Low-dose Aspirin Improves Endometrial Receptivity in Endometriosis

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Low-dose aspirin improves endometrial receptivity in endometriosis

Low-dose aspirin can downregulate progesterone resistance and increase the expression of LIF in endometriosis during the implantation window

doi.org/10.1080/09513590.2021.1918663

Background

Many studies found that chronic inflammation and impaired endometrial receptivity play a role in endometriosis-associated infertility. Progesterone resistance, commonly seen in women with endometriosis, is reported to reduce receptivity for embryo implantation. 

Similarly, leukemia inhibitory factor (LIF), found in the uterus is also involved in embryo implantation. Maximum expression of LIF normally occurs during the implantation window however in women with endometriosis LIF levels are decreased. 

A recent study using normal mice found that low-dose aspirin improved endometrial receptivity, by increasing the expression of LIF, however whether this finding is also true in cases of endometriosis has yet to be investigated.

Aim

Study the effect of low-dose aspirin on the endometrial receptivity in endometriosis rat models.

Methodology

A total of 44 non-pregnant female Sprague-Dawley rats were randomly divided into 3 groups: control (n=12), endometriosis (n=15), endometriosis treated with low dose aspirin (Aspirin) (n=17). 

To ensure identical endometriosis model rats, endometriosis was established using the autotransplantation method. Four weeks post-operation, the control, endometriosis and aspirin groups were administered saline, saline and aspirin (2 mg/kg) respectively, for 3 estrus (sexually receptive) cycles.

Female rats were housed with a male (2:1 ratio), and checked daily for insemination. Five and a half days later following insemination uterus tissue samples was surgically retrieved from pregnant rats for laboratory analysis.

Results

Immunostaining of endometrial tissue for progesterone clearly showed weak levels of progesterone in the endometriosis group, while progesterone expression in both control and aspirin groups was significantly higher (p <0.01).

Similarly western blot (protein) analysis of progesterone receptor protein isoforms A and B also showed significantly lower levels of both isoforms in the endometriosis rat group compared to both control and aspirin groups. The ratio of isoform A/B also decreased following aspirin treatment to control levels however this was not statistically significant due to study size.

Analysis of mRNA levels showed a similar trend with progesterone and isoform B significantly lower in the endometriosis group compared to control. This was partially reversed in the aspirin groups with isoform B back to almost control group levels while mRNA progesterone expression did not improve with aspirin.

Next analysis of LIF in the tissue samples showed a significant reduction in protein, mRNA and serum levels of LIF, within the endometriosis rat group compared to control and aspirin groups. These tests also showed that levels of LIF did not differ significantly between control and aspirin groups, confirming that aspirin treatment in rats can comprehensively increase LIF expression.

Finally to understand how aspirin may affect LIF expression, full analysis of the LIF receptor (LIFR) was performed. Interestingly no significant difference was seen in either protein or mRNA expression levels of LIFR in either control, endometriosis or aspirin groups suggesting aspirin increases LIF expression by decreasing inflammation and progesterone resistance.

SUMMARY: EFFECT OF ASPIRIN ON ENDOMETRIOSIS FERTILITY

Low-dose aspirin treatment of endometriosis downregulated progesterone resistance and increased the expression of leukemia inhibitory factor, in rat endometriosis models, suggesting aspirin may improve endometrial receptivity & increase embryo implantation rates in cases of endometriosis.

Limitations

  1. Biological systems of rats are similar however not identical requiring human studies to confirm the relevance for women with endometriosis.
  2. Study was limited in scope (i.e. progesterone and LIF only) not testing or reporting fertility outcomes.

Funding

The study was supported by the National Key Research and Development Program of China, National Natural Science Foundation of China and the Jinan City Science and Technology Development Plan.

Glossary

Downregulate
The process of reducing or suppressing a response.

Endometrial receptivity
The ability of the endometrium to successfully attach a blastocyst (embryo), nourish it and keep it alive.

Immunostaining
An antibody-based laboratory method to detect a specific protein in a sample.

Isoform (protein)
A member of a set of highly similar proteins that originate from a single gene.

mRNA
A single-stranded RNA molecule that is complementary to one of the DNA strands of a gene.

Progesterone resistance
A decreased responsiveness of target tissue to bioavailable progesterone.

Receptor
Chemical structures, composed of protein, that receive and transduce signals within a biological system.

Saline
A mixture of sodium chloride (salt) in water.

Western blot
A laboratory method used to detect specific protein molecules from among a mixture of proteins.

Similar studies

Wang TF, et al. (2020). Low-dose aspirin improves endometrial receptivity in the midluteal phase in unexplained recurrent pregnancy loss. https://doi.org/10.1002/ijgo.13160

Patel, B G, et al. (2017). Progesterone resistance in endometriosis: origins, consequences and interventions. https://doi.org/10.1111/aogs.13156

Rosario G X and Stewart C L, (2016). The multifaceted actions of leukaemia inhibitory factor in mediating uterine receptivity and embryo implantation. https://doi.org/10.1111/aji.12474

Hauzman E E, et al. (2013). Oocyte donation and endometriosis: what are the lessons? https://doi.org/10.1055/s-0032-1333483

Zhao M, et al. (2010). Treatment with low-dose aspirin increased the level LIF and integrin b3 expression in mice during the implantation window. https://doi.org/10.1016/j.placenta.2010.10.002


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