
Gathering studies have reported that increased expression of IFN-γ results in cell-mediated immune destruction of many organs which in turn leads to activation of humoral immune response and increase cytokine production and this leads to initiation or progression of autoimmune disease. Increased levels of IFN-γ have been strongly linked to HT [11].
Interesting, this cross-sectional study shows that about 37.5 % of studied women with HT had UEI, which is associated with idiopathic poor ovarian reserve as detected by low values of AFC count and AMH in patients suffer from UIE.
Thyroid hormones seem to participate in the complex regulation of ovarian function [6]. According to our results, females with UEI had statistically significant increases in the age of menarche and TSH as compared to the fertile group. Other studies had shown the influence of TSH on fertility. Jokar et al., had investigated the relationship between TSH and conception rates and have shown that women with UEI have significantly higher TSH levels than normal fertile women [12]. High level of TSH in UEI was also concluded by other studies [13, 14].
Thyroid autoantibodies play an essential role in the immunopathogenic process of autoimmune thyroiditis. Increased levels of TPO-abs is considered the most sensitive marker of autoimmune disease [15]. In this study, women with UEI showed statistically significant increases of anti-TPO, anti-TG in relation to the fertile group. Similar to our result, a study conducted by Chen et al. showed a higher rate of positive TPO-Ab is females with UEI [16]. A meta-analysis pooling 4 studies showed that the presence of thyroid antibodies, anti-TPO, anti-TG in with unexplained subfertility (OR 1.5, 95% CI 1.1e2.0) [17]. A study by Jatzko et al., showed high anti-TPO-Ab and TG-Ab levels were associated with failure of in-vitro fertilization process [18]. Similar results confirmed by Deroux et al. they observed that thyroiditis could be a cause of infertility; even in the euthyroid state, the presence of anti-thyroperoxidase antibodies and/or thyroglobulin is related to infertility [19].
T helper cells cytokines contribute to fertility and the success of pregnancy. Th1 cells produce inflammatory cytokines, such as interferon (IFN)-γ to promote cell-mediated immunity. On the other hand, Th2 cells are involved in the humoral immunity by producing interleukin (IL)-4, IL-5, and IL-13. The Th1/Th2 balance has been used as a framework for predicting pregnancy outcomes. Several studies have confirmed that successful pregnancy is associated with a predominant Th2-type immunity, while Th1-type immunity is associated with pregnancy-related disorders [1].
According to our results, women with UEI showed statistically significant increases in the levels of serum IFN- γ, IFN- γ mRNA when compared to the fertile group. To our knowledge, this is the first study investigating the circulating serum and expression levels of IFN- γ in Egyptian women with HT and its possible associations with clinical and laboratory characteristics of UEI as well as thyroid disease.
Similar results were described in Mahdi observed that women with a reproductive failure have a significant increase in serum levels of IFN- gamma [20]. Also, Reid et al. confirmed higher levels of IFN-gamma in infertile females [21].
We investigated our results by ROC test to assess the power of serum IFN- γ and IFN- γ gene expression in the diagnosis of UEI among women with HT.
Regarding the power of serum IFN- γ in differentiating fertile women from women with UEI, the AUC was 0.984, a cutoff values of 16.7mg/dl had sensitivity = 99.6%, and specificity = 96%; Concerning the power of IFN- γ gene expression in differentiating fertile women from women with UEF, the AUC was 0.912 (95% CI = 0.860–0.965) with sensitivity = 90.4%, specificity = 94.2%, and the cutoff values 2.65mg/dl. Regarding the power of the combination of circulating serum IFN- γ and IFN- γ gene expression for differentiating UEI from fertile women, the AUC was 0.953 (95% CI = 0.889–1.000) with sensitivity = 90.4%, specificity = 94.2%. To our knowledge, this is the first study to include the trial of estimating serum IFN- γ and IFN- γ gene expression as diagnostic signatures of unexplained infertility in women with Hashimoto’s Thyroiditis.
Conclusion : 37.5 % of the studied Egyptian women with HT had UEI there were statistically significant increases of the age of menarche, TSH, anti-TPO, anti-TG, serum IFN- γ, IFN- γ mRNA in UEI group as compared to the fertile group. Cutoff values of 16.7pg/dl for IFN- γ and 2.65pg/dl for IFN- γ gene expression are specific and sensitive for differentiating UEI from fertile women.