PCOS is one of the most common metabolic and hormonal disorders, affecting one in ten women of reproductive age (Costantino et al., 2009). Women with PCOS present with a variety of symptoms associated with menstrual dysfunction and androgen excess, including irregular menstrual cycles, weight gain, infertility, and insulin resistance (Costantino et al., 2009; Genazzani et al., 2014). PCOS is the most common cause of infertility due to anovulation (lack of ovulation).
Insulin resistance affects 30–40% of women with PCOS and is believed to play a key role in abnormal ovarian function. Multiple clinical trials support supplementation with myo-inositol and D-chiro-inositol to help with the hormonal and metabolic symptoms of PCOS by promoting healthy glucose metabolism and reducing insulin resistance (Costantino et al., 2009; Genazzani et al., 2014; Gerli et al., 2007; Regidor et al., 2018; Formuso et al., 2015).
Active folate (L-5-MTHF) and methylcobalamin (vitamin B12) support fertility and normal early fetal development, help form red blood cells, and are factors in the maintenance of good health (Imdad et al., 2011; Visentin et al., 2016). Clinical studies show that folate supplementation at least three months before conception and during early pregnancy reduces the risk of neural tube birth defects by 41% (Imdad et al., 2011).
Both myo-inositol and D-chiro-inositol have been clinically shown to support a normal menstrual cycle and ovulation in women with PCOS (Benelli et al; 2016; Gerli et al., 2007). In a meta-analysis of seven trials including 935 infertile women receiving myo-inositol while undergoing ovarian induction prior to ICSI or IVF, a significant improvement in clinical pregnancy rate was accompanied by improvements in embryo quality and necessary ovarian stimulants (Zheng et al., 2017). In a clinical study with 48 women with PCOS and menstrual irregularities, the participants were given 1 g of D-chiro-inositol daily plus 400 mcg of folic acid, for six months. Researchers concluded that D-chiro-inositol is effective for improving ovarian function and metabolism, including statistically significant decreases in systolic blood pressure, LH, LH/FSH ratio, total and free testosterone, delta-4-androstenedione, and HOMA index, as well as statistically significant increases in SHBG and glycemia/IRI ratio. Additionally, there was a statistically significant increase of 62.5%
in regularization of the menstrual cycle (Laganà et al., 2015).
While myo-inositol is converted to D-chiro-inositol in the body, this conversion is believed to occur too quickly in women with PCOS, leading to increased D-chiro-inositol and decreased myo- inositol levels. Excess D-chiro-inositol (>600 mg per day) impairs egg quality, intensifying struggles with infertility. The physiological ratio of myo-inositol to D-chiro-inositol is 40:1, making this the optimal ratio for supplementation (Benelli et al., 2016). In addition, a clinical study supplementing 1.1 g of myo-inositol plus 27.6 mg of D-chiro-inositol daily helped improve oocyte and embryo quality, as well as pregnancy rates in women with PCOS undergoing IVF (Colazingari et al., 2013).
Myo-inositol and D-chiro-inositol in the optimal physiological ratio of 40:1 may help support healthy fertility in PCOS. In a six-month, randomized, placebo-controlled trial with 46 women with PCOS and
a BMI of >30, the participants were assigned to either the treatment group with 40:1 myo-inositol and D-chiro-inositol or to a folic acid placebo. Compared to the placebo group, the women in the treatment group experienced significant improvements in both endocrine and metabolic parameters, with decreases in free testosterone, LH, fasting glucose, fasting insulin, and HOMA index. The treatment group also experienced a significant increase in 17-beta-estradiol levels. No statistically significant endocrine or metabolic improvements were seen in the placebo group (Benelli et al., 2016).
In a placebo-controlled, double-blind clinical trial, women with PCOS were supplemented with 4 g of myo-inositol plus 400 mcg of folic acid daily. After 16 weeks, women taking myo-inositol experienced an 84% increase in whole-body insulin sensitivity, compared to no change in the placebo group. Myo-inositol was also shown to improve glucose tolerance and reduce serum total testosterone and serum- free testosterone concentrations by 66% and 73%, respectively. In addition, 69.5% of these women ovulated, compared to 21% taking the placebo (Costantino et al., 2009). In another double-blind, placebo-controlled trial, PCOS patients were supplemented with 4 g of myo-inositol plus 400 mcg of folic acid daily. Over the 14-week study, parameters of ovarian function improved, including a 25% increase in ovulation frequency (versus a 15% increase in the placebo group) and a significantly shorter time to first ovulation (24.5 days versus 40.4 days for the placebo group) (Gerli et al., 2007). A meta- analysis of seven trials found that supplementation with 4 g of myo- inositol plus 400 mcg of folic acid daily increased pregnancy rates among infertile women undergoing treatments to induce ovulation, such as IVF. Supplementation also allowed for the reduction of ovulation medication needed to promote fertility (Imdad et al., 2011).