Nutraceutical Treatment of Patients with Polycystic Ovary Syndrome

Polycystic Ovary Syndrome (PCOS) is a common cause of infertility, requir-ing antioestrogen and, possibly, gonadotropin treatment for the induction of ovulation. However, patients suffering from this disease need long-term treatment since PCOS is associated with an increased risk of metabolic syndrome, hyperinsulinemia, oxidative stress, inflammation, cardiovascular disease, and cancer. Allopathic treatment includes the continuous use of oral contracep-tives, preferentially with complementary anti-androgen activity, and metformin. However, these treatments only partially correct all aspects of the disease, while carrying potential adverse effects per se. Complementary and alternative medicine (CAM) offers opportunities for treatment through the use of nutraceuticals containing plant extracts, minerals, and vitamins with antioxidant, anti-inflammatory, and adaptogen capacity, as well as for correcting insulin resistance. Here we justify the formulation of the nutraceutical QALY® (Jona Pharma, Elversele, Belgium) that is composed of Ubiquinone Q10, the vitamins B9 and B12, the salts of zinc and selenium, the biomass of Haematococcus pluvialis, and the extracts of Mediterranean pine bark and of Rhodiola rosea. This can be complemented by phytotherapy with the extract of Momordica charantia plus alfa lipoic acid (Momordica plus®).


Clinical Trials
Over the last two decades, a large number of patients have participated in controlled or pragmatic trials using either the QALY® supplement, or its separate constituents, for the treatment of male [1] or female infertility [2]. Overall the complementary intake of QALY® increased the spontaneous pregnancy rate and the success rate of intra-uterine insemination (IUI) of infertile couples with number needed to treat of 4. When given before conception of In Vito Fertilization (IVF) the clinical pregnancy rate increased from 35% up to 50% per treatment cycle [3]. Two out of every 3 patients suffering from myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) or from the post-COVID syndrome (also called "long-COVID") [4] experienced benefit from this nutraceutical with the result of the Fatigue Severity Scale significantly decreasing by an average of 14% after one month. QALY® was also given with the aim to correct the presumed mechanisms of ageing [5] and to prevent, or delay the progression of Alzheimer dementia [6].
Momordica plus® prescribed to patients with the metabolic syndrome or type II diabetes, reduced insulin resistance during follow-up of up to 6 years in over 90% of cases [1].

Literature Study
The results of these personal pragmatic studies were challenged against scientific publications recruited through search in the usual electronic programs (Pubmed, Google) and associated references. The considerations based on our clinical experience, as described in the references cited above, and on the literature search are given in separate paragraphs related to the intended biological effects being relevant to the pathology of PCOS.

Oxidative Stress and Anti-Oxidants
Oxidative stress is an important contributing factor to the pathogenesis of PCOS [7] [8]. Antioxidant treatment has, therefore, been recommended in these patients [9].
The biomass of the microscopic algae Haematococcus pluvialis is a natural source of Astaxanthin, which is a strong antioxidant, with complementary anti-inflammatory activity. Astaxanthin belongs to the group of the carotenoids, and it has no toxic nor teratogenic effects. It protects against oxidative damage to the cell membrane and to DNA, and has favourable effects in various diseases [10].
The oxido-reductase co-enzyme ubiquinol Q10 (CoQ-10) mainly acts as an antioxidant at the mitochondrial level and improves their function [11]. CoQ-10 has successfully been given for the treatment of patients with PCOS [12].

Metabolic Syndrome and Inflammation
The extract of the bark of the Mediterranean pine tree (pine bark extract) is rich in flavonoids, anthocyanidins in particular. Pine bark extract exerts strong activity against inflammation [13], which is an important aspect of PCOS [14], and has anti-oxidant effects as well.
Many patients with PCOS suffer from insulin resistance. Pine bark extract improves this condition [15] and reduces the health risks associated with it [16].
In PCOS patients with the metabolic syndrome, either or not associated with obesity, Momordica charantia extract improves cellular insulin receptivity by activating the adenosine monophosphate-activate protein kinase (AMPK). Its efficacy is enhanced by alfa lipoic acid that facilitates multiple steps of glucose/pyruvate metabolism at the post-receptor level [17].

Hormone Deregulation and Adaptogens
Hyperandrogenism, imbalance of the gonadotropin secretion, and deregulation of the hypothalamic-pituitary-adrenal (HPA) axis are well-known and typical endocrine phenomena in the majority of PCOS patients [18]. The extract of Rhodiola rosea is a strong adaptogen attenuating adrenal hypersecretion through several pathways [19].

Homocysteine and Vitamins B9 & 12
The plasma homocysteine concentration is commonly increased in PCOS patients [20]. Administration of B-group vitamins [21], folic acid in particular [22], reduces circulating homocysteine in patients with PCOS.
Elevated serum homocysteine is associated with increased homocysteine concentration in follicular fluid, which affects oocyte fertilization [3]. In addition, hyper-homocystëinemie is an independent risk factor for cardiovascular disease and osteoporosis, which are both more common in PCOS patients [23].

Minerals: Selenium and Zinc
Selenium-dependant glutathione peroxidase has anti-tumour properties [24] and is relevant to PCOS patients [25]. Indeed, lower levels of selenium have been found in women with PCOS [26]. Food supplementation with selenium-salt was associated with improved metabolic response in these patients [27], and might reduce cancer risk.
Mitochondrial dysfunction and long-term metabolic imbalance are present in many PCOS patients [11] [28]. This can be corrected by zinc supplementation [29], especially when given together with Ubiquinol Q10.

Omega-3 Fatty Acids
The long-chain poly-unsaturated (PUFA) omega-3 fatty acids docosohexaenoic acid (DHA) and eicosapentaenoic acid (EPA) do attenuate PCOS complications through a number of mechanisms [30]. Krill oil is a rich source of these PUFA's that are esterified in phospholipids. The oral absorption of esterified DHA and EPA is better than that of the pure fatty acids, and Krill oil is more environmental friendly than fish oil.

Methylation and Epigenetics
Recently the importance of epigenetic interactions between microRNA and DNA methylation has been highlighted in patients PCOS [31]. Hypermethylation of certain DNA domains was found to play a pivotal role, as it does in many diseases and in carcinogenesis [32].
Food supplementation with QALY® reduces the methylation of the human telomerase reverse transcriptase (hTERT)-promoter region by an average of 14%.
In particular, the second dinucleotide (CpG2), which has been associated with an increased risk of several types of cancers [3], is lowered. It can be speculated that decreased methylation, in synergism with reduced hyperinsulinemia and increased selenium-dependant glutathione peroxidase activity will benefit PCOS patients and will lower their risk of tumorigenesis.

Discussion
Patients suffering from PCOS are at risk of long-term negative health hazards that are not, or only partly addressed by the usual allopathic treatments, the adherence to which is suboptimal in real-world [33]. In addition, Metformin may induce Vitamin B12 deficiency [34]. The mechanisms underlying PCOS-associated health hazards must be targeted and corrected, in order to improve the wellbeing of patients and to reduce the probability of ill-health when aging.
Nutraceutical food supplementation using natural ingredients is devoid of adverse effects, and the judiciously formulated composition presented here uses synergism of several constituents to counteract unfavourable biological processes.
The experience gained from previous clinical trials, together with ample data The biological effectivity can be monitored through periodic measurement of e.g. malondialdehyde in urine as a biomarker of oxidative stress and of the risk of cancer as well as of cardiovascular disease [35]. Glycosylated haemoglobin A1c and C-peptide concentration in blood [36] can serve as measures of glucose metabolism and insulin resistance.

Conclusion
Critical review of the effects of nutritional supplementation of POCS patients [37] with the nutraceutical QALY® and phytotherapy with Momordica plus® sustain the potential benefit of the synergism of their components on the pathogenic mechanisms causing health hazards to patients with this disease. The judicious formulation using natural components should protect these patients from ill-health that is commonly associated with the polycystic ovary syndrome, while being devoid of adverse side effects.

Momordica Plus
Composition per capsule:

Conflicts of Interest
The first author (FC) holds the Belgian patent on the fixed proportion of the combination of the 3 following ingredients present in QALY1: Selenomethionine, Astaxanthin and Mediterranean pine bark extract.