Understanding molecular mechanism of Implantation Failure in Women with Endometriosis and Adenomyosis Undergoing In-vitro Fertilization and Methods to Improve their Fertility Outcomes

Adenomyosis is an uterine pathology characterized by the invasion of endometrial glands and stroma in the myometrium leading to disruption of uterine junctional zone. Women with adenomyosis usually have symptoms of progressive dysmenorrhoea and menorrhagia though some cases may be asymptomatic1. It is found in a high proportion of infertile (24.4%) patients especially in those with endometriosis, repeated miscarriage and recurrent implantation failure and in older women seeking in-vitro fertilization (IVF) treatment2.

The dysmenorrhoea associated with adenomyosis as well as endometriosis may sometimes be so debilitating that the pain management takes precedence over fertility treatment. Medical management of pain associated with these disease processes takes longer time and thus losing the precious years of reproductive age. The evidence showing effect of adenomyosis and endometriosis in assisted reproductive technologies (ART) outcome is controversial3,4. Some researchers have reported decreased implantation rate and negative reproductive outcomes with adenomyosis; however, others failed to observe such association. Although various mechanisms have been postulated regarding the impact of adenomyosis on infertile women, the underlying molecular events responsible for implantation failure in these women remains unclear.

The increased expression of P450 aromatase has been observed in women with endometriosis and adenomyosis5. It is reported that endometrial aromatase expression has been associated with poor reproductive outcomes in IVF6. One of the actions of Letrozole and GnRH agonist is the suppression of endometrial aromatase expression. Few studies have reported that long term use of GnRH agonists before IVF treatment has improved reproductive outcome. The effect of Letrozole on the treatment of adenomyosis before IVF treatment is yet to be studied.

Review of literature:

Endometriosis and adenomyosis is an estrogen-dependent disorder and is associated with increased aromatase expression5. It has been reported that in infertile women the prevalence of adenomyosis with endometriosis is estimated as 79% and without endometriosis as 28%7. The impact of adenomyosis on natural conception or fertility treatment is not clear. The proposed mechanisms responsible for infertility and poor reproductive outcome in adenomyosis may be abnormal junctional zone  myometrium leading to dysregulation of uterotubal contractility8, altered endometrial function and receptivity and abnormal decidualization8 Cytokines, prostaglandins and other inflammatory mediators lead to excessive free radical formation which may deteriorate oocyte quality and embryo development in adenomyosis9. It is hypothesized that free radicals lead to activation of macrophages and T cells and also increased nitric oxide exposure resulting in early miscarriage10.

Kitawaki et al. demonstrated the expression of P450 aromatase protein and mRNA in adenomyotic tissue and eutopic endometrium of adenomyosis, but it was not detected in the endometrium of women without adenomyosis. It is reported that increased endometrial aromatase expression is associated with poor reproductive outcomes in IVF5

Letrozole has been used as a medical treatment for endometriosis associated pain11 and might improve the IVF success rates in a subset of women with endometriosis12. Use of Letrozole inhibits aberrant expression of aromatase in endometriosis and balances estrogen and progesterone action. It normalize the ability of progesterone to down-regulate estrogen receptors, which is essential during implantation.13

GnRH agonist, mainly used in endometriosis for pain management, has also been found to decrease expression of P450arom in the eutopic endometrium of women with adenomyosis and endometriosis.13 A 3-month hormonal therapy before IVF might therefore create a more favorable environment for oocyte maturation, with better oocyte quality and better fertilization rates as well as embryo quality. However the longer duration of stimulation and the higher amount of medication needed argue against this treatment.

Aim of our study is to evaluate molecular marker of implantation in women with adenomyosis and endometriosis, and to assess the role and compare letrozole and GnRH agonist in improving implantation and reproductive outcome in these women undergoing IVF.

 Objectives:

1 1. To assess and compare the reduction in dysmenorrhea/menorrhagia and sonographic features of adenomyosis in Indian women.

2. To evaluate the molecular markers of implantation in patients with adenomyosis alone or with endometriosis and compare them with controls.

3. To evaluate and compare different treatment approaches from molecular perspectives to improve the implantation failure.

4. To further assess and compare the post-treatment implantation and reproductive outcome for the proposed treatment approaches in adenomyosis undergoing in vitro fertilization.