Polycystic ovary syndrome (PCOS) is a prevalent endocrine disorder affecting 5-20% of women of childbearing age, making it a significant cause of infertility. Diagnosing PCOS presents challenges due to the variability of symptoms. The Rotterdam criteria, requiring the presence of at least two of the following: ovulatory dysfunction, hyperandrogenism, or polycystic ovary morphology, are used for diagnosis. Insulin resistance (IR) plays a central role in the pathogenesis of PCOS, present in 75% of lean and 95% of overweight women with PCOS. A significant 60-70% of women with PCOS are overweight, with IR being more severe in obese women. Higher insulin levels reduce sex hormone binding globulin (SHBG) production in the liver, leading to increased free testosterone levels and worsening hyperandrogenism. Hyperinsulinemia also stimulates androgen overproduction of ovarian theca cells.
Metformin is a gold standard metabolic treatment for PCOS. However, it may induce gastrointestinal side effects such as nausea, diarrhea, vomiting, and flatulence. Alternative treatments with fewer side effects would be beneficial in managing these patients. In recent years, studies have analyzed the potential effects of inositol supplementation, suggesting that inositols are potent alternatives for metformin in treating PCOS.
Inositols belong to the vitamin B complex group and are synthesized in the human body. The most important stereoisomers are myoinositol and D-chiro-inositol. Inositols are considered insulin sensitizers, modulating members of insulin signaling pathways. They positively influence menstrual cycle regularity, carbohydrate metabolism, and clinical and laboratory symptoms of hyperandrogenism (e.g., free testosterone, total testosterone, SHBG). However, the level of evidence has not been satisfactory for accepting them as standard therapy in the guidelines.
Objective
This systematic review aims to evaluate the efficacy and safety of inositols in treating PCOS, providing evidence for future guidelines.
Methods
A systematic search was performed in CENTRAL, MEDLINE, and Embase from the inception until October 20th, 2021. Eligible randomized controlled trials (RCTs) included women diagnosed with PCOS and compared any inositols with metformin or placebo. The primary outcome was cycle normalization, and secondary outcomes were body mass index (BMI), parameters of carbohydrate metabolism, and clinical and laboratory hyperandrogenism.
Read also: Berberine and Metformin
Results
Twenty-six RCTs were identified, including data of 1691 patients (806 inositol, 311 with placebo, and 509 metformin groups). The rate of cycle normalization was higher in the inositol group compared to the placebo. Inositol treatment also induced a greater decrease in BMI, free testosterone, total testosterone, androstenedione, glucose levels, and AUC insulin compared to placebo. Inositol increased sex-hormone-binding globulin significantly compared to placebo. Myoinositol had an efficacy similar to metformin regarding cycle normalization and BMI reduction.
Search and Selection
Of 4676 records, 26 RCTs were included with 1691 women with PCOS. Twenty-four studies were included in the quantitative synthesis, but two studies were excluded from the meta-analysis due to inappropriate data reporting.
Basic Characteristics of the Included Studies
Most studies included women in their 30s, with a mean BMI below 30 kg/m2. In two studies, BMI was also an inclusion criterion, meaning they investigated overweight and obese women with PCOS. Eligible studies used either myoinositol or D-chiro-inositol as the investigated intervention. However, the dose and length of administration were different between the studies. One trial compared myoinositol and inositol combinations to diet. A single three-arm trial was included comparing myoinositol to metformin and placebo.
Inositol Treatment Promotes Ovarian Cycle Normalization and Contributes to Weight Loss
The rate of cycle normalization was higher in the inositol group compared to the placebo. The pooled analysis of eight RCTs showed a higher reduction in BMI in the inositol group compared to placebo. Particularly, myoinositol seems to have a beneficial effect on weight loss. Myoinositol had an efficacy similar to metformin regarding cycle normalization and BMI reduction.
Androgens in PCOS
Compared to placebo, inositols significantly reduced total testosterone levels. Two studies showed an advantageous effect of DCI for this outcome. Free testosterone was significantly reduced by inositol treatment compared to placebo. SHBG levels were significantly increased by inositols. Androstenedione was also significantly reduced after inositol treatment. Myoinositol, compared to placebo, also seems to have a beneficial effect on androstenedione. DCI reduced DHEAS levels. However, the combined analysis of different inositols did not reach the level of significance. Finally, only one study investigated the effect of inositol on the FG-score. Compared to metformin, myoinositol significantly increased SHBG levels. However, metformin seemed more effective in decreasing FG-score than inositol. In the case of total testosterone levels, inositol was non-inferior compared to metformin. However, only one RCT reported on DHEAS, and no articles compared inositol to metformin regarding free testosterone and androstenedione levels.
Read also: Comprehensive Study: Metformin and Phentermine/Topiramate
Glucose Metabolism in PCOS
Inositols significantly reduced fasting plasma glucose compared to placebo.
Myoinositol vs. Metformin: A Direct Comparison
A six-month RCT in women with PCOS (n = 45) compared myoinositol (MI) 4 g/day or metformin (MET) 2 g/day. The primary outcome was the homeostasis model assessment of insulin resistance (HOMA-IR). Secondary outcomes were fasting glucose, weight, cycle length, lipids, testosterone, adverse effects, quality of life, and depression scores.
Key Findings
HOMA-IR was unchanged during MI and MET. Median fasting glucose changed +0.2 mmol/L during MI and −0.1 mmol/L during MET. Median weight changed −2.3 kg during MI and −6.1 kg during MET. Median cycle length decreased nine days during MI and 13 days during MET. High-density lipoprotein (HDL) changed +0.1 mmol/L during MET. Adverse effects appeared in four women during MI and 16 women during MET.
Conclusion
There was no effect on the metabolic outcomes during MI, but positive effects on fasting blood glucose, weight, and HDL during MET. The effect on cycle length was comparable during MI and MET.
Recruitment and Study Design
Participants were recruited through the PCOS outpatient clinic, Department of Gynecology and Obstetrics in collaboration with the Department of Endocrinology, Odense University Hospital (OUH), Denmark. Inclusion criteria were PCOS diagnosed according to the Rotterdam criteria and age 18-50 years. The study design was a 6-month open-label RCT.
Read also: Health Benefits of Metformin
Outcomes Measured
The primary study outcome was HOMA-IR. Secondary outcomes included fasting glucose, serum lipids, anthropometric measures (weight, BMI, waist, and hip circumference), Ferriman-Galwey (FG) score, cycle length, gonadotrophins, testosterone, anti-Müllerian hormone (AMH), and scores of QoL and depression as well as adverse effects.
Adverse Effects and Dropouts
Adverse effects were registered in four women during MI and 16 women during MET. Five women withdrew from the study due to adverse effects.
Metabolic and Hormonal Changes
HOMA-IR was unchanged within the MI and MET groups, and Δ-values were comparable between MI vs. MET. Median fasting glucose increased in the MI group and decreased in the MET group, and the Δ-values were different between MI vs. MET. Median HDL cholesterol was unchanged in the MI group but increased in the MET group, and the Δ-values were comparable between MI vs. MET.
Weight and Cycle Length
The weight and BMI did not change significantly in the MI group but decreased significantly in the MET group, and Δ-values were different between MI vs. MET. The reduction in cycle length was 9 days in the MI group and 13 days in the MET group, and the Δ-values were comparable between MI vs. MET.
Implications
MI did not improve the metabolic study outcomes since HOMA-IR, Hb1Ac, insulin, and weight remained unchanged, and fasting glucose even increased during MI treatment. In contrast, MET had beneficial effects on fasting glucose, HDL cholesterol, and weight. MI and MET had a comparable and positive effect on the menstrual cycle length.
Inositol: An Alternative Perspective
Inositols, particularly myo-inositol (MYO) and d-chiro inositol (DCI), are emerging as potential alternatives to metformin for managing PCOS symptoms.
How Inositols Work
MYO and DCI are separate molecules that work differently in the body. Women with PCOS may have a defect in the insulin receptor’s “secondary messengers,” contributing to insulin resistance and infertility. MYO and DCI work as these secondary messengers. Inositols work as secondary messengers to repair the doorbell so that the cell doors open in correct response to glucose, resulting in less insulin needing to be secreted.
Proposed Health Benefits of Inositol for PCOS
- Regulates menstrual cycles
- Promotes Ovulation
- Improves egg quality
- Curbs carb cravings
- Decreases the risk of gestational diabetes in pregnancy
- Lowers insulin and glucose
- Lowers cholesterol
- Lowers inflammation
- Improves anxiety
- Improves acne
Inositol Research
A 2023 meta-analysis reviewed the inositol research and concludes it is a safe and effective treatment for PCOS and as effective as metformin for most outcomes, without the side effects. This study reviewed data from 26 randomized controlled trials (RCTs), including data of 1691 patients.
Compared to placebo, inositol had significant effects on:
- normalizing menstrual cycles
- lowering body mass index (BMI)
- reducing androgens (testosterone, free testosterone, and androstenedione)
- increasing sex hormone-binding globulin (SHBG)
- reducing fasting plasma glucose
Compared to metformin, inositol had:
- 84% fewer side effects
- the same efficacy in normalizing menstrual cycles, lowering BMI, lowering testosterone levels, and improving glycemic outcomes.
Combined Myo and DCI with Metformin
A study published in the Evidence-Based Women’s Health Journal looked at 128 women with PCOS who took 1500 mg metformin or myo + d-chiro inositol (in a 40:1 ratio) daily for 3 months. The results: Myo + DCI showed significantly better results in weight reduction, ovulation, and pregnancy rates (46.7% vs. 11.2%) than metformin.
MYO compared with Metformin
A systematic review and meta-analysis looked at six trials with a total of 355 patients with PCOS. They found similar results with patients who took myo inositol when compared with metformin. Both groups improved insulin and testosterone levels similarly. Metformin was found to have much worse adverse effects.
Mental Health Benefits of Inositol
Women with PCOS who took myo inositol saw greater benefits in improving depression, anxiety, and stress when compared with metformin.
Dosage
The recommended dosage of Ovasitol is 2 packets each day (4 grams myo inositol total) in two divided doses. We recommend taking ovasitol with meals for maximum benefits. Ovasitol is well tolerated.
Metformin vs myoinositol: which is better in obese polycystic ovary syndrome patients?
Thirty-four PCOS obese women (age: 25·62 ± 4·7 years; BMI: 32·55 ± 5·67 kg/m2 ) were randomized to receive metformin (850 mg twice a day) or MYO (1000 mg twice a day) for 6 months. Both metformin and MYO significantly reduced the insulin response to OGTT and improved insulin sensitivity. Metformin significantly decreased body weight and improved menstrual pattern and Ferriman-Gallwey score. Metformin treatment was also associated with a significant decrease in LH and oestradiol levels, androgens and anti-müllerian hormone levels.
Impacts of Metformin, Inositol and Lifestyle Modifications
In a four-arm randomized study, 48 women of reproductive age (25-36 years) will be recruited over a 12-week period to determine the impacts of treatment types (metformin, inositol and lifestyle modifications) in improving symptoms of PCOS. Control group, “Group A” (N=12) will not be going through any treatment; “Group B” (N=12) will be taking 500 mg of metformin daily, with close assessment of side effects; “Group C” will take 2 g of inositol supplements twice daily with a 40:1 myo-inositol and D-chiro-inositol ratio; and “Group D” will undergo lifestyle modifications, closely monitored by personal trainers, nutritionists, and dietitians, to facilitate weight loss.
Previous studies have shown inositol consumption to result in significant improvements in insulin resistance, menstrual cycle regularity, Acne score, Ferriman-Gallwey score, endocrine and metabolic parameters, reduced serum levels of total testosterone, and elevated sex hormone binding globulin in women with PCOS. Metformin may yield similar effects to inositol, but greater adverse effects may be present.