Review articleHormone-induced rat model of polycystic ovary syndrome: A systematic review
Graphical abstract
Introduction
Polycystic ovary syndrome (PCOS), one of the most common endocrine disorders affecting reproductive-aged women, has a worldwide prevalence ranging between 2.2% to 26.7%, depending on the diagnostic criteria used [1], [2], [3]. The three criteria for diagnosis of this syndrome are hyperandrogenism, polycystic ovary, and ovulation dysfunction [4].
This multifactorial disorder, is associated with luteinizing hormone (LH) hypersecretion, hyperandrogenism, relatively decreased levels of follicle stimulating hormone (FSH), polycystic or polyfollicular ovaries, oligo/anovulation (menstrual dysfunction), hirsutism, infertility, increased levels of inflammatory markers, neurological and psychological problems such as anxiety and depression, breast and endometrial cancers, obesity, insulin resistance (IR) and dyslipidaemia with an increased risk for cardiovascular diseases (e.g., hypertension, increased coronary artery calcium scores and increased carotid intima-media thickness) and type 2 diabetes mellitus (T2DM) [5], [6], [7], [8], [9], [10], [11], [12], [13], [14], [15], [16].
Several theories may explain the involved pathophysiological mechanisms in PCOS, which include: neuroendocrine, androgen synthesis/metabolism and/or action, cortisol metabolism, insulin action and/or secretion and lipid metabolism defects, as well as chronic subclinic inflammatory processes [17], [18].
Different potential factors may contribute to the presentation and severity of PCOS such as genetics, prenatal insults, epigenetic changes in fetal life (e.g., DNA methylation following exposure to high levels of androgen in utero), environmental factors (smoking, poor diet, and lack of exercise), high/low birth weight, hormonal imbalances and obesity [15], [16], [19], [20], [21], [22], [23], [24], [25], [26].
Genetic evidence including, familial and identical twin sisters studies and a high prevalence of PCOS and its features including hyperandrogenism and T2DM among first-degree relatives [20], [27], [28], as well as, DNA microarray analysis and genome-wide association studies (GWAS, preliminary area of genetic research in PCOS), have all demonstrated the role of genetic factors on the pathogenesis of PCOS [14].
DNA microarray analyses in women with PCOS have shown dysregulated expression of genes involved in steroidogenesis pathway (CYP11A, CYP17A1, CYP19, GATA6, RoDH2, ALDH6), steroid hormone actions (androgen receptor, SHBG), gonadotropin action and regulation (LH, FST, inhibin βA and inhibin βB, MADH4), insulin action and secretion (insulin and IGF-I, insulin VNTR gene, IGF-II, insulin receptor gene and insulin receptor substrate), obesity and energy regulation (leptin, leptin receptor and PPAR-γ), reproductive system development, amino acid metabolism, cellular development and proliferation of granulosa cells, mitogen activated protein kinase/extracellular regulated kinase (MAPK/ERK) signaling pathways and immune response (TNF-α, IL-6 and IL-6 receptor) [18], [29], [30], [31], [32], [33].
Previous studies report changes at the molecular level in isolated theca and granulosa cell lines from PCOS women. Levels of P4 (progesterone), 17OHP (17-hydroxyprogesterone), T (testosterone), CYP17A1 (17 alpha-hydroxylase), CYP11A1 and 3β-HSD (3β hydroxysteroid dehydrogenase) were increased in the theca cells of women with PCOS compared to normal women [34], [35], [36]. In addition, in granulosa cell lines from PCOS women E2 (estradiol) levels and aromatase activity were increased [36], [37], [38]. The alteration in steroidogenesis in PCOS could partly be explained by elevated Advanced Glycation End Products (AGEs) and their receptor (RAGE). Elevated AGEs affect genes involved in steroid synthesis and follicular development such as LHR, StAR (Steroidogenic Acute Regulatory protein), P450scc (cholesterol side chain cleavage enzyme), CYP17A1, 3β-HSD and AMHR-II (anti-Mullerian hormone receptor); AGEs, also, alter LH and AMH action by inappropriate activation of ERK1/2 and SMAD 1/5/8 phosphorylation pathway, respectively [36].
Despite the high prevalence of PCOS in women of reproductive age and some proposed theories about the pathogenesis of this syndrome, the precise etiology, pathophysiology and underlying mechanisms of this syndrome have not been fully clarified. Regarding the ethical limitations in human studies, ideal animal models of PCOS are crucial resources to study the developmental origin, pathogenesis, underlying mechanisms, long-term health consequences, effects of genetic manipulation and the pathophysiology of organs and tissues not easily accessible in women with PCOS. In addition, animal models of PCOS may contribute to providing optimal treatment and management of this syndrome.
Human and animal studies revealed that exposure of females to sex steroids in their early life could interfere with the function of the hypothalamus-pituitary-gonad axis and lead to the manifestation of the PCOS phenotype in adulthood [8]. In addition, accumulating evidence indicates that reproductive and metabolic dysfunction in adult life might result from programming of developing systems during fetal or prepubertal life.
Sheep and non-human primates with some reproductive and metabolic features of PCOS such as polyfollicular ovaries, LH hypersecretion, enhanced androgen production, increased visceral fat mass and IR, have previously been introduced [39], [40], [41], [42]; however use of these models has some limitations, e.g., high cost, long reproductive lifespan and pregnancy periods and difficulty in genetic manipulation. Therefore, many researchers prefer using rodents as a reasonable model of PCOS since rodents have many benefits, i.e., their smaller size, well understood anatomy, physiology, and genetics, shorter reproductive lifespan and generation times, ease of handling and maintenance, stable genetic backgrounds, feasibility of genetic manipulations, high reproduction index, and their different genetic strains.
Although, in previous studies, mouse model of PCOS with ovarian, endocrine and metabolic manifestations similar to human PCOS, including disrupted estrous cycle, ovarian cyst, atretic cyst, androgen excess, increased body weight, and glucose intolerant has been introduced earlier [43], [44], in this article we aimed to review only rat model of PCOS, because rats have several advantages compared to mice including: larger size of the animal and organs, which may facilitate some surgical procedures or laboratory manipulations and their higher blood volumes enable us to collect more samples for measurements of various parameters, as well as both rat strains (Wistar and Sprague-Dawley) are outbred (most commonly used mouse strains are inbred), more fierce and more resistant against various diseases.
To date, the most widely used PCOS rat model include hormone induction at different stages of development, prenatal life or postnatal life. Overall, hormone-induced rat model of PCOS has shown hyperandrogenemia, LH hypersecretion, ovarian cyst, polyfollicular ovary, oligo/anovulation, disrupted estrous cycle, IR, and increased body weight [8], [45]. Nevertheless there are some limitations in these studies, e.g., differences in findings, long period of hormone exposure and inability to determine all PCOS features (reproductive, neuroendocrine and metabolic), and reported either endocrine or ovarian disturbances. In addition, many of these rats lack some of the traits required to represent the PCOS phenotype and some of them indicate features that are not generally part of the syndrome e.g., vaginal opening atresia and male pseudohermaphroditism [8], [46], [47], [48], [49], [50].
Herein we review rat model of PCOS produced following exposure to hormones during the critical period of pre/postnatal life, with a focus on those associated with the reproductive, neuroendocrine and metabolic disorders. Hereby, we aimed to compare prenatal-induced rat model of PCOS with postnatal ones and introduce the most suitable rat model of PCOS that could show endocrine, ovarian and metabolic disturbances similar to PCOS phenotype in women, while maintaining normal reproductive system morphology in adulthood, in order to facilitate more precise studies on PCOS in the future.
Section snippets
Search strategy and study selection
In this systematic review, we searched Pubmed (1990–2016), Science direct (1990–2016), and Web of science (1990–2016) for relevant manuscripts, using keywords including “Polycystic Ovary Syndrome OR Polycystic Ovarian Syndrome OR Syndrome Polycystic Ovary OR Ovary Polycystic Syndrome OR Ovary Syndrome, Polycystic OR Syndrome, Polycystic Ovary OR Ovarian Syndrome, Polycystic OR PCOS” AND “Rat Model OR Rat Models OR Rat OR Rats” to generate a subset of citations relevant to our research. We
Study selection
Following electronic searches, of the 610 citations identified based on title and abstract, initially 456 titles and abstracts were exported to the endnote file; after studying titles and abstracts, 328 full text articles were studied; finally we included 41 original articles, that met our study objective.
The table given presents phenotypic features of rat model of PCOS and doses, route of administration, timing and duration of exposure; abnormalities of the reproductive, neuroendocrine and
Conclusions
Present studies have demonstrated that rats exposed to sex steroid hormones during critical periods and specific developmental time windows of their life (prenatal or postnatal life) show many traits of PCOS similar to those exhibited in women with PCOS e.g., ovarian cysts, oligo/anovulation, androgen excess, LH hypersecretion, disrupted estrus cycle and IR (Table 1, Table 2). Nevertheless, there are some differences in the findings between PCOS rats, differences which may be due to the degree
Strengths of the present study
Regarding strengths of the study, its main strength is that it is the first systematic review conducted on hormone-induced rat model of PCOS, comparing prenatal hormone-induced PCOS rats with postnatal ones. This systematic review will contribute to a better understanding and more precise comparison of PCOS rats and subsequently the selection of a suitable rat model for further studies regarding this syndrome.
Funding
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Conflict of interest statement
The authors declare that there are no conflicts of interest.
Acknowledgements
The authors would like to acknowledge Ms. Niloofar Shiva for critical editing of English grammar and syntax of the manuscript.
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