Abstract
Polycystic ovary syndrome (PCOS) is a major anovulatory infertility affecting a great proportion of women of childbearing age and is associated with obesity, insulin resistance and chronic inflammation. Poor endometrial receptivity and recurrent implantation failure are major hurdles to the establishment of pregnancy in women with PCOS. The accumulating body of evidence obtained from experimental and clinical studies suggests a link between inherent adaptive and innate immune irregularities and aberrant endometrial features in PCOS. The use of conventional therapeutic interventions such as lifestyle modification, metformin and ovarian stimulation has achieved limited clinical success in restoring ovulation and endometrial receptivity in women with PCOS. Unlike other immunosuppressive drugs prescribed in the clinical management of autoimmune and inflammatory disorders that may have deleterious effects on fertility and fetal development, preclinical studies in mice and in women without PCOS but with repeated implantation failure revealed potential therapeutic benefits for the use of low-dose tacrolimus in treating female infertility. Improved systemic and ovarian immune functions, endometrial progesterone receptor and coreceptor expressions and uterine vascular adaptation to pregnancy were among features of enhanced progesterone-receptor sensitivity in the low-dose tacrolimus-treated mouse model of the disease. In this review, we have compiled available experimental and clinical data in literature on endometrial progesterone resistance and current therapeutic options, as well as mechanisms of actions and reported outcomes relevant to the potential therapeutic benefits for the use of low-dose tacrolimus in treating PCOS-associated female infertility.
Highlights
Polycystic ovary syndrome (PCOS) is a heterogeneous endocrine disorder and a major cause of anovulatory infertility affecting 6–10% of women of reproductive age [1,2,3]
We have demonstrated that the use of low-dose tacrolimus rescued the endometrial expression of protein inhibitor of activated STAT-y (PIASy) and restored its binding capacity to interact with and regulate the transcriptional activity of the nuclear progesterone receptor (PGR) in these uteri [146]
Provision of the best care for women with PCOS requires thorough understanding of the underlying immune and molecular mechanisms associated with poor ovarian functions, heightened progesterone resistance and declining endometrial receptivity
Summary
Polycystic ovary syndrome (PCOS) is a heterogeneous endocrine disorder and a major cause of anovulatory infertility affecting 6–10% of women of reproductive age [1,2,3]. Hyperandrogenemia and associated chronic anovulation, low progesterone (P4) levels and ensuing oligo-menorrhea further leading to endometrial dysfunctions, loss of endometrial plasticity is believed to be among contributing factors in the development of the reported cyclical irregularities in PCOS [8]. Evidence of primary endometrial defects in women with PCOS is demonstrated in the existence of inherent endometrial aberrancies in both ovulatory and anovulatory phenotypes affecting several biological pathways and the anomalous expressions of proteins involved in endometrial receptivity, such as those related to cell adhesion and the cytoskeleton network, transcriptional regulation, DNA repair, apoptosis and cell cycle regulation, cellular transport and signaling and mitochondrial metabolism [11,12,13,14,15].
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