Polycystic ovarian syndrome (PCOS) is one of the most common (about 5–20 %) and complex endocrinopathy in women of reproductive age. PCOS is the most common cause of female infertility, which is incorporated with different phenotypes including oligo‐/anovulation, infertility, and menstrual cycle abnormalities [1] and is also associated with polycystic ovary, acne, hirsutism, hyperandrogenemia, insulin resistance (IR), abdominal obesity, dyslipidemia and elevated serum luteinizing hormone (LH), and an increased risk of metabolic disorder such as the development of type 2 diabetes, cardiovascular diseases, and endometrial cancer [2], [3], [4], [5]. Besides, the aetiology of PCOS is still unclear because of the heterogeneous condition and multifactorial intervention [6]. Due to the ethical and logistic limitations of human experimentation, it is challenging to identify the origins and pathogenic mechanisms of PCOS to unravel the optimum or curative therapies. To date, there is no universal drug for PCOS therapy. Therefore, relevant animal models that can mimic the PCOS condition are being used to study the pathogenesis. Previous studies have suggested that non-human primates and rodent models such as female rats and mice could able to mimic PCOS-like condition like cystic ovaries with elevating androgen level [7], [8]. Moreover, hyperandrogenised mouse models have been shown to manifest many characteristics of PCOS like hyperandrogenism, insulin resistance, cysts in the ovaries, and metabolic disorder [9], [10]. Letrozole is a non-steroidal aromatase inhibitor that prevents the conversion of testosterone and androstenedione to estradiol and estrone respectively [11]. Letrozole causes polycystic ovary alterations that are similar to those seen in PCOS condition, including anovulation, thicker theca interna cell layer, and increased ovarian weight [12], [13], [14].

Adipose tissue dysfunction has been implicated as a key feature in PCOS patients [15], [16]. Previous reports suggested that adipokine level such as visfatin, and apelin was altered in the PCOS condition [9], [17], [18]. Apelin, an adipocytes-derived hormone found to be regulated with the occurrence of obesity and insulin resistance [19], [20]. Thereby, it is more likely to have an important role in PCOS condition. Apelin is an adipokine derived for the first time from bovine stomach extract and identified as an endogenous ligand for an orphan G-protein coupled receptor in 1998 [21]. This receptor was discovered based on its sequence similarity to the angiotensin receptor and named as apelin receptor (APJ) after apelin [22].

The apelinergic system has been found in adipose tissue, the male and female reproductive system, placenta, and also in the hypothalamic-pituitary–gonadal (HPO) axis [19], [23], [24], [25], [26]. Roche et al [23] observed that in the follicular fluid, apelin concentration was elevated along with mRNA expression of apelin and APJ in the PCOS human ovary. Studies suggested that apelin has positive effects on steroidogenesis and proliferation but is suppressive to apoptosis [20]. Some studies have found that serum apelin level increase in PCOS patients and apelin could be a potential target for PCOS management [20], [27], [28].In contrast, apelin level were also found to be low in lean PCOS patients [29], [30]. However, in the rodent PCOS model, the apelin system has not been investigated yet. Our previous study has also shown adipokine like visfatin inhibition could ameliorate PCOS pathogenesis [9]. It is known that PCOS patients exhibit hyperandrogenism, ovarian cysts including hormonal imbalances in the LH, estradiol, androgen hormone. In addition, the apelin/APJ system regulates the synthesis of androgens and estrogens via inhibiting IGFBP-1 in PCOS patients [28]. Previous studies have also shown that elevated APJ in diabetes could be managed by its antagonist [31], [32]. Thus, it can be hypothesized that the apelin system, more importantly, APJ modulation would be important for the management of hyperandrogenism, and ovarian cysts in PCOS conditions. Therefore, the objective of the present study was to investigate the effects of APJ agonist, apelin13, and its antagonist ML221, on the letrozole-induced hyperandrogenised PCOS-like mice model.