Insulin has a direct toxic impact on placenta: learn how Metformin may prevent these deleterious effects during pregnancy

Posted By Braverman IVF & Reproductive Immunology | 6-February-2019

A recent article published in the journal Fertility and Sterility showed strong and direct toxic effects of insulin on trophoblast cells of first trimester (placental cells) resulting in increased levels of DNA damage, increased levels of apoptosis and lower levels of cell survival.

Most interestingly, pretreatment with Metformin prevents trophoblast cells from being injured by elevated levels of insulin.

Insulin resistance during pregnancy significantly increases the risk of poor pregnancy outcomes including recurrent miscarriage (1-2), fetal anomalies such as macrosomia (3), and obstetrical complications such as pre-eclampsia (4). In patients with PCOS, insulin resistance is considered as an important contributing factor of the disease (5).

In the above-mentioned study, first trimester trophoblasts have been collected from elective termination of healthy pregnancy (6-8 weeks of gestation). rophoblasts have been cultured in vitro with insulin dose like those found in women with insulin resistance (6) or left untreated as controls. After 48H, assessment of DNA damage, apoptosis and cell survival have been made. Results in the insulin treated trophoblasts as compared to the controls showed:

  • +386% of DNA damage
  • -66% in cell survival
  • due to increased apoptosis levels (cell death): +4000%

    Strikingly, pretreatment of the cells with metformin followed by culture of the cells in the presence of metformin and insulin prevented any detectable DNA damage or apoptosis and prevented any decrease in cell survival.

    When metformin is added at the same time as insulin, the insulin ‘s toxic effects on trophoblast cells are minimized and reduced by half.

    The insulin’s detrimental effects are specific to trophoblast as similar treatment in other cell line have shown no alterations of DNA, cell survival or apoptosis.

    Some studies have reported the beneficial effects of metformin co-treatment on IVF outcomes in women with PCOS suggesting that oocyte/embryo quality is improved (7).

    Indeed, mice studies have shown that metformin is protective against insulin-induced DNA damage (8), blastocyst apoptosis (9) and developmental embryo defect (10).

    In a systematic review (11), metformin administration, in addition to gonadotropins for ovulation induction in patients with PCOS, was shown to significantly increase the live birth and pregnancy rates of about two-fold as compared to placebo-controlled PCOS patients.

    In addition, a Cochrane study (meta analyze) also confirmed that the use of Metformin during IVF improves clinical pregnancy (12).

    Similarly, a worldwide web-based survey among IVF center (evaluating the effects of Metformin administration during IVF cycles) reported that metformin increases the clinical pregnancy rates in 70% of IVF cycles (13).

    Finally, another Cochrane study showed the benefits of metformin use during IVF cycle in PCOS patients, with increased rates of clinical pregnancy and decreased risk of ovarian hyperstimulation (14).

    We, at Braverman Reproductive Immunology, have high success rate in PCOS patients on Metformin, including patients with endometriosis and significant diminished ovarian reserve.

    Systematic screening for insulin resistance and PCOS are part of our test panel before attempting to conceive.

    When appropriate, we recommend a treatment with Metformin while monitoring your levels throughout the pregnancy to maximize your chances of having a healthy baby.

    Questions? Call 516.584.8710
    We would be happy to help you take control of your fertility journey and answer any questions you may have.


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