Polycystic Ovary Syndrome (PCOS)

Polycystic Ovary Syndrome (PCOS): History

Please note this is an old version of this entry, which may differ significantly from the current revision.

Subjects: Endocrinology & Metabolism

Contributor: Pedro-Antonio Regidor

Polycystic ovary syndrome (PCOS) is a disease that causes irregular bleeding, chronic anovulation, androgen excess, and a typical ovarian ultrasound feature.

PCOS
obesity
inflammation

1. Introduction

Polycystic ovary syndrome (PCOS) is a disease that causes irregular bleeding, chronic anovulation, androgen excess, and a typical ovarian ultrasound feature [1]. It affects between 5 and 10% of women in their reproductive age, thus representing one of the most frequent causes of infertility [2]. The reasons for the development of PCOS have not been resolved yet. Genetic predisposition, together with the gestational environment and lifestyle factors, seem to be critical contributors [3]. Apart from the cardinal diagnostic criteria, including hyperandrogenism, ovulatory dysfunction, and/or the morphology of polycystic ovaries, as defined by the so-called “Rotterdam criteria” [4], other characteristics are related to the disease. PCOS is often accompanied by obesity [5], and 30–40% of women with PCOS show a reduced glucose tolerance, often accompanied by insulin resistance [6]. In total, 80% of obese women and 30–40% of lean individuals with PCOS suffer from hyperinsulinemia [6,7]. It has been found that hyperinsulinemia is a crucial factor in the clinical pathogenesis of PCOS and seems to be independent of weight [8]. Excess insulin may lead to enhanced androgen synthesis by direct stimulation of androgen production on the one hand and by reducing the serum levels of sex hormone-binding globulin (SHBG) on the other, thereby contributing to the androgen excess characteristic for PCOS [8]. In addition, obesity has a substantial impact on the severity of PCOS symptoms [9]. Apart from reinforcing insulin resistance, adipocytes show an altered hormone metabolism that contributes to the endocrinological disorder [10].

Furthermore, excess adipose tissue is a source of chronic low-grade inflammatory processes, and PCOS is considered an inflammatory disease [11]. Inflammatory response has been defined as an ensemble of initiation and active resolution processes. Within this perception, the resolution of inflammation is dependent on a class of lipid mediator molecules called specialized pro-resolving mediators (SPMs) [12]. These molecules are derived from polyunsaturated fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) and are synthesized via specific intermediate molecules by cells of the immune system. This publication will focus on the role of SPMs in chronic inflammatory diseases such as PCOS and the potential benefit of supplementation with their precursor molecules.

2. Polycystic Ovary Syndrome (PCOS)

Polycystic ovary syndrome (PCOS) represents a chronic inflammatory condition since classical indicators for an inflammatory response are present, such as increased values of IL-6, C-reactive protein, fibrinogen, and erythrocyte sedimentation rate [11,31]. The presented data support this concept, as the lipidome of PCOS patients is shifted towards the pro-inflammatory axis with an increase in pro-inflammatory prostanoid derivatives and an elevated ratio of (pro-inflammatory LM)/(the sum of SPMs and their hydroxylated precursors).

Some widespread diseases such as diabetes, cardiovascular disease, and obesity are associated with chronic inflammation [15,17,32]. These pathologies are strongly interlinked with diet, and the positive impact of a polyunsaturated fatty acid (PUFA)-rich diet on cardiovascular health is broadly accepted [33]. Both EPA and DHA show an anti-inflammatory effect, and in this context, their role as precursors for SPM biosynthesis has been discussed [34,35]. The crucial role of SPMs in such chronic inflammatory states has become evident throughout the past years, and the underlying molecular mechanisms are increasingly elucidated [12,36].

For the DHA-derived SPM protectin PD1 and its hydroxylated precursors, for example, a positive influence on the metabolism of fatty tissue was demonstrated, suggesting a potential role in the management of obesity [37]. For DHA-derived SPM RvD1, a molecular mechanism for its possible cardioprotective effect has been demonstrated: it can activate lipoxin A4/formyl peptide receptor 2 (ALX/FPR2), which serves as a sensor for the resolution of inflammation in the context of coronary heart disease. In animal experiments, ALX7FPR-null mice developed obesity, diastolic dysfunction, and showed reduced SPM- levels associated with an impaired resolution of inflammation after cardiac injury [38].

SPM biosynthesis is, of course, based on the abundance of its PUFA precursors. However, in several experimental setups, the SPM biosynthesis was disturbed by altered activities of the involved enzymes [37]. Depending on the affected enzyme, supplementation with the hydroxylated intermediates of the SPM biosynthetic pathways may be efficacious in those cases, as demonstrated in a setting with leukocytes of obese individuals that showed a profound deficiency in the biosynthesis of RvD. Incubating the leukocytes with 17-HDHA, the precursor of RvD, restored the SPM production [39].

Therefore, supplementation with DHA- or EPA-derived SPMs and their corresponding hydroxylated precursor metabolites 18-HEPA, 17-HDHA, and 14-HDHA may represent a promising approach to address the pathologic features often associated with PCOS. Hyperandrogenemia, obesity, and insulin resistance all aggravate each other and are all associated with chronic inflammatory processes.

Another possible approach is the combination of PUFAs with Myo-inositol and/or D-chiro inositol. These two molecules have been classified as insulin sensitizers and seem to adequately counteract several insulin-resistant metabolic alterations with a safe nutraceutical profile. Paul et al. [40] concluded that supplementation with these two molecules complement each other in their metabolic actions and act in synergy with other insulin-sensitizing drugs and/or nutraceuticals.

Laganà et al. [41] also described that insulin resistance causes a rise in free-fatty-acid (FFA) plasma levels due to an increased synthesis from the liver and increased mobilization from adipose tissue. The excess of free fatty acids (especially the derivatives of omega-6) seems to lead to insulin resistance by inactivation of key enzymes such as pyruvate dehydrogenase (PDH) or by decreasing glucose transport activity in the cells. Therefore, a possible combination between the mediators of omega-3 and inositol may play a new treatment approach for women with PCOS.

An association with the lipid mediator profile was demonstrated that was significantly shifted towards the pro-inflammatory axis compared to healthy women. Exciting was the greatly increased level of thromboxane TXB2 in PCOS patients compared to the test group, as its precursor, TXA2, plays an essential role in platelet activation and aggregation. PCOS-affected women are known to have a 2-fold increased risk for venous thromboembolic events compared to healthy women.

It is important to mention that the metabolites of omega-3 fatty acids show profound anti-inflammatory activity, as they diminish the synthesis and action of pro-inflammatory mediators such as LTs, PGs, and PAF, stimulate the anti-inflammatory M2 phenotype of macrophages and increase the number of anti-inflammatory molecules such as IL-10, limit recruitment of neutrophils, trigger the macrophage switch to the anti-inflammatory M2 phenotype, and increase their phagocytotic and efferocytotic action, thus contributing to clearance of the site of inflammation. They are increasingly proposed for treatment of chronic inflammatory states such as cardiovascular disease or obesity and diabetes. As PCOS women are highly affected by these diseases, we suppose that SPMs will play an essential role in the future management of this clinical condition.

The fact that white blood cells, cytokines, and interleukins are elevated could be reaffirmed with our data showing a metalipidinomic disbalance in women with PCOS.

Treatment of PCOS is mainly focused on weight loss, use of anti-androgenic hormone preparations, treatment with insulin-sensitizing agents or the whole repertoire of ovulation induction, and in vitro fertilization techniques when child wish comes into focus. At the same time, the underlying inflammatory processes are relatively neglected as a therapeutic target [43].

This entry is adapted from the peer-reviewed paper 10.3390/biomedicines10020456

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