Study of the Effect of a Nutritional Supplement on Microbiota, Metabolic Control, Inflammatory Profile, and Quality of Life in Patients With Polycystic Ovary Syndrome.

Polycystic Ovary Syndrome (PCOS) is an endocrine-metabolic disorder that affects many women of reproductive age. PCOS is not just a reproductive disorder but a systemic condition, as cases of PCOS have been described even in menopause, although its prevalence in post-reproductive stages is not high. The diagnosis of PCOS is made using the Rotterdam criteria, agreed upon in 2003 by ESHRE and ASRM (European Society for Human Reproduction and Embryology/American Society for Reproductive Medicine). According to these criteria, a patient must meet two of the following three criteria to be diagnosed with PCOS: oligo-anovulation, clinical or biochemical hyperandrogenism, and polycystic ovarian appearance.

The Rotterdam criteria are widely used but can sometimes lead to an erroneous diagnosis of PCOS. Therefore, in 2006, the AES (Androgen Excess Society) decided that, in addition to the 2003 Rotterdam criteria, hyperandrogenism-either physical or biochemical-was necessary for a PCOS diagnosis. Depending on the criteria used and the diversity of the population studied, epidemiological results can vary. Despite this variability, it is estimated that PCOS affects 6-12% of women of reproductive age.

The most common manifestations of PCOS include androgenic alopecia, hirsutism, acne, irregular cycles, or periods of amenorrhea. An ultrasound image showing polycystic ovarian morphology alone is insufficient for diagnosing PCOS. In polycystic ovaries, more than 12 follicles of 2-9 mm in size and increased ovarian volume (>10 ml) should be visualized using transvaginal ultrasound. Despite the complex and not fully understood pathophysiology of PCOS, two main types of alterations are identified.** On one hand, there is an accelerated release of gonadotropin-releasing hormone (GnRH), which leads to an increased release of luteinizing hormone (LH), resulting in greater androgen production, altered folliculogenesis, and long menstrual cycles or amenorrhea. On the other hand, there is an alteration in ovarian steroidogenesis and folliculogenesis due to increased activity of cytochrome P450c17, an enzyme involved in the synthesis of ovarian and adrenal androgens, leading to elevated androgen levels.

In 70-80% of PCOS cases, women present insulin resistance (IR), with 30-50% of these also exhibiting obesity. High body fat percentage and hyperinsulinemia play significant roles in the development and progression of PCOS. Chronically elevated insulin levels can be associated with elevated androgen levels in a bidirectional manner. Elevated insulin levels may stimulate LH production and increase the activity of the P450c17 enzyme in the ovaries and adrenal glands, resulting in reduced hepatic production of sex hormone-binding globulin (SHBG), which increases the amount of free androgens. Conversely, elevated androgens are associated with increased insulin resistance in the muscles, leading to poorer glucose uptake.

Obesity is considered an amplifying factor in the pathophysiology of PCOS. Adipose tissue is an endocrine organ, and a high amount of adipose tissue increases the production of inflammatory cytokines, which can worsen IR by interfering with glucose uptake. While 70-80% of women with PCOS have IR, there is a 20-30% subgroup without metabolic involvement. Women with PCOS who have a healthy body fat percentage also present with insulin resistance, suggesting that obesity is not the cause of PCOS.

PCOS is a syndrome with a significant genetic basis, complex, and multifactorial pathophysiology. Lifestyle benefits in improving symptoms and the syndrome's progression are an important therapeutic tool. PCOS directly affects the quality of life of patients due to the long-term symptoms and comorbidities associated with this condition, such as obesity, type 2 diabetes mellitus (T2DM), metabolic syndrome (MS), and psychological and emotional issues. Consequently, women with PCOS generally have poorer health compared to those without the condition. Furthermore, comorbidities directly impact quality of life and individual perception of it.

To improve symptoms and prevent the comorbidities, the first line of treatment for patients with PCOS and IR should involve lifestyle modifications. Nutritional intervention and physical exercise are fundamental in maintaining a proper body composition, which can prevent the worsening of PCOS symptoms. The quality and composition of the diet are crucial, beyond the implications of body weight. A hypocaloric diet including low glycemic load foods has been shown to improve the homeostatic model assessment of insulin resistance (HOMA-IR), low-density lipoprotein (LDL) levels, triglycerides (TGC), cholesterol, and free androgen index (FAI). Improving lifestyle will directly impact body fat percentage, which, in turn, will improve hyperandrogenism and ovarian function.

Mental health disorders are highly prevalent among women with PCOS, particularly anxiety, depression, and sleep disorders. Sleep disturbances impact the onset and progression of anxiety and depression in PCOS patients; thus, treating sleep-related issues should be part of the overall treatment. Sleep deprivation is associated with an increased risk of IR, obesity, and type 2 diabetes (T2D). It has been observed that patients with PCOS have decreased melatonin levels in follicular fluid. Melatonin is a potent antioxidant that protects ovarian follicles during maturation. Therefore, sleep disorders can worsen insulin resistance and consequently exacerbate PCOS with metabolic involvement.

Additionally, the microbiota, through the production of various metabolites, impacts complex mechanisms such as hunger and satiety regulation, carbohydrate and lipid metabolism, which can directly affect body composition and PCOS symptoms. The gut microbiota can regulate up to 10% of the transcriptome and host genes involved in metabolism, proliferation, and immune response. Moreover, diet can modulate the gut microbiota composition in patients with PCOS and IR, as an increase in bifidobacteria correlates with improved insulin sensitivity and reduced inflammation. Short-chain fatty acids (SCFAs) such as acetate and butyrate, produced by beneficial gut microbiota, influence glycemia. Given the role of these metabolites in carbohydrate and lipid metabolism, achieving a healthy microbiota state could be a therapeutic goal to reduce systemic inflammation and improve IR.

The two specific inositol stereoisomers, Myo-inositol (MI) and D-chiro-inositol (DCI), act as second messengers of insulin. MI transforms into an insulin second messenger, Myo-inositol phosphoglycan (MI-IPG), which is involved in cellular glucose uptake, while DCI converts into another insulin second messenger, DCI-IPG, which is involved in glycogen synthesis. In patients with PCOS, there appears to be an increased epimerization of Myo-inositol (MI) to D-chiro-inositol (DCI) at the ovarian level due to insulin's effect. Consequently, there is an excess of DCI and a deficiency of MI, which can affect follicle-stimulating hormone (FSH) signaling and deteriorate oocyte quality. Therefore, inositol supplementation is considered an effective and safe method for improving PCOS symptoms by enhancing insulin sensitivity, follicular development, and oocyte maturation. This insulin-sensitizing effect of inositol can help normalize blood androgen levels and improve glycemia. Metformin is a common treatment for women with PCOS and IR. Recent results show that Myo-inositol can be as effective as metformin without its side effects. Both inositol and metformin can improve the metabolic and clinical profile of PCOS patients, as well as metabolic disorders related to diabetes.

Additionally, adequate vitamin D levels should also be considered in patients with PCOS, as vitamin D is involved in increasing the synthesis and release of insulin, enhances insulin receptor presence, and improves insulin response in glucose transport. Vitamin D indirectly affects carbohydrate metabolism by normalizing extracellular calcium levels and parathyroid hormone concentration. It also impacts systemic inflammation by inhibiting the production of pro-inflammatory cytokines, which could contribute to the development of IR. Patients with PCOS who took 20,000 IU of cholecalciferol (Vitamin D) weekly benefited from improved carbohydrate metabolism and better menstrual frequency. Combined supplementation of magnesium, zinc, calcium, and vitamin D in another study led to a significant reduction in total testosterone compared to placebo, although it did not affect sex hormone-binding globulin (SHBG) levels or the free androgen index (FAI). However, the combination of vitamin D and fish oil reduced inflammation markers in the body, such as serum C-reactive protein (CRP), downregulated interleukin 1 (IL-1), and total testosterone levels. A beneficial effect on mental health parameters was also observed, assessed through the Beck Depression Inventory. Available literature shows that zinc supplementation may be indicated in patients with PCOS, as zinc plays an important role in glucose and lipid metabolism. Zinc deficiency may play a significant role in PCOS pathophysiology and also serve as a prognostic marker for the syndrome. It appears that zinc levels in PCOS patients are significantly lower compared to healthy controls. Low zinc intake in individuals with high body fat percentage is associated with hyperinsulinemia, low-grade inflammation, and deterioration of the lipid profile. Zinc ions can act as insulin mimetics in adipocytes, stimulating lipogenesis and glucose transport through the translocation of glucose transporter 4 (GLUT4) to the plasma membrane.

In PCOS patients, there is known to be higher oxidative stress, which could worsen the symptoms of PCOS. Curcumin, extracted from turmeric (Curcuma longa), is a biologically active phytochemical with antioxidant properties. Studies with curcumin in animals have shown promising results, but in PCOS patients, the literature is inconclusive, and it is limited to suggesting that curcumin may have beneficial effects in the clinical management of PCOS symptoms.