Effect of hormone replacement therapy with estradiol in frozen embryo transfer on estrogen metabolism in women with various polymorphisms of catechol-O-methyltransferase gene

Objective: To compare the content of estradiol metabolites in the urine of women with various catechol-O-methyltransferase (COMT) rs4680 gene polymorphisms, who underwent natural frozen embryo transfer cycle andgonadotrophin-releasing hormone (GnRH) agonist long protocol with hormone replacement therapy (HRT). Materials and methods: We analyzed 28 assisted reproductive technology (ART) cycles with vitrified embryo; each of them was assessed for the level of estrone and estradiol metabolites in the urine and polymorphisms of the COMT rs4680 gene. Ultrasound monitoring of the endometrium and biochemical monitoring of estrogen and progesterone levels in blood serum were conducted. Levels of hydroxy- and methoxyestrone and estradiol in urine of women who had a frozen embryo transfer (FET) cycle were evaluated depending on COMT rs4680 gene polymorphism. A comparative analysis of the indicators was carried out depending on the FET type (progestogens in the natural cycle or GnRH agonist long protocol with HRT using 0.1% transdermal gel with estradiol). Results: GGpolymorphism of the COMTgene has been shown to be associated with a higher level of methoxylated forms of estrogens in the urine compared to that in women with AA and GA polymorphism of the COMT gene. Indicators of methoxylated estrogens in women with AA polymorphism in GnRH agonist long protocol were found to be better than those in women in the natural cycle, according to the content of non-dangerous methoxy forms in the urine of the patients. There was no increase in pro-oncogenic hydroxylated forms of estrogens in women who had a long protocol with HRT. Conclusion: The level of methoxylated estrogens formation is associated with COMT gene polymorphism: the lower level of methoxy forms is associated with AA and GA variants. At the same time, none of the polymorphism variants are associated with the increase of potentially dangerous metabolites of estrogen in women who had GnRH agonist long protocol. Therefore, the FET cycle with GnRH agonists combined with the use of 0.1% transdermal gel with estradiol does not result in a rise of pro-oncogenic estrogen metabolites and does not lead to an increase of oncological risks in ART programs compared to those with embryo transfer in a natural ovulatory cycle.

0, transdermal estradiol gel 0.1%, COMT polymorphism, FET cycle safety, hormone replacement therapy