| Untreated maternal subclinical hypothyroidism(SCH)associated with increased maternal and foetal complications,such as miscarriage,premature delivery,intrauterine retardation,stillbirth,and a lower-than-normal IQ in offspring.Now guidelines recommend Levothyroxine(LT4)as First-Line Therapy patients with SCH during pregnancy.It is unknown what is the optimal cut-off value after LT4 therapy and how controlled ovarian hyperstimulation(COH)impact on hypothalamic pituitary thyroid axis in patients with SCH.Although evidence suggests thyroid dysfunction being associated with female infertility,the exact pathophysiology of thyroid hormone in ovulation and embryo implantation remains unknown.Polyfluorinated chemicals(PFCs)are a large family of manmade fluorinated chemicals used in hundreds of products from nonstick pans to water-resistant coating and firefighting foam.Growing evidence suggests that PFCs could adversely affect ovarian function and female fecundity.Majority of studies suggested PFCs affect human fecundity through longer time to pregnancy.However,the evidence remains insufficient to infer a causal relationship between PFCs exposure and adverse assisted reproductive technology(ART)outcomes.In this study,we aimed to investigate the effect of hypothyroidism on in vitro fertilization or intra-cytoplasmic sperm injection and embryo transfer(IVF/ICSI-ET)outcome of infertile women and the physiological functions and regulatory mechanisms of hypothyroidism leading to abortion.On the other hand,we aimed to evaluate if follicular fluid PFCs level is a prognostic marker of adverse reproductive outcome following IVF treatment.Fisrst,270 SCH were enrolled from a cohort of 4720 subfertile women who underwent either classical IVF or IVF-intracytoplasmic sperm injection(ICSI).We found SCH in women receiving LT4 replacement with a basal TSH level between0.2-2.5m IU/L displayed a similar rate of clinical pregnancy(47.4% vs 38.7%,p =0.436),miscarriage(7.4% vs 16.7%,p = 0.379)and live birth(43.9%vs 32.3%,p =0.288)compared to women with a basal TSH level between 2.5-4.2 m IU/L.Compared to the baseline level,serum TSH ascended distinctly and reached peak level on 14 days after ET in all patients.The two groups had similar trends of alteration.However,TSH?2.5m IU/L group had a significant higher proportion of patients with elevated serum TSH than TSH< 2.5 m IU/L(77.8% vs 40.9%,p=0.018).Second,we enrolled 299 women undergoing ART.Blood samples were drawn on the day of human chorionic gonadotrophin(HCG)administrationand.FF was obtained on the oocyte pick up(OPU)day.Each sample was analysed for TSH,thyroxine(T4),triiodothyronine(T3),FT4,FT3,thyroid peroxidase antibody(TPOAb)and thyroglobulin antibody(Tg Ab)levels.There were significant positive correlations between serum and FF TH and thyroid autoantibody levels.Statistically significant differences were discovered in serum and FF levels of TSH(p ? 0.001),T4(p?0.001),T3(p?0.001).2.Serum T4 levels [121.9(104.8,140.8)vs 114.1(98.6,130.6)nmol/L,p = 0.026],serum FT4 levels [(19.0(17.7,21.8)vs18.6(17.0,20.1)pmol/L,p = 0.026],serum T4/T3 ratios [62.5(55.7,66.2)vs 59.4(53.4,64.9),p = 0.029],FF FT4 levels [19.0(17.5,21.3)vs 18.1(16.8,19.9)pmol/l,p= 0.009] and FF T4/T3 ratios [52.6(46.4,57.3)vs 50.0(43.7,53.1),p = 0.004] were evaluated in the successful pregnancy group than the implantation failure group.Third,hypothyroidism was induced by administration of PTU at a concentration of 0.05% in the drinking water.The decuvialization of hESC cells was induced in vitro,and RT-PCR or Western blotting were used to detect the expressions of TSH receptor,LIF,LIF receptor,p-JAK1,JAK1,p-STAT3,and STAT3.In our study,the numbers of implant sites decreased while LIF and LIFR were higher in hypothyroidism group.In the hESC cells,TSH upregulated LIF,LIFR,p-JAK1 and p-STAT3 expression.Finally,we examine follicular fluid PFCs exposure and ART outcomes in poor ovarian reserve(POR)population in a prospective study.After adjustment for age and BMI,perfluorooctanoic acid(PFOA),perfluorononanoic acid(PFNA),perfluorohexane sulfonate(PFHx S)and ?PFAS was strongly associated decreased probability of pregnancy(PFOA highest vs.lowest tertile: OR=1.95,95%CI:1.61,2.38;PFNA highest vs.lowest tertile: OR= 3.0,95%CI: 2.46,3.68;PFHx S highest vs.lowest tertile: OR= 1.95,95%CI: 1.61,2.35;?PFAS second vs.lowest tertile: OR=3.31,95%CI: 2.74,3.89).PFOS and PAUn A were inversely associated with failed implantation.There were no relationships between failed implantation and other PFCs analytes.The same result was obtained,when using live birth as outcome measure.In conclusion,strictly controlled TSH(less than 2.5 m IU/L)before IVF may have no effect on the pregnancy rate in LT4 treated SCH women.COH can significantly increase serum TSH levels in treated SCH patients.Infertile patients with serum TSH ? 2.5 m IU/L are more susceptible to COH.Furthermore,TSH may affect endometrial stromal cell decidualization through activation of LIF/JAK1/STAT3 pathway.On the other hand,in women with POR,follicular fluid PFCs exposure may decrease the probability of clinical pregnancy and live birth. |
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