The Role of Oxytocin in Polycystic Ovary Syndrome: A Systematic Review

1. Introduction

Polycystic Ovary Syndrome (PCOS) is the most common endocrine disorder that affects women of reproductive age [1]. Depending on the diagnostic criteria used its worldwide prevalence goes from 4% up to 20% [2]. PCOS is characterized by polycystic ovary morphology, androgen excess and ovulatory dysfunction [3]. In combination with its typical metabolic, reproductive as well as psychological features, PCOS is a relevant public health concern [4]. In particular, if taken into consideration that about 75% of PCOS cases are estimated to be undiagnosed [5]. PCOS is associated with high levels androgens including dehydroepiandrosterone and androstenedione of adrenal origin as well as androstenedione and testosterone of ovarian origin [6]. PCOS is also usually characterized by increased luteinizing hormone (LH) levels, elevated LH/FSH ratio [6,7,8,9], and low to normal follicle-stimulating hormone (FSH) levels [7,10]. However, other studies suggest there are no significant differences in LH/FSH ratio [11] between PCOS and control groups.

Furthermore, PCOS is the primary cause of anovulatory infertility [12] and accounting for 80% of those cases [13,14]. Pregnant PCOS women, on the other hand have a higher risk of developing gestational diabetes mellitus or suffering a first-trimester spontaneous abortion [15,16]. Interestingly, even though elevated baseline LH/FSH ratio in PCOS was found to be related to poor ovulatory response, PCOS cases with elevated LH/FSH ratio were more likely to achieve a clinical pregnancy and live birth than women with normal LH/FSH [9].

Ovarian function and cycles are regulated by the hypothalamic-pituitary-ovarian (HPO) axis, in particular by GnRH and the Gonadotropins. During the last years, the nonapeptide oxytocin (OT) attracted the attention of the scientific community. OT is synthesized in the paraventricular and supraoptic nuclei of the hypothalamus, along with a few neurons in the accessory nuclei of the hypothalamus, and is transported to the neurohypophysis where it is released in the blood circulation [17,18,19]. OT plays a crucial role in several behavioral and reproductive functions in human beings, such as breastfeeding, pregnancy and parturition but also in other processes like bonding decision-making, prosocial behavior, and physical activity [20]. It is also related to the pleasure associated with orgasm ,both in males and females, being released in elevated quantities during this process. OT receptors (OXTR) are expressed in several body parts including the ovaries and prostate gland. Specifically, OXTR are found to be expressed in the granulosa cells, and in the small follicles in several mammal species including humans [21], and OT takes a still unclear role in steroidogenesis [22]. Despite the growing interest in the role played by oxytocin in several human functions, its possible role in one or more psychological symptoms, such as depression, anxiety, and social cognitive impairments or physical symptoms, such as metabolic dysfunctions or infertility, of PCOS [23] is still not clear or little studied. In the present systematic review, we aimed to disentangle the role played by oxytocin in PCOS, taking into account all animal and human studies. In particular, we aimed to understand (i) the presence of possible alterations of basal plasmatic OT level in PCOS, (ii) in which manner a possible alteration of the OT plasmatic level can be related to the symptoms of PCOS, and (iii) the presence of a possible effect of OT administration in PCOS.

2. Materials and Methods

The present systematic review (PROSPERO reg. n. 531987) followed the procedure recommended by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [24]. We performed a computer-based search in the principal databases, such as PubMed, Web of Science, and Scopus, combining terms related to polycystic ovary syndrome and oxytocin (Figure 1).

Moreover, our research question used the PICO strategy protocol. In particular, our research question was related to the role played by oxytocin (O - Outcome) in women or animal models with polycystic ovary syndrome (P- Population), determining the level of oxytocin in body fluids, such as blood and saliva (I- Intervention) in comparison with healthy women or animals (C- Comparison- Table 1- Appendix A).

In the present systematic review, databases were selected to explore the published studies using the following keywords: "polycystic ovary syndrome" [MeSH Terms] OR ("polycystic" [All Fields] AND "ovary" [All Fields] AND "syndrome"[All Fields]) OR "polycystic ovary syndrome" [All Fields]) AND ("oxytocin"[MeSH Terms] OR "oxytocin"[All Fields] OR "oxytocin s [All Fields] OR "oxytocin [All Fields] OR "oxytocin [All Fields]”, with no time limit, and using the Boolean operators AND and OR. The inclusion and exclusion criteria were determined based on the topic, study design, and population (Table 2).

In the second stage, we removed the duplicates and manually screened both the titles and abstracts to evaluate if they fulfilled the inclusion and/or exclusion criteria. After that, we retrieved the full text of the possibly pertinent studies to verify their eligibility. Two authors independently carried out the literature search, article screening, and methodologic evaluation. Both authors discussed the results and a consensus was reached. However, a third opinion was required when a consensus was not reached.

The included studies were subsequently screened to find further articles in the reference lists related to the topic of interest. Similarly, we screened all the excluded studies to identify additional relevant bibliographic sources. To estimate the quality of the selected studies, when possible, in the current systematic review, it was used the “NOS- Newcastle-Ottawa Scale Quality assessment scale for case-control and cohort studies” (https://www.ohri.ca/programs/clinical_epidemiology/nosgen.pdf- Supplementary material).

Then, information associated with the characteristics of the participants and inclusion and exclusion criteria were extracted from each included article, according to the previously mentioned guidelines. The flowchart in Figure 1 depicts the steps of the selection process.

3. Results

The flowchart depicted in Figure 1 shows the selection process of the studies. We included 6 published studies in the systematic review, after reaching a consensus. Moreover, we calculated Cohen's k with 87.17 % (k = 0.742) indicating substantial agreement (https://idostatistics.com/cohen–kappa–free–calculator/)[25]. The characteristics of the studies are shown in Table 3.

Both human and animal studies were included. However, the selected studies did not show homogeneity in terms of both study design and population. The four human studies included 609 women and were published between 2010 and 2023. Among these, two were randomized or pseudo-randomized clinical trials, one was a case-control study and another one was a population genetics study.

Moreover, the principal focus of the included studies was related to the relationship between fertility and nasal oxytocin administration. Similarly, Ochsenkühn et al. included patients with PCOS as a cause of infertility together with different infertile groups [26]. Conversely, the clinical trial performed by Masrour et al. [27], included only infertile patients with PCOS [27]. During the clinical trial, the patients underwent eight units of OT, but the authors did not observe any significant changes in terms of infertility. Ochsenkühn et al. who did not observe any improvement in the fertility of the PCOS group after OT treatment [26] obtained similar results. Despite the administration of OT, these two above-mentioned studies did not assess the level of blood or salivary oxytocin in the participants [26,27]. However, since the main topic of both RCTs was to assess the effect of 8 IU of intranasal OT on infertility in PCOS, the studies found the treatment not relevant to improving fertility in PCOS patients affected by infertility. As underlined by Ochsenkühn et al., the failure to detect the effect of OT on the pregnancy rate can be the result of inadequacy in dose and or mode of administration [26]. The level of OT in PCOS before a treatment can be relevant, but none of the two RCTs collected such samples in PCOS groups. However, Jahromi et al. compared the level of oxytocin and other hormones (table 3) in both infertile women with or without PCOS [28]. These authors found that in PCOS the mean level of OT was inferior to the non-PCOS, with a mean value of 124.94ng/l compared to 207.42ng/l (p<0.0001). Moreover, since the anti-mullerian hormone usually shows high levels in PCOS, it was negatively correlated with oxytocin and the same occurred with insulin resistance. However, the authors did not observe a significant effect of BMI on oxytocin in both groups. According to the authors, the hormonal imbalances in hypothalamic-pituitary-ovarian (HPO), namely high LH and low FSH in the PCOS group, could be connected to the lower oxytocin levels. These low levels can in turn be implicated in chronic anovulation. Notably, this study was the first that proposed a cut-off value of the oxytocin level in women with PCOS.

Similar results were observed in a case-control study, [29] assessing the hypothalamic-pituitary-ovary axis dysfunction in a sample of 56 infertile PCOS women before the ovarian stimulation, with 2.5 mg of letrozole, and before the human chorionic gonadotropin (hCG) administration. The authors assessed the serum levels of OT, Dopamine(DA), phoenixin-14 (PNX-14), and nesfatin-1(NEF-1) in the group of pregnant and non-pregnant PCOS women. Moreover, FSH, LH, AMH, TSH, and prolactin have been assessed. In the whole sample, they found a weak association of OT with BMI and a stronger one with FSH (p<0.0002). However, in the pregnant group, higher baseline NES-1 and OT levels (+29.2% and +44%) were observed. Similarly, the OT level increase was associated with positive pregnancy rates. After OS in pregnant women the OT levels increase compared to non-pregnant.

Finally, Amin and colleagues [30] assessed the presence of the polymorphisms of the gene responsible for the expression of the receptor of oxytocin (OXTR) in 212 Italian PCOS patients. OXTR is widely expressed in the human body, including the brain and ovary tissue [31]. In their genetic population study, the authors tested the hypothesis whereby the OXTR variants are in linkage disequilibrium with PCOS in Italian families. They found that five variants, out of 22, were significantly (p < 0.05) linked to or were in linkage disequilibrium with PCOS. However, all these variants were not previously related to clinical manifestations of PCOS. Still, three of them (rs60345038, rs35498753, and rs237900) were found to intersect with the repressed chromatin state in the ovaries, with a negative OXTR gene expression.

In the present systematic review, animal studies were included. The two animal studies included 30 female rats and were published in 2018 and 2022, respectively. These two studies were classified as RCTs and both administered OT to PCOS rat models. However, Sajadi et al, [32] also administered carbachol. Despite the use of OT, the main objective of the two studies was different. Sajadi and Colleagues [32] studied the uterine contraction and tone in PCOS and non-PCOS rats after administration of OT or carbachol, while Yamamoto et al. [33] measured the effects of the administration of acute and chronic OT on metabolic disorders as well as the changes in endogenous OT in PCOS model rats.

Sajadi et al, [32] found that PCOS rats showed more irregular uterine contractions than controls and that after being exposed to carbachol their frequency and resting tone were significantly increased compared to controls. However, after the exposure to OT, there were no differences in frequency, resting tone, and amplitude of rhythmic contractions between both groups.

Yamamoto et al. [33] found that PCOS model rats showed lower serum OT levels than control rats. Nonetheless, the two groups did not differ in hypothalamic OT mRNA expression levels. The authors found that there were reductions in body weight gain and food intake only in PCOS model rats after the acute intraperitoneal OT administration during the dark phase, whereas the chronic administration of OT decreased the food intake in both the PCOS model rats and control rats.

4. Discussion

Despite the relevant role played by the nonapeptide oxytocin in several functions, such as social cognition, metabolic regulation, and reproduction, only a few recent studies investigated its role in PCOS. However, given the novelty of the topic, the present systematic review took into consideration all the studies that investigated the role played by not only serum oxytocin but also randomized clinical trials with the administration of synthetic oxytocin. The present review took into account also animal studies, since most of the current knowledge about PCOS was obtained by studies on rat models. These played a crucial role for studying and gaining insights into human pathologies during the last two centuries. Despite some similarities between animals and humans, they also showed distinct characteristics. Acknowledging important disparities in OT between animals and humans, the insights from rat studies are nevertheless important for the comprehension of the role played by OT in PCOS.

Most of the studies underestimated the relevance of the levels of OT in women with PCOS, by not reporting a possible OT basal levels difference. Notably, only two studies found that in PCOS the levels of OT were lower than healthy controls. Indeed, one human and one animal study agreed about lower levels of PCOS, confirming a possible implication of OT, in the pathogenesis of the syndrome, which can negatively affect the effect of OT administrations. Despite the complexity of the symptoms of PCOS, anovulatory infertility represents one of the most relevant issues. According to Pirog and colleagues, OT can be considered a predictor of pregnancy before ovarian stimulation therapy [29].

According to Dinsdale and Crespi [34], the relevance of oxytocin and possible alterations in the OT and OTXR system in PCOS is still not well understood. According to their review, PCOS and Autism spectrum disorder share several behavioral features that can induce speculation about a possible common role of OT in the two disorders [34]. However, the focus of the studies that we included was only related to the infertility issues related to PCOS. In different animal models, oxytocin seems to have a role in fertility by promoting the release of PGF2α from endometrial cells. Moreover, OT is involved in the process of luteolysis [35,36]. A similar mechanism is also present in human beings, but a positive role of administration of OT in the folliculogenesis and the increasing pregnancy rate in both humans and animals was reported in a few studies [37,38]. Ochsenkühn and colleagues [26] did not observe any increase in the pregnancy rate in couples affected by PCOS and infertility after 8 IU intranasal OT administration. The role of OT in uterine contractions has been assessed in a recent study [32], which compared PCOS and non-PCOS female rats uteri. After administration of the oxytocin, no significant differences were observed in the amplitude, tone, and frequency in the rhythmic uterine contraction of PCOS rats. However, the increase in the dose of OT stimulated higher levels of tone, with a decrease in the contraction frequency in PCOS rats' uterine tissues. It is well-studied that in the myometrium the number of oxytocin receptors increases, during the pregnancy [39], allowing the uterus to become more sensitive to oxytocin thus affecting the pattern of contraction during the pregnancy and labor. Despite this, Leonhardt et al, [40] did not find uterine morphological differences using magnetic resonance imaging, and less uterine peristaltic movement was found in PCOS assessed with transvaginal ultrasonography.

Despite the increase in the number of receptors, their genetic expression can be different in PCOS. Amin et al., [26] reported five novel genetic variants for the receptor of OT (OXYTR) associated with the risk of developing PCOS in multigenerational Italian families. These variants of the OXTR gene were found to be related to the principal symptoms of PCOS, such as anovulation or oligovulation, hyperandrogenism, polycystic ovaries, and the increased risk for metabolic alterations [41].

Some of the variants found by Amin are considered relevant for vulnerability to different disorders. The variant OXTR rs237902 found by Amin et al., [30] has been associated with schizophrenia vulnerability. Specifically, a significant association between rs237902 and negative symptoms, such as blunted affect, alogia, avolition asociality, and anhedonia, in schizophrenic patients and an overrepresentation in male aggressive children were observed [42,43,44]. Among the variants observed in PCOS, rs60345038 was also found to be relevant for type 2 diabetes [41].

Metabolic alterations were also studied in PCOS rats [33]. Rats to which OT was administered showed a significant decrease in weight and food intake [33]. However, this study did not quantify the lipolysis in the adipose tissue of the rats. Previous findings indicated that OT administration significantly reduced the area of adipocytes, the serum triglyceride, aspartate aminotransferase level alanine aminotransferase, and alkaline phosphatase in ovariectomized rats [46]. The menopausal period is considered to be a risk factor for visceral adiposity and metabolic disorders.

Several findings showed that oxytocin is useful for treating obesity and for preventing metabolic disorders [47,48,49,50,51,52].

5. Conclusions

PCOS is a multifaceted syndrome involving several symptoms affecting the patients' quality of life at different levels. The present review described the studies that analyzed the levels or the effects of administering OT in PCOS.

The studies reported in the present systematic review took into account only a part of the possible roles played by OT in PCOS. Most of the studies highlighted the role played by OT in fertility issues related to PCOS. Studies that analyzed the basal levels of OT in PCOS women agreed that PCOS is accompanied by a reduction in the serum level of oxytocin.

In what concerns the effects of OT administration it was noticeable that different dosage regimens or patterns of administration were not sufficiently studied. Besides, despite the novelty and relevance of the topic, none of these studies analyzed the effect of OT administration on prosocial behavior, or in couples’ relationships and sexual satisfaction in PCOS. Indeed, OT is not only implied in maternal behavior and reproduction but also in the relationship and importantly in orgasm[53].

6. Future Directions

Several outstanding issues need to be clarified by further studies that could disentangle the role played by OT administration in social behavior and the improvement of psychological symptoms in PCOS. Further studies are needed to clarify if the OT basal serum levels are associated with metabolic disorders in PCOS. Moreover, none of the studies that were included in the present systematic review assessed the relationship between OT and psychiatric comorbidities, such as mood and anxiety disorders, in PCOS.