Myo-Inositol and Polycystic Ovary Syndrome (PCOS) - Information for Healthcare Professionals

What is Polycystic Ovary Syndrome?

Polycystic ovary syndrome (PCOS) is an endocrine disorder characterised by ovulatory dysfunction, metabolic changes (e.g., obesity and insulin resistance) and hyperandrogenism (e.g., hirsutism and acne) (1). Around 40-60% of people with PCOS live with obesity, which itself is a risk factor for metabolic syndrome and cardiovascular disease risk (2). A common metabolic symptom of PCOS is insulin resistance (IR), which was initially thought to be a complication secondary to obesity. However, it is understood that 44-70% of people with PCOS have IR independent of their body mass index (BMI) (3). PCOS has a prevalence of 8-13% amongst people of reproductive age (1). This article will focus on PCOS in adults over 18 years old.

Presentation of PCOS

PCOS presents in several different ways. Common features include:

• Infertility secondary to oligomenorrhea and/or amenorrhea (4).

• Overweight or obesity; seen in 30-80% of people with PCOS (5).

• Hirsutism (excessive hair growth) and the presence of hairs in androgen-dependent areas (e.g., upper lip, chin, chest, back, upper arm, and shoulders). Hirsutism can be classified using the modified Ferriman-Gallwey score, with levels ≥4-6 indicating hirsutism (1,5).

• Severe acne persisting beyond adolescence. There are no universally accepted visual assessments for evaluating acne (1,5).

• Alopecia is a rare symptom but can occur in PCOS. Scalp hair loss tends to be at the vertex and crown (4).

• Acanthosis nigricans occur as a result of insulin resistance. It appears as brown or grey, velvety, occasionally verrucous, hyperpigmented areas over the nape, groin, umbilicus, sub-mammary areas, elbows, and knuckles (4).

People with PCOS are at increased risk of:

• Pregnancy complications including gestational diabetes, preeclampsia and premature delivery (6).

• Endometrial cancer in the presence of prolonged oligomenorrhea and/or amenorrhea (1,4).

• Long-term health complications including type 2 diabetes (secondary to IR causing raised blood glucose levels), cardiovascular disease (CVD), sleep apnea and depression. Annual monitoring, including screening for metabolic and cardiovascular risks, should be conducted (1,7).

Investigations and Diagnosis of PCOS

Although there is some controversy regarding the diagnosis of PCOS, international guidelines for the assessment and management of PCOS endorse the Rotterdam 2003/4 criteria. Diagnosis of PCOS in adults requires at least two of the following three clinical features (1):

• Oligoovulation or anovulation (usually manifested as oligomenorrhea or amenorrhea) (1). Anovulation is the leading cause of secondary amenorrhea in people with PCOS attending fertility clinics (8). Irregular menstrual cycles are defined as <21 or >35 days, or less than eight cycles per year for people over three years post menarche to perimenopause (1).

• Clinical and/or biochemical signs of hyperandrogenism.

• Polycystic ovaries on ultrasound.

The table below outlines the pathway of investigations as advised by the National Institute for Health and Care Excellence (NICE), 2018 (7).

Table 1: Investigations for the Diagnosis of PCOS

Investigation

Normal Range

Outcome Measures

Measure total testosterone

12.4 to 15.8ng/dL (9)

Normal to moderately raised

Measure sex hormone-binding globulin (SHBG)

Females ≤50 years: 19-145 nmol/L

 

Females ≥ 50 years: 14-136 nmol/L (10)

Normal to low

Free androgen index (the measurement of active testosterone).

< 5 (7)

Normal to moderately raised

Measure luteinizing hormone, (LH), follicle-stimulating hormone (FSH), LH/FSH ratio, thyroid-stimulating hormone (TSH)

LH/FSH ratio: < 3 (4)

 

TSH: 0.4–4.5 mU/L (7)

To exclude other causes of oligomenorrhea and/or amenorrhea

Prolactin

<500 mU/L (7)

Mildly elevated

Ultrasound

 

Polycystic ovaries are defined as the presence of 12 or more follicles in at least one ovary (measuring 2–9 mm diameter) or increased ovarian volume (greater than 10 cm3).

Management of PCOS

Management of PCOS is tailored towards the individual goals and needs of the patient. Therapy is focused on alleviating symptoms of hyperandrogenism and/or improvement of fertility. Long-term measures should also be taken to restore regular menstruation to prevent endometrial hyperplasia (4).

Pharmacotherapy

• The oral contraceptive pill (OTC) or the levonorgestrel-releasing intrauterine device can help to induce or regulate menstruation (4,7).

• If fertility is desired, medications including letrozole or clomifene (Clomid) are used for ovulation induction (4).

• Metformin is used to improve IR, decrease testosterone levels, promote weight loss and induce ovulation (4,7).

• Topical therapies for hirsutism include eflornithine and minoxidil (4).

Surgical Intervention

Laparoscopic ovarian drilling (LOD) uses lasers to reduce the amount of functional ovarian tissue present which in turn reduces androgen production. This has been proven to restore ovulation and result in pregnancy rates of 25% to 65% (4). It is offered when there has been a poor response to medication.

Nutrition and Lifestyle Changes

People who are overweight or obese should be offered weight loss advice and referral to a dietitian should be considered. Healthy lifestyle changes should be encouraged, focusing on improving diet and activity levels. The health benefits of achieving a 5% weight loss via a healthy energy-restricted diet and regular exercise should be discussed (e.g., reduces hyperinsulinism, can improve menstrual regularity and efficacy of pregnancy, if desired) (7,11). Evidence has shown that low glycemic index (GI) and low carbohydrate dietary interventions have demonstrated improved insulin sensitivity and weight loss, in people with PCOS (12,13).

It should be noted that not all people with PCOS are overweight. Dietary changes, however, can still be beneficial. For example, a Mediterranean diet has been shown to reduce IR and improve ovarian function and should be encouraged in place of a ’western style’ diet (14). A Mediterranean diet is characterised by one that is high in vegetables, legumes, fruits, nuts, olive oil and fish, with moderate amounts of dairy products and wholegrains, and low in red meat, processed foods and saturated fats.

Mental Health Support

A systematic review found that PCOS is associated with an increased risk of depression or anxiety (15). PCOS affects a person’s life in various ways, such as impacting self-esteem, appearance and/or the ability to start a family. It is inevitable that this will impact mental health. Early screening by healthcare professionals (HCPs) can help people with PCOS to access early and effective interventions.

HCPs can signpost people with PCOS to Verity, the national PCOS charity. The charity hosts an online community to enable people with PCOS to give and receive peer support, which can help break the isolation that often accompanies the diagnosis.

Myo-Inositol

Recently, myo-inositol (MI) supplementation has gained momentum in the management of PCOS patients, due to its evidence base and the absence of side effects (16).

What is Myo-Inositol?

Myo-Inositol (MI) is one of nine different forms of inositol. It is a naturally occurring sugar alcohol found in dietary sources such as fruits, vegetables, nuts and cereals (17,18). MI acts as an intracellular messenger to regulate several hormones including thyroid-stimulating hormone (TSH), follicle-stimulating hormone (FSH) and insulin (17).

How does Myo-Inositol help people with PCOS?

There is much interest in the role of MI in the management of people living with PCOS. Emerging data from small studies is promising, however further large-scale studies are needed. Table 2 provides an overview of the clinical benefits of MI in people living with PCOS.

Table 2: Benefits of Myo-Inositol in patients with PCOS

Clinical Feature

Potential Benefit of myo-inositol

Insulin Resistance

Myo-inositol has been found to mediate the post-receptor effects of insulin-modifying intracellular metabolism and inhibits duodenal glucose absorption, helping to decrease blood glucose levels (19). A recent meta-analysis demonstrated a significant decrease in fasting insulin in PCOS patients who received myo-inositol compared to other treatments (17). Although findings are limited by inconsistent definitions of PCOS and confounding factors e.g., dose and duration. A systematic review of six RCTs comparing treatment with metformin vs. myo-inositol in people with PCOS found no difference in the short-term effect on fasting insulin, Homeostatic Model Assessment for Insulin Resistance (HOMA) index, testosterone, androstenedione, SHBG and BMI. Additionally, there was an absence of adverse reactions in patients treated with myo-inositol (20).

Obesity

Myo-inositol reduces leptin secretion and therefore may promote weight loss (21). Small trials have shown a small amount of weight loss in patients taking myo-inositol supplements. However, myo-inositol has not been found to cause weight loss in people with a BMI > 40kg/m2 (21).

Anovulation

Clinical trials show promising results:

- An RCT (137 people with PCOS/IR) found those treated with myo-inositol were six times as likely to report regular menstrual cycles as compared to placebo groups (22).

- An RCT found that myo-inositol supplementation induced menstrual cycle regularity in 75 (53.6%) PCOS patients after 6 months. Ovulation occurred in 101 (72.1%) cases after 6 months of myo-inositol treatment (23)..

- A meta-analysis in anovulatory women with PCOS found that treatment with inositol significantly increased the ovulation rate (RR 2.3; 95% CI 1.1–4.7; I 2 = 75%) compared with placebo (n=257 participants) (24).

Oocyte Quality

Myo-inositol has been associated with decreased oestradiol levels on the day of ovulation, which increased the number of large follicles without increasing the total number of oocytes. This reduced the risk of ovarian hyperstimulation and in turn improved oocyte quality (19). A recent study examined the effects of myo-inositol and folic acid in 50 women with PCOS undergoing assisted reproductive technology. The fertilisation rate and embryo quality significantly improved in the study group, but the number of retrieved oocytes were not statistically different between groups (25). A 2017 systematic review concluded that myo-inositol was insufficient at improving oocyte quality. Future studies are needed to examine appropriate dose, and duration of myo-inositol to clarify its role in the management of fertility and PCOS (26).

Gestational Diabetes Mellitus (GDM)

Existing results of antenatal myo-inositol supplementation are promising. A systematic review found that myo-inositol reduced fasting blood glucose and one‐hour postprandial blood glucose by an average of 0.47 mmol/L and 0.90 mmol/L respectively in people with GDM (18). A Cochrane review found that antenatal supplementation of myo-inositol did not impact on other outcomes such as the risk of having a caesarean section, a large baby, obstructed labour or a baby with low blood glucose levels. Further studies are needed to assess the maternal and infant outcomes of myo-inositol during pregnancy (27).

Hirsutism

A small study (n=26) provided people with mild and moderate hirsutism with 2g myo-inositol bi-daily for 6 months. This led to a significant decrease in the levels of total androgens and severity of hirsutism (28). The data is promising, but further large-scale studies are needed.

 

Acne

More studies are needed to investigate effects of myo-inositol on acne. However, small trials have shown promising results.

- A prospective study evaluated myo-inositol 2g plus folic acid 200µg twice daily for 6 months to treat acne in 38 patients with PCOS. Improvement in acne was reported and the acne had disappeared in 53% of patients (29).

- An RCT (n=50) patients with PCOS and acne showed papulopustular lesions were reduced and inflammation was eliminated when given 2g of inositol, twice daily, for 6 months (30).

Introducing MyOva Myoplus

MyOva Myoplus is a natural food supplement for adults aged 18 years and over, who are experiencing PCOS symptoms (see Table 3). MyOva Myoplus presents in a convenient, easy to swallow tablet format which can easily be crushed and taken with food. The optimum dose is achieved by taking two tablets in the morning and two in the evening, daily with water or food. Patients should seek advice from their GP if they are taking regular medication, pregnant or lactating. MyOva Myoplus should not be taken as a substitute for a healthy and balanced diet.

Table 3: MyOva Myoplus ingredients and their role in PCOS

Ingredient*

Role

Myo-Inositol (4000mg)

4000mg of myo-inositol has produced optimal results in clinical studies including improved insulin sensitivity, reduction in BMI and normalisation of menstruation (31). No side effects have been observed at a dosage of 4000mg (19).

Folate (200μg) **

Folate supplementation has improved insulin resistance and total cholesterol in people with PCOS (32). (Note: supplementation for clinical effect was 5mg for eight weeks)

Chromium Picolinate (100μg)

PCOS increases the risk of insulin resistance and T2DM. Chromium is an essential nutrient for the maintenance of normal glucose tolerance and deficiency can cause insulin resistance (33). A systematic review showed that supplementation of chromium picolinate led to a decrease in BMI, fasting insulin and free testosterone in people with PCOS (34).

Introducing MyOva Fertilityplus

MyOva Fertilityplus is a natural food supplement for adults aged 18 years and over, who have PCOS and are trying to conceive. It is a natural preconception supplement containing essential micronutrients to help support reproductive health for pregnancy. It contains additional nutrients that have been found to support ovulation and metabolic health specifically for people living with PCOS (as outlined in table 4).

MyOva Fertilityplus presents in a convenient, easy to swallow tablet format which can easily be crushed and taken with food. The optimum dose is achieved by taking two tablets in the morning and two in the evening, daily with water or food. Patients should be advised to discuss with their GP first if they are taking regular medication or are lactating. MyOva Fertilityplus should not be taken as a substitute for a healthy and balanced diet.

Table 4: MyOva Fertilityplus ingredients and their role in PCOS

Ingredient*

Role

Alpha-Lipoic Acid (ALA) (600mg)

There is a possible beneficial effect on oocyte and embryo quality using a combination of myo-inositol, ALA, and folate supplementation for people with PCOS and undergoing In Vitro Fertilisation (IVF) (35). In a small patient cohort (n = 40), the combination of myo-inositol and ALA for six months decreased BMI, waist-hip ratio, hirsutism score, AMH, ovarian volume, antral follicle count, and increased the number of menstrual cycles (36). Another small study (n=16) examined the effects of a combination of MI and ALA over 24-months. A decrease in BMI was noted at six months and menstruation cycle length continued to normalise at 24 months (37). Further RCTs are needed to assess its clinical impact on IVF.

Folate (400μg)

At least 400μg of folic acid is recommended daily before pregnancy and throughout the first 12 weeks to prevent neural tube defects (38). In an observational study, 3,602 infertile women used MI and folic acid between 2- 3 months in a dosage of  4000mg myoinositol with 400 μg folic acid per day. In a subgroup of 32 patients, hormonal values for testosterone, free testosterone, and progesterone were analysed before and after 12 weeks. During this time 70% of these women had restored ovulation, and 545 pregnancies were obtained. Pregnancy rate was 15.1% in the MIl and folic acid users (39).

N-acetyl cysteine (600mg)

N‐acetyl cysteine has been found to improve the metabolic profile in people with PCOS (40, 41).

Coenzyme Q10 (10mg)

Coenzyme Q10 appears to be a promising treatment to stimulate and maintain ovarian health in people with PCOS who are trying to conceive. Further studies are needed to assess this association (42).

Take home message

The clinical features and challenges faced by people with PCOS can negatively affect their quality of life and mental health. Medications and surgery are effective at improving symptoms and supporting fertility to an extent. HCPs can further support people living with PCOS to make sustainable and positive dietary and lifestyle changes to benefit their health via education on diet and physical activity as well as providing advice on targeted supplementation using a suitable brand for PCOS such as MyOva.

Disclaimer

The information included in this booklet is not a substitute for professional medical advice, examination, diagnosis or treatment. The content in this booklet is aimed at a healthcare professional audience only. MyOva is a food supplement and is not listed within the British National Formulary, and therefore cannot be prescribed. MyOva supplements can be purchased online. Individuals should consult with their own healthcare professional before taking a food supplement.

References

1. Teede H, et al. (2018). International evidence-based guideline for the assessment and management of polycystic ovary syndrome. National Health and Medical Research Council (NHMRC).[Internet]. Available online: https://www.monash.edu/__data/assets/pdf_file/0004/1412644/PCOS_Evidence-Based-Guidelines_20181009.pdf 

Read more

2. Sawant S, Bhide P (2019). Fertility Treatment Options for Women With Polycystic Ovary Syndrome. Clinical Medicine Insights Reproductive Health. [Internet]. Available from: /pmc/articles/PMC6935873/ 

3.Diamanti-Kandarakis E, Dunaif A (2012). Insulin resistance and the polycystic ovary syndrome revisited: an update on mechanisms and implications. Endocrine reviews;33(6):981–1030. [Internet]. Available from: https://pubmed.ncbi.nlm.nih.gov/23065822/ 

4. The British Medical Journal (BMJ). Polycystic ovary syndrome - History and exam | BMJ Best Practice. 2021. [Internet]. Available from: https://bestpractice.bmj.com/topics/en-gb/141/history-exam#keyFactors
5. The Rotterdam ESHRE/ASRM‐sponsored PCOS consensus workshop group. Revised 2003 consensus on diagnostic criteria and long‐term health risks related to polycystic ovary syndrome (PCOS). Human Reproduction. 2004. [Internet].Available from: https://academic.oup.com/humrep/article/19/1/41/690226
6. Palomba S, et al. (2015). Pregnancy complications in women with polycystic ovary syndrome. Human Reproduction Update;21(5):575-92. [Internet]. Available from: doi: 10.1093/humupd/dmv029.
7. National Institute for Health and Care Excellence (NICE). Scenario: Management - adults | Management | Polycystic ovary syndrome. 2018. [Internet]. Available from: https://cks.nice.org.uk/topics/polycystic-ovary-syndrome/management/management-adults/
8.Kriedt K, Alchami A, Davies M (2019). PCOS: diagnosis and management of related infertility. Obstetrics, Gynaecology & Reproductive Medicine;29(1):1–5.  [Internet]. Available from: https://doi.org/10.1016/j.ogrm.2018.12.001
9. Ayala C, et al. (1999). Serum testosterone levels and reference ranges in reproductive-age women. Endocrine practice : official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists. [Internet]. Available from: https://pubmed.ncbi.nlm.nih.gov/15251653/ 

10. Gloucestershire Hospitals NHS Trust. Sex Hormone Binding Globulin (SHBG). 2021. [Internet]. Available from: https://www.gloshospitals.nhs.uk/our-services/services-we-offer/pathology/tests-and-investigations/sex-hormone-binding-globulin-shbg/
11. National Institute for Health and Care Excellence (NICE). Recommendations  | Weight management: lifestyle services for overweight or obese adults | Guidance | NICE. 2014. [Internet]. Available from: https://www.nice.org.uk/guidance/ph53
12.Barr S, et al. (2013). An isocaloric low glycemic index diet improves insulin sensitivity in women with polycystic ovary syndrome. Journal of the Academy of Nutrition and Dietetics;113(11):1523–31. [Internet]. Available from: https://pubmed.ncbi.nlm.nih.gov/23999280
13. Zhang X, et al. (2019). The Effect of Low Carbohydrate Diet on Polycystic Ovary Syndrome: A Meta-Analysis of Randomized Controlled Trials. International Journal of Endocrinology. 26;2019:4386401. [Internet]. Available from: doi: 10.1155/2019/4386401.
14. Barrea L,  et al. (2019). Adherence to the Mediterranean Diet, Dietary Patterns and Body Composition in Women with Polycystic Ovary Syndrome (PCOS). Nutrients;11(10). [Internet]. Available from: https://pubmed.ncbi.nlm.nih.gov/31547562/ 

15. Brutocao C, et al. (2018). Psychiatric disorders in women with polycystic ovary syndrome: a systematic review and meta-analysis. Endocrine.[Internet]. Available from: https://pubmed.ncbi.nlm.nih.gov/30066285/ 

16. Nordio M, Basciani S, Camajani E (2019). The 40:1 myo-inositol/D-chiro-inositol plasma ratio is able to restore ovulation in PCOS patients: comparison with other ratios. European Review for Medical and Pharmacological Sciences;23(12):5512-5521.[Internet]. Available from: doi: 10.26355/eurrev_201906_18223. 

17. Unfer V, et al. (2017). Myo-inositol effects in women with PCOS: a meta-analysis of randomized controlled trials. Endocrine Connections; 6(8):647–58[Internet]. Available from: https://ec.bioscientifica.com/view/journals/ec/6/8/EC-17-0243.xml 

18. Brown J, et al. (2016). Dietary supplementation with myo‐inositol in women during pregnancy for treating gestational diabetes. Cochrane Database of Systematic Reviews [Internet].Sep 7 [cited 2021 Oct 19];2016(9). Available from: https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD012048.pub2/full 

19. Merviel P, et al.  (2021). Impact of myo-inositol treatment in women with polycystic ovary syndrome in assisted reproductive technologies. Reproductive Health;18(1):1–8 18. [Internet]. Available from: https://reproductive-health-journal.biomedcentral.com/articles/10.1186/s12978-021-01073-3 

20. Facchinetti F, et al. (2019). Short-term effects of metformin and myo-inositol in women with polycystic ovarian syndrome (PCOS): a meta-analysis of randomized clinical trials. Gynecological endocrinology.[Internet]. Available from: https://pubmed. :ncbi.nlm.nih.gov/30614282/ 

21. Gerli S, et al. (2007). Randomized, double blind placebo-controlled trial: effects of myo-inositol on ovarian function and metabolic factors in women with PCOS. European Review for Medical and Pharmacological Sciences;11(5):347-54. [Internet]. Available from: PMID: 18074942.
22. Formuso C, Stracquadanio M, Ciotta L (2015). Myo-inositol vs. D-chiro-inositol in PCOS treatment. Minerva Obstetrics and Gynaecology;67(4):321-5. [Internet]. Available from: PMID: 25670222.

23. u-Allah I, et al. (2020). Myoinositol In Restoring Spontaneous Ovarian Activity in Patients with Polycystic Ovarian Syndrome (PCOS). [Internet]. Available from: doi: 10.51273/esc20.2516310.
24. Pundir J, et al. (2018). Inositol treatment of anovulation in women with polycystic ovary syndrome: a meta-analysis of randomised trials. An International Journal of Obstetrics and Gynaecology;125: 299– 308.
25. Akbari Sene A,  et al.  (2019). The myo-inositol effect on the oocyte quality and fertilization rate among women with polycystic ovary syndrome undergoing assisted reproductive technology cycles: a randomized clinical trial. Archives of Gynaecology and Obstetrics;299(6):1701-1707. [Internet]. Available from: doi: 10.1007/s00404-019-05111-1
26. Mendoza N, et al. (2017). Inositol supplementation in women with polycystic ovary syndrome undergoing intracytoplasmic sperm injection: a systematic review and meta-analysis of randomized controlled trials. Reproductive biomedicine online. [Internet]. Available from: https://pubmed.ncbi.nlm.nih.gov/28756130/
27. Crawford T,  et al. (2015). Antenatal dietary supplementation with myo-inositol in women during pregnancy for preventing gestational diabetes. Cochrane Database of Systematic Reviews. [Internet]. Available from:  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6599829/
28. Minozzi M, D'Andrea G, Unfer V (2008). Treatment of hirsutism with myo-inositol: a prospective clinical study. Reproductive biomedicine;17(4):579–82.  [Internet]. Available from: https://pubmed.ncbi.nlm.nih.gov/18854115/ 

29. Zacche M, et al. (2009).  Efficacy of myoinositol in the treatment of cutaneous disorders in young women with polycystic ovary syndrome. Gynecol Endocrinol; 25: 508–13.

30. Pezza M, Carlomagno V (2017) Inositol in women suffering from acne and PCOS: a randomized study. Glob Dermatol 4: doi: 10.15761/GOD.1000203
31. Fruzzetti F,  et al. (2017). Comparison of two insulin sensitizers, metformin and myo-inositol, in women with polycystic ovary syndrome (PCOS). Gynecological Endocrinology;2;33(1):39–42. 
32. Asemi Z, Karamali M, Esmaillzadeh A (2014). Metabolic response to folate supplementation in overweight women with polycystic ovary syndrome: A randomized double-blind placebo-controlled clinical trial. Molecular Nutrition and Food Research;58(7):1465–73.
33. Cochrane Central Register of Controlled Trials. Chromium and Insulin Resistance. 2018. [Internet]. Available from: https://www.cochranelibrary.com/central/doi/10.1002/central/CN-01499500/full
34. Fazelian S, et al. (2017). Chromium supplementation and polycystic ovary syndrome: A systematic review and meta-analysis. Journal of Trace Elements in Medicine and Biology;42:92-96.[Internet]. Available from: doi: 10.1016/j.jtemb.2017.04.008.
35. Canosa S, et al. (2020). Effect of a combination of myo-inositol, alpha-lipoic acid, and folic acid on oocyte morphology and embryo morphokinetics in non-PCOS overweight/obese patients undergoing IVF: A pilot, prospective, randomized study. Journal of Clinical Medicine;1;9(9):1–13.
36. De Cicco S, et al. (2017). Myoinositol combined with alpha-lipoic acid may improve the clinical and endocrine features of polycystic ovary syndrome through an insulin-independent action. Gynecology and. Endocrinology;.33:698–701.[Internet]. Available from: doi: 10.1080/09513590.2017.1313972
37. Fruzzetti F, et al, (2020).. Long-term treatment with α-lipoic acid and myo-inositol positively affects clinical and metabolic features of polycystic ovary syndrome. Gynecology and Endocrinology;36:152–155. [Internet]. Available from: doi: 10.1080/09513590.2019.1640673
38. National Institute for Health and Care Excellence (NICE). Recommendations  | Maternal and child nutrition PH11. (2008). [Internet]. Available from: https://www.nice.org.uk/guidance/ph11
39. Regidor P, Schindler A (2016) . Myoinositol as a Safe and Alternative Approach in the Treatment of Infertile PCOS Women: A German Observational Study. International Journal of Endocrinology. Available from: doi: 10.1155/2016/9537632.
40. Lak T, et al. (2017). N-acetyl cysteine in ovulation induction of PCOS women underwent intrauterine insemination: an RCT. International journal of reproductive biomedicine. [Internet]. Available from: https://www.cochranelibrary.com/central/doi/10.1002/central/CN-01394549/full?highlightAbstract=pcos%7Cacetyl%7Ccystein%7Cn%7Ccysteine 

41. Gupta V,  et al. (2017). A study of N-acetyl cysteine, metformin and vitamin D3 with calcium on clinical and metabolic profile in PCOS. International journal of reproduction, contraception, obstetrics and gynecology.[Internet]. Available from: https://www.cochranelibrary.com/central/doi/10.1002/central/CN-02255231/full?highlightAbstract=pcos%7Cacetyl%7Ccystein%7Cn%7Ccysteine42. Sharma D sen (2017). Co-enzyme Q10-A mitochondrial antioxidant -a new hope for success in infertility in clomiphene-citrate-resistant polycystic ovary syndrome. An International Journal of Obstetrics and Gynaecology. [Internet]. Available from: https://www.cochranelibrary.com/central/doi/10.1002/central/CN-01781078/full