Endocrine and paracrine factors related to pregnancy and infertility

Abstract

Unexplained infertility, one of the common gynecological disorders, affecting 10 to 15 % of women worldwide. Recurrent pregnancy loss affects approximately 1 to 3 % of pregnant women with an unknown etiology in 50 % of cases. Endocrine dysfunctions, including thyroid dysfunction, are one of the related factors to female reproductive disturbances. The aim of the thesis was to explore the importance of thyroid function and endometrial factors for implantation and pregnancy.

Three groups of pregnant women, one group with high risk (n = 88) was compared to a low-risk (n = 511) and a general screening group (n = 699) to study the incidence of subclinical hypothyroidism and hypothyroidism, defined as TSH < 2.5 mIU/L. Women with recurrent pregnancy loss, (n = 165), and controls, (n = 289), were included in genetic analysis and gene expression array of endometrium, (n = 4 and n = 5 respectively). Infertile women (n = 19) and fertile women were included to study thyroid-related proteins in endometrium (n = 28) and Fallopian tube (n = 13). Human embryos, (n= 36), were used to study the effect of thyroid hormone on embryo development.

Thyroid stimulating hormone (TSH), free thyroid hormone (fT4) and TPO antibodies (TPO-Ab) levels were analyzed by use of immunological methods. Genetic variations in the HABP2 gene was performed by use of TaqMan SNP Genotyping Assays. Gene expression array was used to study mRNA in endometrium of women with recurrent miscarriage at the time of implantation. Immunohistochemistry was used to analyze the presence and distribution of thyroid related proteins in endometrium. Additionally, influence of thyroid hormone (T4) on the early embryo development was analyzed.

Approximately 10 % of all pregnant women, regardless of risk, had elevated TSH levels. Furthermore, hypothyroid women on levothyroxine supplementation had in almost 50 % of cases inadequate treatment. There were no significant differences in the presence of polymorphism in HABP2 genes in comparison to fertile controls. In total, 124 genes were differently expressed in women with recurrent miscarriage mainly related to immunological processes, particularly shown by upregulation of IL8 in women with recurrent miscarriage. The infertile women showed lower protein staining of TRα1 and MCT8 in endometrium compared to the fertile women. Staining of thyroid related proteins was observed in all different parts of Fallopian tube. T4 supplementation showed improvement of blastocyst development in T4 added media.

In conclusion, general screening for thyroid dysfunction during first trimester of pregnancy is needed to find all women in need to LT4 supplementation. Inflammatory events, especially IL8, might offer a clue to recurrent pregnancy loss while variations in the HABP2 gene does not seem to be associated with recurrent miscarriage. The expression and distribution of thyroid-related factors in endometrium seem to be related to unexplained infertility. The presence of thyroid-related proteins in fallopian tube and the improvement of embryo development after T4 treatment suggest that a functional thyroid system is important form achievement of a normal pregnancy.