Effect of TSH on oocyte maturation of PCOS patients with normal thyroid function in IVF

Thyroid hormone is an endocrine hormone that can maintain nervous system excitation, promote the development of tissues and organs, and regulate metabolism [12].

Due to the interaction between the hypothalamus pituitary ovary axis and the hypothalamus pituitary thyroid axis, thyroid hormone can have negative feedback effect on hypothalamus and pituitary. When TSH level is abnormal, it will affect hypothalamus function, resulting in abnormal hypothalamus pituitary gonad axis function [5,6,7]. Some studies have shown that the majority of female patients with thyroid dysfunction have symptoms such as irregular menstrual cycle, rare menstruation, irregular uterine bleeding, and some of them have polycystic ovarian changes with abnormal blood glucose metabolism and lipid metabolism disorder [19,20,21], which are considered to be related to insulin resistance and islet cell damage. At the same time, the imbalance of gonadal axis in PCOS patients may affect the pituitary thyroid axis. Many studies found that PCOS patients with severe hyperandrogenemia and insulin resistance are prone to be associated with abnormal thyroid function [22, 23]. Compared with normal women of childbearing age, PCOS patients are often accompanied by elevated TSH [8,9,10]. It is not known whether the elevated TSH levels in PCOS patients with normal thyroid function is associated with negative outcomes of in-vitro fertilization, such as poor oocyte maturation, low fertilization rate and high incidence of OHSS [24,25,26].

Our study showed that the average TSH level of PCOS patients with normal thyroid function was significantly higher than that of non-PCOS patients (2.42 ± 0.86VS2.00 ± 0.89, P < 0.001). This is consistent with the results of literature studies reported so far. The oocyte maturation rate of PCOS group was lower than that of non-PCOS group (90.9% vs 92.4%, P = 0.02), which further led to the lower 2PN fertilization rate in PCOS group than that in non-PCOS group (84.57% vs 86.77%, P = 0.02). However, there was no significant difference in cleavage rate and high-quality embryo rate between the two groups, and the pregnancy outcomes including clinical pregnancy rate, abortion rate and live birth rate were not significantly different between the two groups. We believe that this may be due to the development of IVF/ICSI therapy and the improvement of embryo culture system, which improves the adverse effects of elevated TSH on oocytes, so there was no significant difference between embryo outcome and pregnancy outcome. We adopt multi-factor linear regression analysis to evaluate the relationship between oocyte maturation and related variables. The results showed that TSH was negatively correlated with oocyte maturation of each patient [β = -124, P = 0.013,95% CI (- 0.027 ~ -0.003)], which suggested that TSH might be an independent risk factor for oocyte maturation in PCOS patients with normal thyroid function when undergoing IVF-ET.

TSH receptors are widely expressed in human oocytes, cumulus cells and granulosa cells of ovary. TSH cooperates with FSH to regulate the proliferation, apoptosis and morphological differentiation of granulosa cells, and play a direct role in promoting the function of granulosa cells [27]. TSH promotes the production of LH and hCG receptors on the surface of granulosa cells,while there is a close relationship between granulosa cells in follicles and oocytes, and gap junctions exist between them, the information transmission, mutual promotion and synchronous development between cells was put in to effect depend on the connexins [28].The functional status of granulosa cells directly affects the maturation of oocytes, granulosa cells also support oocyte maturation in an endocrine manner, and affects fertilization and even embryo development potential. Those maybe the main mechanism of the influence of TSH on oocyte quality in PCOS patients. In addition, the E2 levels on hCG trigger day of PCOS group is greater than that of non-PCOS group, and it is reported that the supraphysiological E2 levels during COH will also lead to the transient increase of TSH, this is mainly due to the increase of thyroxine binding protein caused by the super physiological high estrogen level in the serum, which reduces the concentration of free thyroid hormone and then causes the increase of serum TSH. Studies shown that the concentration of TSH increases with the increase of super physiological E2 level [29]. This may be another mechanism by which TSH affects oocyte maturation rate in PCOS group. However, the impact of of COH on TSH may be transient, the increased TSH after COH can not really reflect the state of thyroid function. TSH level after COH was not detected in this study, which is the deficiency of this paper.

There is no unified standard for what levels TSH should be controlled before IVF-ET at present. The American Society for reproductive medicine (ASRM) issued guidelines which suggested that if the TSH level of women of childbearing age before pregnancy is higher than 2.5mIU/ L, it is feasible to monitor the serum TSH level for many times. Once the serum TSH level is higher than 4.0mIU/L, levothyroxine can be used to maintain the serum TSH level below 2.5mIU/ L [14]. But it is controversial whether or not to use 2.5mIU/L thresholds for upper limit of TSH in first-trimester pregnancy and infertility [30,31,32].

In this study, we plotted the ROC curve of the effect of TSH on the oocyte maturity of each PCOS patient. The results showed that the area under the curve was 0.550, p = 0.037, and the specificity was 28.9%, the sensitivity was 83.0%. According to the cut-off threshold TSH 2.98uIU/ml, the patients were divided into two groups. There was a significant difference in oocyte maturity between the two groups (p < 0.001); The clinical pregnancy rate (64.3% vs57.4%, P = 0.085) and Live birth rate (53.7% vs 47.5%, P = 0.116) in TSH < 2.98 group was higher than that of TSH ≥ 2.98 group, but the difference was not statistically significant. Therefore, our results suggest that when TSH ≥ 2.98uIU/ml, the possibility of oocyte immaturation is higher (specificity 28.9%, sensitivity 83.0%), and it may have a negative effect on pregnancy outcomes.

Conclusion

The TSH level of PCOS patients with normal thyroid function is higher than that of normal people, and it is negatively related to the oocyte maturation in IVF. We suggest that for PCOS patients with normal thyroid function, when TSH is higher than 2.98uIU/ml, intervention should be given before IVF cycle was conducted, which may be helpful to improve oocyte maturation.

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