What causes PCOS?

The aetiology of PCOS remains largely unknown. However, accumulating evidence suggests that PCOS might be a complex multigenic disorder with strong epigenetic and environmental influences, including diet and lifestyle factors.¹

Two major PCOS phenotypes can be distinguished: overweight/obese and lean. Their estimated prevalence is about 80% and 20%, respectively. Insulin resistance (IR) is an important pathogenic component of PCOS. Up to 75% of lean and up to 95% of overweight women with PCOS have IR.^2,3

Why are so many women undiagnosed?

Diagnosis of PCOS is complex because it is a heterogeneous disorder. Women with PCOS present with diverse symptomology, including psychological (anxiety, depression, body image), reproductive (irregular menstrual cycles, hirsutism, infertility, and pregnancy complications) and metabolic features (IR, metabolic syndrome, prediabetes, type 2 diabetes [T2DM]) and cardiovascular risk factors.¹

A combination of anovulation (the lack or absence of ovulation ) and androgen excess are considered hallmarks of PCOS. Irregular menstrual cycles or ovulatory dysfunction are included in the 2003 Rotterdam criteria for the diagnosis of PCOS. However, it should be noted that ovulatory dysfunction can occur with regular cycles as well. When anovulation needs to be confirmed, hormonal assessment is relevant if PCOS is clinically suspected and cycles are regular.²

Another key feature is hyperandrogenism, which affects between 60% and100% of women with PCOS. Both clinical (hirsutism, alopecia, and acne) and biochemical hyperandrogenism features may be present. The features of hyperandrogenism are challenging to assess and vary by methods of assessment, and confounding factors including excess weight and age.²

Although rare, signs and symptoms of severe androgen excess can result in virilisation (eg male pattern balding, severe hirsutism, and clitoromegaly) and masculinisation. Clinical evidence of mild to moderate androgen excess is more common including hirsutism, acne, and androgen-related alopecia.²

Polycystic ovarian morphology (PCOM) was incorporated into the diagnosis of PCOS in the Rotterdam criteria, as a common feature associated with clinical and endocrine features of the condition. The definition of PCOM in the Rotterdam criteria is 12 or more follicles measuring 2mm-9mm throughout the entire ovary or an ovarian volume ≥10cm3.²

How is PCOS treated?

No single treatment for PCOS is available. Treatment should be individualised and adapted to the patient. Treatment should aim to improve symptoms and signs that represent the patient's real needs and can be changed over time.³

Lifestyle modification and off-label pharmaceutical agents are used to manage the symptoms of PCOS. Lifestyle modifications include healthy eating habits, regular physical activity to help patients achieve and/or maintain a healthy weight and to optimise hormonal outcomes, manage IR, general health, and overall quality of life.²

Behavioural strategies (eg goal-setting, self-monitoring, stimulus control, problem-solving, assertiveness training, slower eating, reinforcing changes and relapse prevention) are important to help patients implement and maintain lifestyle modifications.²

Pharmaceutical treatment options in PCOS

The pharmaceutical management of PCOS comprises agents that are prescribed off-label. These include: ²

• Combined oral contraceptives (COCs) for patients with PCOS who do not wish to fall pregnant: As monotherapy, COCs is recommended in adult women with PCOS for management of hyperandrogenism and/or irregular menstrual cycles. COC monotherapy can be considered in adolescents with a clear diagnosis of PCOS as well as those at risk but not yet diagnosed with PCOS to manage clinical hyperandrogenism and/or irregular menstrual cycles.²
• Metformin: Metformin is currently widely used by women with PCOS and can be considered in adult women with PCOS with BMI ≥25kg/m2 for management of weight and metabolic outcomes. Metformin in addition to lifestyle could be considered in adolescents with a clear diagnosis of PCOS or with symptoms of PCOS before the diagnosis is made. It should be noted that metformin is often associated with gastrointestinal side effects.²
• Anti-obesity medications: These agents can be considered in addition to lifestyle modifications for the management of obesity in adults with PCOS after lifestyle intervention, as per general guideline recommendations.²
• Anti-androgens: Can be considered to treat hirsutism and androgen-related alopecia if COCs are contraindicated or poorly tolerated, in the presence of other effective forms of contraception. Specific types or doses of antiandrogens cannot currently be recommended with inadequate evidence in PCOS.²

Nutraceuticals as a strategy for PCOS management

According to the international panel of experts, several nutraceuticals have been investigated for their possible benefits in the management of PCOS-related insulin resistance and anovulation.³

These include amongst others:³

• Inositols
• Lipoic acid
• Folic acid.

Inositols

Myoinositol (MI) and D-chiro-inositol (DCI) are both involved in insulin signalling and have been shown to alter insulin signalling in steroid and ovarian folliculogenesis. Numerous studies have shown the effectiveness in patients with PCOS. Both MI and DCI show insulin-mimetic properties and decrease postprandial blood glucose through different mechanisms of action.³

DCI acts on glycogen synthesis at the level of the skeletal muscle by up-regulating glucose transporter type 4 (GLUT4) expression, influencing the insulin-dependent synthesis of androgens. MI is involved in glucose uptake and follicle-stimulating hormone (FSH) signalling in the ovaries.³

In human ovaries, about 99% of the intracellular pool of inositol consists of MI, and the remaining part of DCI. An imbalance in the ovarian concentration between MI and DCI can compromise the release rate of FSH, which can affect gametogenesis and gonadal steroid production, thereby reducing fertility.³

A number of studies show that the treatment with MI and/or DCI improves reproductive outcomes in terms of spontaneous induction of ovulation and leads to a modification of the standard treatments used for ART, that is, a reduction in either the gonadotropin units required for the controlled ovarian hyperstimulation or in the overall number of days required to reach the maximal stimulation.³

Lipoic acid

Lipoic acid (ALA) is a powerful antioxidant and enzymatic cofactor of the mitochondrial respiratory chain, capable of increasing insulin sensitivity. It is believed to directly scavenge reactive oxygen species (ROS) and reactive nitrogen species (RNS), both in vitro and in vivo. Excessive ROS formation can induce oxidative stress, leading to cell damage that can culminate in cell death.³

ALA regenerates essential antioxidant molecules such as coenzyme Q10, vitamin C, vitamin E, and chelates several heavy metals involved in oxidative processes. Also, ALA can repair oxidative stress-damaged proteins, lipids, and DNA.³

ALA supplementation has recently been proposed in T2DM, obesity, and pregnancies complicated by gestational diabetes. ALA has been shown to either decrease glycaemic or inflammation levels especially in dysmetabolic patients with an increased T2DM risk occurrence. A recent meta-analysis indicated that it decreases body weight and leptin levels and increases adiponectin levels in obese participants.³

ALA improves glycaemic control due to the ALA-induced GLUT-4 expression with subsequent uptake of glucose within tissues. A systematic review and meta-analysis also suggest that ALA might be able to decrease serum leptin concentrations - especially in younger adults - depending on the longer time of assumption and a significant increase in serum levels of adiponectin in studies, which lasted for more than eight weeks.³

ALA possibly decreases both adipose tissue leptin and circulating leptin mRNA levels through enhanced peroxisome proliferator-activated receptor-γ activity, which has an important role in decreasing leptin gene expression and in determining appropriate insulin signalling.³

This effect may be considered important given a recent meta-analysis suggesting that ALA decreased bodyweight among participants with obesity. Therefore, it might be possible that ALA by activated protein kinase activation and weight reduction decreases leptin and increases adiponectin levels, thus representing a very promising molecule in reducing some frequent features of PCOS, that is, increased body weight and inflammation.³

Several studies support the use of ALA for its direct and indirect antioxidant effects through the regeneration of other antioxidants and its anti-inflammatory activities exerted by inhibiting some cytokines. Some authors have shown that the endometrial inflammasome, in which prevails the overexpression/activation of NLR family pyrin domain containing 3 (NALP-3), is associated with idiopathic recurrent pregnancy loss and that the combined treatment with MI can re-modulate the endometrial pathway of NALP-3 with a decrease of the concentrations of apoptotic cytokines.³

In a pilot study, De Cicco and colleagues treated 40 patients with normo-insulinemic overweight PCOS with a combination of MI plus ALA for six months and the results showed a decrease in BMI, waist-hip ratio, hirsutism score, anti-Müllerian hormones (AMH), ovarian volume, and antral follicle count, and an increase in the number of menstrual cycles (from two to five). AMH is a unique biochemical marker of gonadal development and fertility in humans.³

Genazzani and colleagues demonstrated that the combined administration of ALA and MI to obese PCOS women, grouped by the presence or absence of familiarity with T1 or T2DM, led to an improvement of insulin sensitivity in patients with T2DM and an improvement in the insulin response to oral glucose tolerance test (OGTT) in both groups, unlike what was observed after treatment with MI alone.³

In PCOS women with T2DM and a reduced expression of lipoic acid synthase and epimerase, the combination of ALA plus MI markedly reactivated the stimulus on GLUT4 and therefore was able to improve insulin sensitivity. Also, the treatment with ALA (400mg/d) improved the metabolic features especially in the presence of T2DM.³

At the same time, an improvement in oocyte quality and pregnancy rate has been observed both in humans and in animal models. A randomised trial evaluated the effects of MI alone or in combination with ALA in a population of non-obese PCOS women undergoing assisted reproductive therapy.³

Significant reductions in BMI, insulin (baseline and after OGTT), ovarian volume, and gonadotropin units used for COH were observed. The oocyte quality was inversely correlated with the decrease of the BMI, resulting in greater recovery of M-II oocytes, the formation of classes I and II embryos, and the increase in the pregnancy rate.³

Folic acid

An observational study by Regidor et al found that the use of MI combined with folic acid was shown to be a safe and promising tool in the effective improvement of symptoms and infertility for patients with PCOS.⁴

The study recruited 3602 infertile women and was administered a daily dose of 4000mg of myoinositol and 400mcg of folic acid, in divided doses, for two to three months. Within the study, a subgroup of 32 patients had hormonal values tested for testosterone, free testosterone and progesterone at baseline and following treatment.⁴

Results showed that, during the study, 70% of the women had a restoration of ovulation and 545 women fell pregnant, yielding a 15.1% pregnancy rate for the myoinositol and folic acid intervention.⁴

The study also demonstrated that, in the tested subgroup, testosterone levels changed from 96.6ng/mL to 43.3ng/mL and progesterone from 2.1ng/mL to 12.3ng/mL (p < 0.05) after 12 weeks of treatment.⁴

The authors concluded that not only was MI and folic acid a safe intervention, with no reported side effects, but they also noted that the achieved pregnancy rates are at least equivalent or even superior, to those reported by the use of the leading drug therapy metformin.⁴

Conclusions

Inositols, ALA, vitamins, antioxidant supplementation, and multiple combinations of these compounds, associated with diet and lifestyle modifications, can be an important therapeutic option to manage PCOS and pregnancy-related complications. Evaluation of the safety of these compounds and their combinations concludes that they are safe, and there is no evidence of adverse events both in mothers and foetuses.³

REFERENCES:

1. Escobar-Morreale HF. Polycystic ovary syndrome: definition, aetiology, diagnosis and treatment. Nature Reviews Endocrinology, 2018.

2. International PCOS Network. International evidence-based guideline for the assessment and management of polycystic ovary syndrome, 2020. https://www.guidelines.co.uk/womens-health/management-of-polycystic-ovary-syndrome/455535.article

3. Aversa A, La Vignera S, Rago R, et al. Fundamental Concepts and Novel Aspects of Polycystic Ovarian Syndrome: Expert Consensus Resolutions. Front Endocrinol, 2020.

4. 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.