PCOS and myo-inositol

Poly Cystic Ovary Syndrome (PCOS) is a common condition affecting reproductive function in women. PCOS may present itself differently across individuals and doesn’t always have the same pathophysiology. Diagnostic criteria, healthcare services, education and geographical location means that diagnosis can differ wildly across the globe, but it is thought to affect 4-20% of women in the world. In the UK, it is estimated that about 1 in every 5 (20%) women in the UK has polycystic ovaries, but more than half of these have no symptoms.¹

The three main features of the condition are: cysts that develop in the ovaries (polycystic ovaries), ovaries do not regularly release eggs (ovulate) and having high levels of “male hormones” called androgens. Polycystic ovaries contain a large number of harmless cysts up to 8mm in size. The cysts are under-developed sacs in which eggs develop. Often in PCOS, these sacs are unable to release an egg, meaning ovulation doesn’t take place.²

Symptoms typically begin in the late teens or early 20s and can vary in severity. It is also important to mention that not all of the symptoms will occur with every single case of PCOS.

The NHS have reported that “a diagnosis” of PCOS is usually made if other causes of the same symptoms have been ruled out and you meet at least two of the following three criteria:

• You have irregular or infrequent periods – this indicates your ovaries do not regularly release eggs (ovulate)
• Blood tests show you have high levels of “male hormones” (androgens), such as testosterone (or sometimes just the signs of excess male hormones even if the blood test is normal)
• Scans show you have polycystic ovaries.

Additional symptoms associated with PCOS may include:

• Excess facial or body hair (hirsutism)
• Oily skin and acne
• Thinning hair or hair loss from the scalp
• Weight problems including overweight, rapid weight gain, and difficulty losing weight
• Depression and mood changes.
• A Frequently Unnoticed Condition²

Skip to key takeaways

As symptoms are variable, an individual’s awareness of the presence of the condition is sometimes overlooked for extended periods of time. As many of the symptoms can be long-term and commonly associated with teenagers and youth as well (for example, acne, weight gain, low mood and changing mood frequently) it makes diagnosis especially difficult.

Additionally, irregular or light menstruation may not be seen as a concern and for many the menstrual cycle is modulated by the contraceptive pill. One may become aware of the potential diagnosis of PCOS when a lack of ovulation impacts fertility.

Insulin

The above criteria may trigger a diagnosis, but the pathophysiology is less straightforward. PCOS is a complicated metabolic disorder associated with inflammation and insulin resistance. Although insulin resistance is considered a major mediator of PCOS, it is not present in all cases. It is, however, relevant in up to 70% of women with PCOS.^1,3

Insulin resistance is considered progressive as a direct result of elevated insulin, further creating a compensatory chronic hyper insulin state. Hyperglycaemia (high blood sugar levels) and high insulin levels can contribute to weight gain and obesity.

Women with PCOS often show signs of insulin resistance. This elevated level of insulin in the bloodstream is thought to be one of the underlying reasons why PCOS develops due to hormonal imbalance, with higher testosterone levels.

Multiple studies have shown that insulin stimulates androgenesis in normal ovarian in vitro models. Indeed, PCOS thecal cells in culture show increased androgen responsiveness to insulin and luteinising hormone (LH) when compared to normal thecal cells. Physiological doses of insulin are able to activate androgen production in PCOS thecal cells, while higher concentrations of insulin are necessary in normal thecal cells. In both type of thecal cells, the combination of physiological doses of LH and insulin synergistically increases androgen biosynthesis.³ It has been demonstrated that abnormally increased insulin levels cross-react with insulin and IGF receptors on the ovary, leading to androgen overproduction.^3,4

Additionally, women with PCOS have an increased risk of other metabolic disorders including infertility, hypertension, type 2 diabetes, depression, anxiety, sleep apnoea, menstrual irregularities, and more – further suggesting the importance of metabolic pathophysiology.¹

Oestrogen and Testosterone

Sex Hormone Binding Globulin (SHBG) is an important regulator of oestrogen balance in the body. High levels of SHBG are associated with an oestrogen dominant environment. Lower levels of SHBG, which are more likely to be associated with a higher testosterone to oestrogen ratio, are often seen in those with PCOS. A diet high in processed refined foods, sugars and elevated insulin levels is commonly associated with a decline in the production of SHBG.⁵

In some cases of PCOS, ovulation is impeded due to higher levels of LH. The Follicle Stimulating Hormone (FSH) is the hormone responsible for the development of the egg and follicle, whereas LH triggers the release of the egg from the follicle.

Some ovaries are known to develop multiple cysts due to undeveloped follicles but not all will lead to symptoms or impact negatively on fertility. It is only when hormonal imbalance occurs that this is shown, which is why ultrasound scans of the ovaries alone are not conclusive for PCOS.

Hair-related symptoms associated with PCOS (excess hair growth on the body, facial hair and thinning of the hair on the scalp) is considered to be a result of increased circulating testosterone blood levels.

A hormonal cascade

The cascade of excess insulin, insulin resistance, hyperandrogenism and oestrogen dominance is self-perpetuating. Increased insulin from high blood glucose due to excessive carbohydrate intake and/or stress, leads to insulin resistance which increases androgen production but additionally promotes central obesity. Both high insulin and central obesity triggers excess androgens to be converted to oesterone. This disrupts GnRH (gonadotrophin releasing hormone from the hypothalamus) and in turn affects the production of LH and FSH, leading to excess LH and insufficient levels of FSH. These imbalanced hormones further exacerbate androgen production leading to hirsutism, acne and male hair distribution but also cessation of menses and anovulation and hence infertility.⁵

Therefore, when considering interventions for PCOS ameliorating insulin excess and resistance must be considered.

Dietary interventions

We know that the Palaeolithic diet and the Mediterranean diet do not include refined or processed foods or foods high in sugar and this is avital factor – natural unrefined diets promote good blood sugar control and increase insulin sensitivity. It is important to consider low glycaemic load diets with fibre, healthy fats and lean protein as they are essential for blood sugar regulation,reducing insulin levels and improving insulin sensitivity.

Including spices into your diet, such as cinnamon, may provide assistance; this spice has long been considered supportive of blood sugar control. Garlic and onions have also been shown to be beneficial, although it may be important to look at more specific support.

Focusing on insulin resistance – Myo-inositol

Studies have identified myo-inositol (MI) as a useful intervention for PCOS due to its insulin sensitising properties.

Inositol is a word that collectively refers to molecules with a similar structure, a collection of nine stereoisomers-MI is a specific stereoisomer. Inositol was defined in the past as a “myometrial sugar,” but it is indeed not a substance belonging to the carbohydrate group if we use modern definitions. Defining inositol as a vitamin B is also being discussed with controversy as inositol is not an essential substance and it can be produced in human cells from glucose and is often referred to as a pseudovitamin.⁶

The actions of MI are directly linked to its ability to improve insulin sensitivity. Uptake of free inositol by tissues occurs by a membrane dependant sodium inositol cotransporter. MI is mediated by some inositolphosphoglycans (IPGs), known as second messengers. These mediators are then internalised and modify enzymatic activity and intracellular metabolism, mimicking the action of insulin. These effects allow a decrease in blood glucose levels (insulin-like effect), regardless of the signal passing through the insulin receptor.⁷ Therefore MI is considered a useful adjunct to PCOS interventions.

Research

• One observational study 3602 infertile women used MI and folic acid between 2 and 3 months in a dosage of 2 × 2000 mg MI + 2 × 200 μg folic acid per day. It was demonstrated that 70% of the patients had restored ovulation after the treatment. Furthermore, the achieved pregnancy rates are at least in a range equivalent to, or even superior to, those reported by the use of the insulin sensitizer metformin (a pregnancy rate of 14.4% in a cohort of 90 women and of 12.3% in a cohort of 75 women with PCOS were described).⁸
• Studies show that MI leads to a decrease in LH and androgen levels, as well as a decrease in insulin resistance. Thus, MI is believed to be able to re-establish ovulatory menstrual cycles (especially in obese women with PCOS) but its effect on pregnancy rates is difficult to determine.⁹
• MI, at a dose of 4 g per day (2 g twice per day), three months prior to ovarian stimulation, is effective in normalizing ovarian function, improving oocyte and embryo quality in PCOS. However, further evaluations by large multicentre randomized controlled trials are needed to assess the clinical pregnancy and live birth rates in ART, because many published studies were heterogeneous. In addition, MI is a secure and cost-effective alternative in the treatment of PCOS, with no side effects observed in the standard dosage.⁹

Inositol in anxiety and depression

MI may indirectly support PCOS further by eliciting benefits to mood and anxiety disorders. Research suggests that MI may improve depressive and anxious conditions. The mechanism of this not fully understood, however, what is known is that inositol is used for the production of inositol triphosphate and diacylglycerol, important ‘second messengers’ allowing cell surface receptors for neurotransmitters, including serotonin, to affect intracellular processes.¹⁰

It has been seen that lower-than-normal levels of inositol are found in the cerebrospinal fluid of people with depression. Post-mortem studies have shown that levels of inositol in particular areas of the cortex of suicide victims, and people with bipolar disorder are also lowered. This suggests that it plays an essential role in the normal maintenance of psychological funciton.

Meta-analysis suggest that inositol may be beneficial for depressed patients, especially those with premenstrual distress disorder (PMDD). The main limitation of this report is that a small number of studies were included in this meta-analysis.¹¹

The effect of PCOS on fertility and mood cannot be underestimated as disruption to normal reproductive function can be detrimental to mood, self esteem and contribute to HPA dysfunction due to excess stress. These potential benefits to cognitive health are therefore supportive.

A general guide to further supplement support

A good quality multivitamin and mineral provides a balanced start to supporting health and reduces the risk of potential dietary led deficiencies through providing essential micronutrients needed for optimum health. Many of the nutrients important for carbohydrate metabolism, blood sugar balance and insulin regulation will be found in a well-balanced multi-formula that includes the B vitamins, vitamin D, zinc and chromium.

Chromium

Chromium encourages the formation of glucose tolerance factor (GTF) which is a substance released by the liver and an important part of carbohydrate metabolism and the maintenance of normal glucose levels. When chromium levels are low in the body, GTF levels are also low, and the activity of insulin is blocked leaving elevated glucose levels in the blood. Note: if you are diabetic and on medication, you should speak with your doctor before taking chromium.

Magnesium

Low levels of magnesium are considered to be associated with a decreased level of insulin sensitivity.

Omega 3

Diets high in saturated fats and with a higher ratio of omega 6 to omega 3 are considered to increase triglycerides and have a detrimental impact on insulin resistance. Increasing intake of omega 3 from nuts, seeds and oily fish supports the healthier ratio of omega 3 to 6.

This is not a complete list of nutrients and herbs, which many consider beneficial in support of conditions such as blood sugar control, energy distribution and PCOS.

Key Takeaways

• Although not present in all cases of PCOS, approximately 70% of cases are associated with insulin resistance.
• High insulin stimulates the production of androgens and hence luteinising hormone by theca cells in the ovaries to exacerbate PCOS symptoms and trigger oestrogen dominance, dysmenorrhoea and anovulation. Therefore, interventions to support insulin sensitivity are essential.
• The cascade of excess insulin, insulin resistance, hyperandrogenism and oestrogen dominance is self-perpetuating.
• Studies have identified myo-inositol (MI) as useful intervention for PCOS due to its insulin sensitising properties.
• Studies have shown that MI can improve insulin sensitivity, restore ovulation and potentially improves pregnancy outcomes (although more research is required for this) in PCOS patients.
• It is also important to support insulin sensitivity with dietary interventions, specifically low glycaemic load, Mediterranean or palaeolithic diets as well as use of chromium, magnesium and omega 3 fatty acids.
• MI also shows promise in supporting mood disorders, particularly when related to female hormonal conditions including PCOS and premenstrual distress disorder.

References

1. Learn More About Treating PCOS | Institute for Functional Medicine (ifm.org)
2. Polycystic ovary syndrome – NHS (www.nhs.uk)
3. Baptiste CG, Battista MC, Trottier A, Baillargeon JP. Insulin and hyperandrogenism in women with polycystic ovary syndrome. J Steroid Biochem Mol Biol. 2010;122(1-3):42-52.
4. Unluhizarci K, Karaca Z, Kelestimur F. Role of insulin and insulin resistance in androgen excess disorders. World J Diabetes. 2021;12(5):616-629.
5. Bland J et al. Textbook of Functional Medicine.; 2008.
6. Merviel P, James P, Bouée S, et al. Impact of myo-inositol treatment in women with polycystic ovary syndrome in assisted reproductive technologies. Reprod Health. 2021;18(1):13. Published 2021 Jan 19. doi:10.1186/s12978-021-01073-3
7. Bevilacqua A, Bizzarri M. Inositols in Insulin Signaling and Glucose Metabolism. Int J Endocrinol. 2018;2018:1968450. Published 2018 Nov 25. doi:10.1155/2018/1968450
8. Regidor PA, Schindler AE. Myoinositol as a Safe and Alternative Approach in the Treatment of Infertile PCOS Women: A German Observational Study. Int J Endocrinol. 2016;2016:9537632.
9. Merviel P, James P, Bouée S, Le Guillou M, Rince C, Nachtergaele C, Kerlan V. Impact of myo-inositol treatment in women with polycystic ovary syndrome in assisted reproductive technologies. Reprod Health. 2021 Jan 19;18(1):13. doi: 10.1186/s12978-021-01073-3. PMID: 33468143; PMCID: PMC7816413.
10. Taylor MJ, Wilder H, Bhagwagar Z, Geddes J. Inositol for depressive disorders. Cochrane Database Syst Rev. 2004;2004(2):CD004049.
11. Mukai T, Kishi T, Matsuda Y, Iwata N. A meta-analysis of inositol for depression and anxiety disorders. Hum Psychopharmacol. 2014 Jan;29(1):55-63. doi: 10.1002/hup.2369. Epub 2013 Dec 3. PMID: 24424706.

Last updated on 18th May 2022 by cytoffice