Archives

  • 2018-07
  • 2018-10
  • 2018-11
  • 2019-04
  • 2019-05
  • 2019-06
  • 2019-07
  • 2019-08
  • 2019-09
  • 2019-10
  • 2019-11
  • 2019-12
  • 2020-01
  • 2020-02
  • 2020-03
  • 2020-04
  • 2020-05
  • 2020-06
  • 2020-07
  • 2020-08
  • 2020-09
  • 2020-10
  • 2020-11
  • 2020-12
  • 2021-01
  • 2021-02
  • 2021-03
  • 2021-04
  • 2021-05
  • 2021-06
  • 2021-07
  • 2021-08
  • 2021-09
  • 2021-10
  • 2021-11
  • 2021-12
  • 2022-01
  • 2022-02
  • 2022-03
  • 2022-04
  • 2022-05
  • 2022-06
  • 2022-07
  • 2022-08
  • 2022-09
  • 2022-10
  • 2022-11
  • 2022-12
  • 2023-01
  • 2023-02
  • 2023-03
  • 2023-04
  • 2023-05
  • 2023-06
  • 2023-07
  • 2023-08
  • 2023-09
  • 2023-10
  • 2023-11
  • 2023-12
  • 2024-01
  • 2024-02
  • 2024-03
  • 2024-04
  • 2024-05

    • The causes for implantation failure in PCOS patients

    2018-10-23

    The causes for implantation failure in PCOS patients might be due to endometrial defects as indicated by the dysregulation of the expression of proteins required for implantation in the human pim inhibitor (Piltonen, 2016). A major finding of our study is that metformin treatment reverses endocrine (hyperandrogenism), metabolic (insulin resistance), and reproductive (absence of estrous cycle) abnormalities, and it also partially reverses the implantation failure to a large extent in most of the PCOS-like rats (Fig. 7A). A number of molecules in the uterus have been shown to be required for implantation, and aberrations in these molecules cause reproductive failure (Cha et al., 2012; Zhang et al., 2013). Together with studies showing that endometrial decidualization is impaired in PCOS patients (Piltonen et al., 2015) and that several implantation-related genes (e.g., Lif, Ihh, Sgk1, Msx1, Hand2, and Muc1) are dysregulated in the DHEA-treated mouse uterus (Li et al., 2016a), we found that metformin fails to correct the abnormal levels of some of the implantation-related genes (Lif, Pc6, and Sgk1) in the PCOS-like rat uterus. Moreover, PCOS-like rats with implantation failure despite metformin treatment exhibited significant dysregulation of uterine Prl, Maoa, Ednrb, and Hbegf mRNA expression compared with control and PCOS-like rats with implantation. MAOA, EDNRB, and HBEGF all contribute to the enhancement of endometrial receptivity (Gibson et al., 2016), vascular permeability, and blood flow (Keator et al., 2011; Paria et al., 2001; Zhang et al., 2011). Although our study was not designed to determine whether aberrant regulation of Maoa, Ednrb, and Hbegf gene expression reduces endometrial receptivity and blood flow in PCOS-like rats, our results combined with a clinical study indicating the beneficial effect of metformin on endometrial receptivity and blood flow in PCOS patients (Palomba et al., 2006) led us to speculate that metformin improves uterine receptivity and blood flow through the correction of aberrant Maoa, Ednrb, and Hbegf gene expression under hyperandrogenism and insulin resistance conditions and that this is important for the establishment of implantation and subsequent fertility. Indeed, several clinical studies have reported that endometrial MAOA and HBEGF expression is decreased in infertile women (Leach et al., 2012; Vargas et al., 2012). Our findings also indicate that the failure of implantation is not due to disturbed follicular development or anovulation in PCOS-like rats treated with metformin. Because clinical studies have reported that metformin therapy improves endometrial receptivity and reduces the risk of miscarriage and premature birth in PCOS patients (Feng et al., 2015; Palomba et al., 2006), the present study provides molecular evidence for treatment with metformin in PCOS patients with endometrial-induced infertility. However, it cannot be discounted that treatment of control rats with metformin contributed to reduced body weight in the offspring during their development. Whether such a reduction of body mass will lead to alteration of reproductive or other functions in adults warrants further investigation. Previous results, including reports from our group, have indicated a significant difference in endometrial AMPKα expression and activation between non-PCOS and PCOS patients (Carvajal et al., 2013; Li et al., 2015b), but our current findings suggest that AMPKα is expressed in the rat uterus but its protein level is not changed in PCOS-like rats compared to control rats. Moreover, unlike what is seen in humans, we show that the uterine AMPKα activation is much more stable in PCOS-like rats. It has been suggested that increased expression and activation of AMPK is one of the crucial cellular mediators responsible for the effects of metformin treatment in several tissues and cell types (Foretz et al., 2014). Although others have reported that treatment with metformin enhances endometrial AMPKα expression and activation in PCOS patients with hyperinsulinemia (Carvajal et al., 2013), the present study does not support the hypothesis that uterine AMPKα expression and activation are preferentially regulated by metformin in rats with hyperandrogenism and insulin resistance. While the reasons for different regulation and activation of uterine AMPKα by metformin between humans and rats are not clear, it is tempting to speculate from these observations that the regulation of uterine AMPK is species specific and that the effects of metformin in the rat uterus are the same as in other tissues and cells (Foretz et al., 2014) and are independent of AMPK expression and activation.