OBM Genetics

(ISSN 2577-5790)

OBM Genetics is an international Open Access journal published quarterly online by LIDSEN Publishing Inc. It accepts papers addressing basic and medical aspects of genetics and epigenetics and also ethical, legal and social issues. Coverage includes clinical, developmental, diagnostic, evolutionary, genomic, mitochondrial, molecular, oncological, population and reproductive aspects. It publishes a variety of article types (Original Research, Review, Communication, Opinion, Comment, Conference Report, Technical Note, Book Review, etc.). There is no restriction on the length of the papers and we encourage scientists to publish their results in as much detail as possible.

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Open Access Review

Hormonal and Physiological Manipulation Methods to Induce Polycystic Ovary in Rodents: A Review of the New Findings

Leila Naseri 1 ORCID logo , Mohsen Akbaribazm 2,* ORCID logo , Mozafar Khazaei 3,* ORCID logo

  1. Clinical Research Development Unit, Ayatollah Taleghani Hospital, Ilam University of Medical Sciences and Health Services, Ilam, Iran

  2. Department of Basic Medical Sciences, Khoy University of Medical Sciences, Khoy, Iran

  3. Fertility and Infertility Research Center, Health Technology Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran

Correspondences: Mohsen Akbaribazm ORCID logo and Mozafar Khazaei ORCID logo

Academic Editors: Thomas Liehr and Darren Griffin

Received: February 06, 2024 | Accepted: June 20, 2024 | Published: July 04, 2024

OBM Genetics 2024, Volume 8, Issue 3, doi:10.21926/obm.genet.2403248

Recommended citation: Naseri L, Akbaribazm M, Khazaei M. Hormonal and Physiological Manipulation Methods to Induce Polycystic Ovary in Rodents: A Review of the New Findings. OBM Genetics 2024; 8(3): 248; doi:10.21926/obm.genet.2403248.

© 2024 by the authors. This is an open access article distributed under the conditions of the Creative Commons by Attribution License, which permits unrestricted use, distribution, and reproduction in any medium or format, provided the original work is correctly cited.

Abstract

Polycystic ovary syndrome (PCOS) is the most common endocrinopathy causing non-ovulation infertility in women. Women with PCOS have higher levels of luteinizing hormone (LH), testosterone, cholesterol and triglycerides but, in contrast, lower levels of follicular stimulating hormone (FSH) and sex hormone-binding globulin (SHBG) compared with healthy counterparts. Because of the limitations of human studies, animal models of PCOS have been developed to identify appropriate therapeutics and to explore their mechanisms of action. This study aimed to review the methods of PCOS induction in animal models. This systematic review used the keywords of PCOS, induction methods and animal models. The literature search was performed in PubMed, ScienceDirect and Scopus databases to recruit studies published from 1900 to 2023. The titles and abstracts were read to eliminate unrelated studies. There are two types of hormonal and non-hormonal PCOS animal models. These animal models (i.e. female rats) present similarities to human PCOS regarding inflammatory and pathogenic pathways. The hormonal and metabolic functions of the hypothalamic-pituitary-ovarian axis, which plays a vital role in the development of the ovary can be modulated by these pathways. In this review study, various PCOS induction methods in animal models, including the use of dehydroepiandrosteron, dihydrotestosterone, testosterone, human chorionic gonadotropin, estradiol valerate, letrozole, RU486 (mifepristone), and adenocorticotropin, belong long-term use of light is mentioned along with the effect mechanism and their advantages and disadvantages. Some PCOS animal models are considered the first generation, which present advantages and disadvantages compared with second-generation PCOS animal models. These animal models can be developed based on the researcher’s purpose. Considering their advantages and disadvantages, different types of PCOS animal models may be used for clinical research.

Keywords

Polycystic ovary syndrome; animal models; PCOS induction

1. Introduction

Polycystic ovary syndrome (PCOS) is a common endocrine, metabolic and genetic disorder characterized by non-ovulation, polycystic ovary, and biochemical and clinical signs of hyperandrogenesis. PCOS is associated with adrenal-pituitary-hypothalamic dysregulations and is observed in about 4 to 18% of women at fertility age [1]. Women with PCOS have higher levels of luteinizing hormone (LH), testosterone, cholesterol and triglycerides but, in contrast, lower levels of follicular stimulating hormone (FSH), sex hormone-binding globulin (SHBG), and high-density lipoproteins (HDLs) compared with healthy counterparts [2]. The increased LH/FSH ratio leads ovaries to produce androgens preferentially. The synthesis of androgens is further promoted by the action of insulin and insulin-like factors, which are also elevated in women with PCOS. According to the Rotterdam criteria, PCOS is diagnosed when two of the three following criteria are met: 1) Oligo- and/or anovulation, 2) Clinical and/or biochemical signs of hyperandrogenism, and 3) Polycystic ovaries [3].

Along with an-ovulation, type 2 diabetes, and cardiovascular diseases, menstrual disorders, which can lead to infertility if they remain untreated, are the most common complications of PCOS. PCOS can trigger acne, obesity, hirsutism, and alopecia. Nevertheless, environmental risk factors and complications of PCOS vary in societies regarding different lifestyles. It is, therefore, critical to early diagnose and treat PCOS to prevent its complications, particularly cardiovascular diseases and infertility [4]. Although various genetic and environmental factors, hormonal disorders, chronic inflammation, oxidative stress, and inappropriate lifestyle can facilitate the development of PCOS, the exact pathogenic mechanisms remain unclear [5].

Sheep and non-humane primates with some reproductive and metabolic features of PCOS (such as polyfollicular ovaries, excessive LH secretion, increased androgen production, elevated mass of visceral fat, and IR) have already been introduced. Nevertheless, using these models has some limitations, such as high costs, long periods of reproduction and gestation, and difficulty in performing genetic manipulation. Because of this, many researchers prefer to use rodents as reasonable models of PCOS. Rodents present many advantages such as small size, anatomical, physiological, and genetic features, relatively short reproduction period, high rate of reproduction, and ease of use and maintenance. In comparison to mice, rats have several advantages, including larger sizes of animals and limbs (which may facilitate some surgical procedures and laboratory manipulations) and larger blood volume, which provides more specimens to measure various parameters. In addition, rats are more resistant to multiple diseases. In order to better understand these mechanisms, this review addresses the methods of PCOS induction in animal models.

2. Materials and Methods

2.1 Search Strategy and Study Framework

This review recruited related articles from PubMed, SID, Springer, Medlib, and ScienceDirect databases without any language restrictions from 1900 to 2023. The keywords included PCOS, animal model, and PCOS induction. In the primary search, 460 related articles were found, of which 342 unrelated studies were eliminated after reading the titles and abstracts. Finally, 118 articles were selected, categorized and reviewed (Figure 1). In this study, the literature search was conducted using MeSH keywords, including "female infertility," "PCOS," "dehydroepiandrosteron," "dihydrotestosterone," "human chorionic gonadotropin", "testosterone," "letrozole", "RU486 (mifepristone)," and "adenocorticotropin."

Click to view original image

Figure 1 Flowchart steps of selecting information from different articles.

This article does not contain any studies with human and laboratory animals participants performed by any of the authors.

2.2 Inclusion Criteria

English-language articles evaluating the effects of methods on PCOS induction and their different mechanisms in animals were selected. Overall, 98 studies on animal models investigating the positive impact of different methods on PCOS induction in animals were selected.

2.3 Exclusion Criteria

Non-English language papers, those with insufficient data, studies with poor methodology, those assessing indirect effects of agents/drugs, and studies reporting ineffective (negative) effects on PCOS induction were excluded from the analysis.

3. Results

In this study, all the methods of PCOS induction in animal models were investigated. Generally, PCOS models are developed using either chemical compounds or long-term light irradiation. The animals are exposed to the chemicals by either intramuscular, subcutaneous, or oral administration for a specific period. The commonly used chemicals include androgens (dihydrotestosterone (DHT), dehydroepiandrosterone (DHEA), testosterone, and androgen), human chorionic gonadotropin (HCG), aromatase inhibitor (letrozole), estrogen (estradiol valerate), ACTH (Adenocorticotropin), D-chiro-inositol and progesterone antagonist (RU486) (Table 1). These chemicals are selected based on researchers’ needs and may be administrated during embryogenesis (e.g. androgens).

Table 1 PCOS induction methods.

4. Discussion

4.1 Dehydroepiandrosterone (DHEA)

DHEA is an androgen that is mainly produced by the adrenal gland. Women with PCOS have high levels of DHEA. In experimental studies, DHEA is used to develop animal models of PCOS. Roy et al. showed that DHEA administration promoted ovulation and cyst formation in the ovary [42]. In addition, subcutaneous injection of DHEA (dose of 6 g/100 mg body weight daily) over 20 days induced PCOS in rats [98,99,100]. DHEA increases the levels of prolactin hormone, which in turn converts DHEA into estrogen and subsequently increases the estrogen level in ovaries [101].

4.1.1 Ovarian Morphology

In postnatal induction, there was an increase in ovarian weight due to a rise in the number of cystic follicles and a thickened theca layer.

4.1.2 Sex Steroid Hormone and Gonadotropin

In animals induced by DHEA, low LH serum levels but high T and elevated LH/FSH ratio were seen. This was while E2 levels did not change.

4.2 Dihydrotestosterone (DHT)

DHT is a non-aromatizing androgen that has been used for the induction of PCOS in animal models. In one study, rats continuously treated with DHT (7.5 mg for 90 days) showed impaired estrous cycle and reduced ovarian weight [29]. In this model of PCOS, the most common clinical manifestations included increased body fat and weight, elevated glucose and leptin levels, insulin resistance, and increased systolic and diastolic blood pressures [102].

4.2.1 Ovarian Morphology

In both prenatal and postnatal inductions, there was an increase in the number of cystic atretic follicles. Also, there were decreases in antral follicles and corpus lutea.

4.2.2 Sex Steroid Hormone and Gonadotropin

In prenatally induction, T, LH, E2, and P4 levels increased, but postnatal induction increased T and decreased P4 levels, with no significant changes in other hormones (Table 2).

4.3 Testosterone

Testosterone is one of the androgenic hormones. Exposure to testosterone before and after birth can cause hyperandrogenesis in rats. In addition, embryos exposed to testosterone during the fetal period have shown developmental and morphological abnormalities in their reproductive systems [103]. Immature rats that received testosterone for 8 weeks showed increased testosterone levels, LH, LH/FSH ratio, increased body weight, and decreased insulin sensitivity [104]. In a study by John Nesar et al., PCOS was induced by daily subcutaneous injections of testosterone propionate (dose of 1 mg per 100 g body weight) in 21-day-old rats. Ovarian histological analysis clearly showed the presence of cystic follicles, increased pre-antral follicles, and a lack of ovulation and yellow bodies. The number of primary follicles was remarkably higher. In comparison, the number of pre-antral and antral follicles was significantly lower in rats exposed to testosterone for four weeks compared with those treated for one week and control animals [32].

4.3.1 Ovarian Morphology

In prenatal induction of PCOS, there was an increase in the number of antral follicles, while there were decreases in pre-antral and preovulatory follicles and corpus lutea. Also, following this method, cystic follicles were observed, which showed successful induction of PCOS. On the other hand, in postnatal induction of PCOS, there were increases in the preantral and atretic follicles.

4.3.2 Sex Steroid Hormone and Gonadotropin

In rats with prenatally-induced PCOS, the levels of T and LH increased, but no prominent changes were observed in FSH, E2, and P4 levels. T and LH levels increased in rats with postnatally-induced PCOS, and E2 and P4 levels decreased.

4.4 Androgen Treatment during Embryonic Period

Early embryonic stages are crucial developmental phases that can be easily irritated by any chemical or hormonal insult, leading to long-term developmental problems. In particular, an imbalanced concentration of androgens in the early embryonic stages can cause PCOS (33, 35). In their study, Wu et al. subcutaneously administrated testosterone (3 mg) and DHT (3 mg) to mice at the days of 16 to 19 of gestation. In both groups, the number of pre-antral follicles increased. The biochemical analysis also showed an elevation of gonadotropins, indicating PCOS induction. Increased LH levels led to the elevation of androgens in this method [104].

4.5 Human Chorionic Gonadotropin (HCG)

The placenta produces HCG during pregnancy. Ota et al. subcutaneously administrated HCG (10 IU for 80 days) to create rat models of PCOS. As mentioned earlier, prolactin stimulates the production of adrenal androgens, which in turn lead to PCOS. In addition to the induction of prolactin, HCG administration also inhibits the production of progesterone [105,106].

4.5.1 Ovarian Morphology

An increase in cystic follicles was seen.

4.5.2 Sex Steroid Hormone and Gonadotropin

Continuous stimulation with HCG initially increased estrogen secretion in the ovary. The high levels of estrogen subsequently modulate the function of the hypothalamus-pituitary axis and inhibit dopamine production, leading to prolactin secretion [107] and subsequently suppression of the pulsatile output of gonadotropins and LH in the middle of the menstrual cycle. These events finally result in the cease or severe reduction of ovulation.

4.6 Estradiol Valerate (EV)

EV disrupts the ovarian cycle by activating the ovary's sympathetic nerve and increasing intra-ovarian norepinephrine's expression. Silva et al., showed that a single-dose intramuscular injection of EV (two mg dissolved in 0.2 mm corn oil) induced PCOS in rats [106]. EV decreases the secretion of tyrosine kinase, which is a restriction enzyme for norepinephrine in the ovaries of PCOS rats. Therefore, EV-induced elevation of norepinephrine interferes with the ovarian cycle and ceases ovulation [108,109].

4.6.1 Ovarian Morphology

There were decreases in primary, antral, and Corpus lutea follicles while the number of cystic follicles increased. The number of atretic follicles increased 5 to 16 days after the injection.

4.6.2 Sex Steroid Hormone and Gonadotropin

Serum levels of LH and FSH decreased. The levels of T and E2 increased after the injection of 2 mg, but after 4 mg injection, the levels of LH and P4 decreased.

4.7 Letrozole

Letrozole is a non-steroidal inhibitor of aromatase. The inhibition of aromatase in granulosa cells prevents the conversion of androgens to estrogen, which can lead to PCOS. Manneras et al. investigated ovarian morphology, body weight, body and mesenteric fats, and insulin resistance in rats treated with subcutaneous letrozole (36 mg for 90 days). They observed that cystic follicles and testosterone levels were increased in the experimental group [32]. In another study, administration of letrozole (1 mg/kg for 21-23 days) induced PCOS in rats [18]. In a recent study, the most characteristic features of PCOS included ovarian weight gain, atretic follicles, decreased luteinization, decreased or no ovulation, increased insulin levels, and progression of insulin resistance [65].

4.7.1 Ovarian Morphology

An increase in cystic follicles was seen.

4.7.2 Sex Steroid Hormone and Gonadotropin

The levels of T, LH, FSH and E2 increased while that of P4 decreased.

4.8 RU486 (Mifepristone)

The RU486 is one of the most common drugs used to terminate pregnancy. This is an industrial drug that acts as a P4 antagonist and results in severe depletion of progesterone receptors. The administration of RU486 increases the levels of gonadotropins, leading to an excess in the secretion of LH and testosterone, which ultimately triggers PCOS development [110].

4.8.1 Ovarian Morphology

The growth of ovarian follicles halted. On the other hand, the number of cystic follicles increased in the animals.

4.8.2 Sex Steroid Hormone and Gonadotropin

The levels of T, LH, FSH, P4, and E2 increased.

4.9 Adenocorticotropin (ACTH)

ACTH stimulates the secretion of adrenal cortex hormones, which induce the release of weak androgens such as dihydroepiandrosterone (DHEA). The DHEA is then converted to testosterone in both sexes. Increased androgen levels subsequently trigger PCOS, evidenced by ovarian morphological changes and clinical symptoms. Baravalle et al. induced PCOS in rats by subcutaneously injecting ACTH (dose of 20 UI/kg) for 18 days [89].

4.9.1 Ovarian Morphology

There were elevations in atretic and cystic follicles.

4.9.2 Sex Steroid Hormone and Gonadotropin

The levels of T, LH, and FSH declined.

4.10 Long-Term Use of Light

In studies on animal models, PCOS has also been induced by prolonged continuous light exposure. In a study, PCOS was induced by exposing mice to light for 90 days. Continuous exposure to light can disrupt the estrous cycle and increase estrogen levels. The morphological features of ovaries in this model appeared similar to those found in human PCOS [90].

4.10.1 Ovarian Morphology

Increased numbers of atretic and cystic follicles were observed.

4.10.2 Sex Steroid Hormone and Gonadotropin

While serum T level increased, no changes were seen in LH and FSH levels.

Experimental models of PCOS induction are essential in understanding the disease's underlying physiopathology. Hormonal imbalance during prenatal or postnatal periods may trigger the syndrome. Table 2 shows the changes in the levels of hormones produced by ovaries and follicles in PCOS induced by different experimental methods. In the testosterone-induced method, PCOS can be developed both prenatal and postnatal; however, the syndrome is only inducible postnatal in other methods.

Table 2 Hormonal and follicular changes in different PCOS induction methods.

5. Conclusions

There are various methods to induce PCOS in animal models. The animal models developed by these methods mimic the hormonal profile of human PCOS and, therefore, are suitable for studying the pathogenesis of this syndrome in humans. Appropriate methods can be exploited depending on the researcher’s needs and intended hormonal features. Among various PCOS induction methods, those developed by the infusion of estrogen and testosterone is considered first-generation because they induce PCOS by emulating hormonal profiles. However, these animal models have some limitations compared with second-generation PCOS animal models, which are developed by administrating letrozole and DHT. In testosterone-induced PCOS, this hormone is transformed into its metabolites in the animal's body. This is while DHT undergoes no such transformations (e.g. conversion to estradiol). On the other hand, letrozole can increase internal testosterone in PCOS animal models. The effects of androgens on the reproductive system are highly dependent on the time of exposure to these compounds. According to this study, we can conclude that the time of exposure to hormones may play an essential role in the development of PCOS. In comparison to postnatal-induced PCOS, the models created by prenatal exposure to androgen seem to be more persistent and similar to human PCOS. This may be due to higher sensitivities of the reproductive and nervous systems to hormonal changes during their development and at the time of the formation and differentiation of the organs. Therefore, prenatal induction of PCOS requires lower doses and shorter times of exposure to hormones. In addition, prenatal hormone-induced PCOS persistently represents the features of PCOS. In contrast, in most animal models of postnatal-induced PCOS, these features may be transient and dependent on hormone exposure. They may not be re-established after the withdrawal of the hormone. Since human studies are associated with ethical limitations and other problems, studies on PCOS animal models can provide critical new insights into the pathophysiology of PCOS in humans.

Author Contributions

All authors participated in the performance of the research, data analysis, research design and writing of the paper.

Competing Interests

The authors declare that there is no conflict of interest.

References

  1. Ahmadi A, Nasirinezhad F, Parivar K. Effect of aqueous extract of the aerial part of the Ruta graveolens on the spermatogenesis of immature Balb/c mice. Razi J Med Sci. 2007; 14: 13-20.
  2. Tehrani R. Association of serumomentin levels in women with polycystic ovarian syndrome. Iran J Endocrinol Metab. 2012; 14: 375-379.
  3. Rotterdam ESHRE/ASRM‐Sponsored PCOS Consensus Workshop Group. Revised 2003 consensus on diagnostic criteria and long‐term health risks related to polycystic ovary syndrome (PCOS). Hum Reprod. 2004; 19: 41-47. [CrossRef]
  4. Jalilian A, Kiani F, Sayehmiri F, Sayehmiri K, Khodaee Z, Akbari M. Prevalence of polycystic ovary syndrome and its associated complications in Iranian women: A meta-analysis. Iran J Reprod Med. 2015; 13: 591-604.
  5. Urbanek M, Legro RS, Driscoll DA, Azziz R, Ehrmann DA, Norman RJ, et al. Thirty-seven candidate genes for polycystic ovary syndrome: Strongest evidence for linkage is with follistatin. Proc Natl Acad Sci U S A. 1999; 96: 8573-8578. [CrossRef]
  6. Demacopulo B, Kreimann EL. Bisphenol S increases EZRIN expression and the detrimental effects induced by dehydroepiandrosterone in rat endometrium. Mol Cell Endocrinol. 2019; 483: 64-73. [CrossRef]
  7. Maurya VK, Sangappa C, Kumar V, Mahfooz S, Singh A, Rajender S, et al. Expression and activity of Rac1 is negatively affected in the dehydroepiandrosterone induced polycystic ovary of mouse. J Ovarian Res. 2014; 7: 32. [CrossRef]
  8. Wang YX, Zhu WJ, Xie BG. Expression of PPAR-γ in adipose tissue of rats with polycystic ovary syndrome induced by DHEA. Mol Med Rep. 2014; 9: 889-893. [CrossRef]
  9. Li SY, Song Z, Song MJ, Qin JW, Zhao ML, Yang ZM. Impaired receptivity and decidualization in DHEA-induced PCOS mice. Sci Rep. 2016; 6: 38134. [CrossRef]
  10. Wang M, Zhao D, Xu L, Guo W, Nie L, Lei Y, et al. Role of PCSK9 in lipid metabolic disorders and ovarian dysfunction in polycystic ovary syndrome. Metabolism. 2019; 94: 47-58. [CrossRef]
  11. Rencber SF, Ozbek SK, Eraldemır C, Sezer Z, Kum T, Ceylan S, et al. Effect of resveratrol and metformin on ovarian reserve and ultrastructure in PCOS: An experimental study. J Ovarian Res. 2018; 11: 55. [CrossRef]
  12. Huang Y, Yu Y, Gao J, Li R, Zhang C, Zhao H, et al. Impaired oocyte quality induced by dehydroepiandrosterone is partially rescued by metformin treatment. PloS One. 2015; 10: e0122370. [CrossRef]
  13. Jang M, Lee MJ, Lee JM, Bae CS, Kim SH, Ryu JH, et al. Oriental medicine Kyung-Ok-Ko prevents and alleviates dehydroepiandrosterone-induced polycystic ovarian syndrome in rats. PloS One. 2014; 9: e87623. [CrossRef]
  14. Zhu JQ, Zhu L, Liang XW, Xing FQ, Schatten H, Sun QY. Demethylation of LHR in dehydroepiandrosterone-induced mouse model of polycystic ovary syndrome. Mol Hum Reprod. 2010; 16: 260-266. [CrossRef]
  15. Utkan Korun ZE, Gocmez SS, Furat Rencber S, Kavram Sarıhan K, Eraldemir FC, Sahin D. Etanercept ameliorates vascular, endocrine, and ovarian changes in a rat model of DHEA-induced polycystic ovary syndrome. Reprod Sci. 2024; 31: 714-726. [CrossRef]
  16. Wang D, Wang W, Liang Q, He X, Xia Y, Shen S, et al. DHEA-induced ovarian hyperfibrosis is mediated by TGF-β signaling pathway. J Ovarian Res. 2018; 11: 6. [CrossRef]
  17. Mahmoud YI, Mahmoud AA, Abo-Zeid FS, Fares NH. Effects of dehydroepiandrosterone on the ovarian reserve and pregnancy outcomes in perimenopausal rats (DHEA and fertility in perimenopausal rats). Life Sci. 2018; 199: 131-138. [CrossRef]
  18. Xia Y, Zhao P, Huang H, Xie Y, Lu R, Dong L. Cryptotanshinone reverses reproductive disturbances in rats with dehydroepiandrosterone-induced polycystic ovary syndrome. Am J Transl Res. 2017; 9: 2447.
  19. Singh A, Fernandes JR, Chhabra G, Krishna A, Banerjee A. Liraglutide modulates adipokine expression during adipogenesis, ameliorating obesity, and polycystic ovary syndrome in mice. Endocrine. 2019; 64: 349-366. [CrossRef]
  20. Zhang H, Yi M, Zhang Y, Jin H, Zhang W, Yang J, et al. High-fat diets exaggerate endocrine and metabolic phenotypes in a rat model of DHEA-induced PCOS. Reproduction. 2016; 151: 431. [CrossRef]
  21. Ikeda K, Baba T, Morishita M, Honnma H, Endo T, Kiya T, et al. Long-term treatment with dehydroepiandrosterone may lead to follicular atresia through interaction with anti-Mullerian hormone. J Ovarian Res. 2014; 7: 46. [CrossRef]
  22. Honnma H, Endo T, Henmi H, Nagasawa K, Baba T, Yamazaki K, et al. Altered expression of Fas/Fas ligand/caspase 8 and membrane type 1-matrix metalloproteinase in atretic follicles within dehydroepiandrosterone-induced polycystic ovaries in rats. Apoptosis. 2006; 11: 1525-1533. [CrossRef]
  23. Zhang F, Ma T, Cui P, Tamadon A, He S, Huo C, et al. Diversity of the gut microbiota in Dihydrotestosterone-induced PCOS rats and the pharmacologic effects of Diane-35, probiotics, and Berberine. Front Microbiol. 2019; 10: 175. [CrossRef]
  24. Zheng Y, Yu J, Liang C, Li S, Wen X, Li Y. Characterization on gut microbiome of PCOS rats and its further design by shifts in high-fat diet and dihydrotestosterone induction in PCOS rats. Bioprocess Biosyst Eng. 2021; 44: 953-964. [CrossRef]
  25. Hu Q, Jin J, Zhou H, Yu D, Qian W, Zhong Y, et al. Crocetin attenuates DHT-induced polycystic ovary syndrome in mice via revising kisspeptin neurons. Biomed Pharmacother. 2018; 107: 1363-1369. [CrossRef]
  26. Tang M, Huang C, Wang YF, Ren PG, Chen L, Xiao TX, et al. CMKLR1 deficiency maintains ovarian steroid production in mice treated chronically with dihydrotestosterone. Sci Rep. 2016; 6: 21328. [CrossRef]
  27. Nikolić M, Macut D, Djordjevic A, Veličković N, Nestorović N, Bursać B, et al. Possible involvement of glucocorticoids in 5α-dihydrotestosterone-induced PCOS-like metabolic disturbances in the rat visceral adipose tissue. Mol Cell Endocrinol. 2015; 399: 22-31. [CrossRef]
  28. Tepavčević S, Milutinović DV, Macut D, Žakula Z, Nikolić M, Božić-Antić I, et al. Dihydrotestosterone deteriorates cardiac insulin signaling and glucose transport in the rat model of polycystic ovary syndrome. J Steroid Biochem. 2014; 141: 71-76. [CrossRef]
  29. Masszi G, Buday A, Novak A, Horvath EM, Tarszabo R, Sara L, et al. Altered insulin-induced relaxation of aortic rings in a dihydrotestosterone-induced rodent model of polycystic ovary syndrome. Fertil Steril. 2013; 99: 573-578. [CrossRef]
  30. Benrick A, Maliqueo M, Miao S, Villanueva JA, Feng Y, Ohlsson C, et al. Resveratrol is not as effective as physical exercise for improving reproductive and metabolic functions in rats with dihydrotestosterone‐induced polycystic ovary syndrome. Evid Based Complementary Altern Med. 2013; 2013: 964070. [CrossRef]
  31. Feng Y, Johansson J, Shao R, Holm LM, Billig H, Stener-Victorin E. Electrical and manual acupuncture stimulation affect oestrous cyclicity and neuroendocrine function in an 5α‐dihydrotestosterone-induced rat polycystic ovary syndrome model. Exp Physiol. 2012; 97: 651-662. [CrossRef]
  32. Manneras L, Cajander S, Lönn M, Stener-Victorin E. Acupuncture and exercise restore adipose tissue expression of sympathetic markers and improve ovarian morphology in rats with dihydrotestosterone-induced PCOS. Am J Physiol Regul Integr Comp Physiol. 2009; 296: R1124-R1131. [CrossRef]
  33. Tehrani FR, Amiri M. Polycystic ovary syndrome in adolescents: Challenges in diagnosis and treatment. Int J Endocrinol Metab. 2019; 17: e91554. [CrossRef]
  34. Kalhori Z, Azadbakht M, Bazdar A, Zeinali H. Polycystic ovary induction in mouse by testosterone enanthate. J Adv Biomed Sci. 2014; 3: 387-391.
  35. Abbott DH, Vepraskas SH, Horton TH, Terasawa E, Levine JE. Accelerated episodic luteinizing hormone release accompanies blunted progesterone regulation in PCOS-like female rhesus monkeys (Macaca mulatta) exposed to testosterone during early-to-mid gestation. J Neuroendocrinol. 2018; 107: 133-146. [CrossRef]
  36. Chaudhari NK, Nampoothiri LP. Neurotransmitter alteration in a testosterone propionate-induced polycystic ovarian syndrome rat model. Horm Mol Biol Clin Investig. 2017; 29: 71-77. [CrossRef]
  37. Noroozzadeh M, Tehrani FR, Sedaghat K, Godini A, Azizi F. The impact of prenatal exposure to a single dose of testosterone on insulin resistance, glucose tolerance and lipid profile of female rat’s offspring in adulthood. J Endocrinol Investig. 2015; 38: 489-495. [CrossRef]
  38. Hu M, Richard JE, Maliqueo M, Kokosar M, Fornes R, Benrick A, et al. Maternal testosterone exposure increases anxiety-like behavior and impacts the limbic system in the offspring. Proc Natl Acad Sci U S A. 2015; 112: 14348-14353. [CrossRef]
  39. Amalfi S, Velez LM, Heber MF, Vighi S, Ferreira SR, Orozco AV, et al. Prenatal hyperandrogenization induces metabolic and endocrine alterations which depend on the levels of testosterone exposure. PLoS One. 2012; 7: e37658. [CrossRef]
  40. Beloosesky R, Gold R, Almog B, Sasson R, Dantes A, Land-Bracha A, et al. Induction of polycystic ovary by testosterone in immature female rats: Modulation of apoptosis and attenuation of glucose/insulin ratio. Int J Mol Med. 2004; 14: 207-215. [CrossRef]
  41. Ota H, Fukushima M, Maki M. Endocrinological and histological aspects of the process of polycystic ovary formation in the rat treated with testosterone propionate. Tohoku J Exp Med. 1983; 140: 121-131. [CrossRef]
  42. Miao M, Peng M, Zhu Z, Yan X, Wei Z, Li M. Effects of dodder total flavone on polycystic ovary syndrome rat models induced by DHEA combined HCG. Saudi J Biol Sci. 2019; 26: 821-827. [CrossRef]
  43. Lima MH, Souza LC, Caperuto LC, Bevilacqua E, Gasparetti AL, Zanuto R, et al. Up-regulation of the phosphatidylinositol 3-kinase/protein kinase B pathway in the ovary of rats by chronic treatment with hCG and insulin. J Endocrinol. 2006; 190: 451-459. [CrossRef]
  44. Ota H, Fukushima M, Wakizaka MA, Maki M. Ovarian membrane receptors for LH, FSH and prolactin during the menstrual cycle and in polycystic ovary syndrome. Tohoku J Exp Med. 1986; 149: 231-240. [CrossRef]
  45. Yang Y, Liu J, Xu W. Naringenin and morin reduces insulin resistance and endometrial hyperplasia in the rat model of polycystic ovarian syndrome through enhancement of inflammation and autophagic apoptosis. Acta Biochim Pol. 2022; 69: 91-100. [CrossRef]
  46. Shao YY, Chang ZP, Cheng Y, Wang XC, Zhang JP, Feng XJ, et al. Shaoyao-Gancao Decoction alleviated hyperandrogenism in a letrozole-induced rat model of polycystic ovary syndrome by inhibition of NF-κB activation. Biosci Rep. 2019; 39: BSR20181877. [CrossRef]
  47. Hong Y, Yin Y, Tan Y, Hong K, Zhou H. The flavanone, naringenin, modifies antioxidant and steroidogenic enzyme activity in a rat model of letrozole-induced polycystic ovary syndrome. Med Sci Monit. 2019; 25: 395. [CrossRef]
  48. Karateke A, Dokuyucu R, Dogan H, Ozgur T, Tas ZA, Tutuk O, et al. Investigation of therapeutic effects of erdosteine on polycystic ovary syndrome in a rat model. Med Princ Pract. 2018; 27: 515-522. [CrossRef]
  49. Patel R, Shah G. Insulin sensitizers modulate GnRH receptor expression in PCOS rats. Arch Med Res. 2018; 49: 154-163. [CrossRef]
  50. Areloegbe SE, Peter MU, Oyeleke MB, Olaniyi KS. Low-dose spironolactone ameliorates adipose tissue inflammation and apoptosis in letrozole-induced PCOS rat model. BMC Endocr Disord. 2022; 22: 224. [CrossRef]
  51. Jahan S, Abid A, Khalid S, Afsar T, Shaheen G, Almajwal A, et al. Therapeutic potentials of Quercetin in management of polycystic ovarian syndrome using Letrozole induced rat model: A histological and a biochemical study. J Ovarian Res. 2018; 11: 26. [CrossRef]
  52. Fu LL, Xu Y, Li DD, Dai XW, Xu X, Zhang JS, et al. Expression profiles of mRNA and long noncoding RNA in the ovaries of letrozole-induced polycystic ovary syndrome rat model through deep sequencing. Gene. 2018; 657: 19-29. [CrossRef]
  53. Rajan RK, Balaji B. Soy isoflavones exert beneficial effects on letrozole-induced rat polycystic ovary syndrome (PCOS) model through anti-androgenic mechanism. Pharm Biol. 2017; 55: 242-251. [CrossRef]
  54. Lee YH, Yang H, Lee SR, Kwon SW, Hong EJ, Lee HW. Welsh onion root (Allium fistulosum) restores ovarian functions from letrozole induced-polycystic ovary syndrome. Nutrients. 2018; 10: 1430. [CrossRef]
  55. Yang H, Lee SY, Lee SR, Pyun BJ, Kim HJ, Lee YH, et al. Therapeutic effect of Ecklonia cava extract in letrozole-induced polycystic ovary syndrome rats. Front Pharmacol. 2018; 9: 1325. [CrossRef]
  56. Pandey V, Shukla R, Krishna A, Tripathi Y. Effect of combined treatment of Modern and herbal supplement in the management of letrozole induced Polycystic Ovary syndrome. J Endocrinol Diabetes. 2017; 4: 1-6. [CrossRef]
  57. Kabel AM, Al-Shehri AH, Al-Talhi RA, Abd Elmaaboud MA. The promising effect of linagliptin and/or indole-3-carbinol on experimentally-induced polycystic ovarian syndrome. Chem Biol Interact. 2017; 273: 190-199. [CrossRef]
  58. Ullah A, Jahan S, Razak S, Pirzada M, Ullah H, Almajwal A, et al. Protective effects of GABA against metabolic and reproductive disturbances in letrozole induced polycystic ovarian syndrome in rats. J Ovarian Res. 2017; 10: 62. [CrossRef]
  59. Li C, Chen L, Zhao Y, Chen S, Fu L, Jiang Y, et al. Altered expression of miRNAs in the uterus from a letrozole-induced rat PCOS model. Gene. 2017; 598: 20-26. [CrossRef]
  60. Mihanfar A, Nouri M, Roshangar L, Khadem-Ansari MH. Ameliorative effects of fisetin in letrozole-induced rat model of polycystic ovary syndrome. J Steroid Biochem Mol Biol. 2021; 213: 105954. [CrossRef]
  61. Cao SF, Hu WL, Wu MM, Jiang LY. Effects of exercise intervention on preventing letrozole-exposed rats from polycystic ovary syndrome. Reprod Sci. 2017; 24: 456-462. [CrossRef]
  62. Aliabadi E, Namavar MR, Mortezaee K, Toolee H, Keshtgar S, Mirkhani H, et al. Kisspeptin expression features in the arcuate and anteroventral periventricular nuclei of hypothalamus of letrozole-induced polycystic ovarian syndrome in rats. Arch Gynecol Obstet. 2017; 296: 957-963. [CrossRef]
  63. Wang F, Wang S, Zhang Z, Lin Q, Liu Y, Xiao Y, et al. Defective insulin signaling and the protective effects of dimethyldiguanide during follicular development in the ovaries of polycystic ovary syndrome. Mol Med Rep. 2017; 16: 8164-8170. [CrossRef]
  64. Lian Y, Zhao F, Wang W. Central leptin resistance and hypothalamic inflammation are involved in letrozole-induced polycystic ovary syndrome rats. Biochem Biophys Res Commun. 2016; 476: 306-312. [CrossRef]
  65. Rezvanfar MA, Saeedi S, Mansoori P, Saadat S, Goosheh M, Shojaei Saadi HA, et al. Dual targeting of TNF-α and free radical toxic stress as a promising strategy to manage experimental polycystic ovary. Pharm Biol. 2016; 54: 80-90. [CrossRef]
  66. Kauffman AS, Thackray VG, Ryan GE, Tolson KP, Glidewell-Kenney CA, Semaan SJ, et al. A novel letrozole model recapitulates both the reproductive and metabolic phenotypes of polycystic ovary syndrome in female mice. Biol Reprod. 2015; 93: 69. [CrossRef]
  67. Maliqueo M, Benrick A, Alvi A, Johansson J, Sun M, Labrie F, et al. Circulating gonadotropins and ovarian adiponectin system are modulated by acupuncture independently of sex steroid or β-adrenergic action in a female hyperandrogenic rat model of polycystic ovary syndrome. Mol Cell Endocrinol. 2015; 412: 159-169. [CrossRef]
  68. Kelley ST, Skarra DV, Rivera AJ, Thackray VG. The gut microbiome is altered in a letrozole-induced mouse model of polycystic ovary syndrome. PloS One. 2016; 11: e0146509. [CrossRef]
  69. Maharjan R, Nagar PS, Nampoothiri L. Effect of Aloe barbadensis Mill. formulation on Letrozole induced polycystic ovarian syndrome rat model. J Ayurveda Integr Med. 2010; 1: 273. [CrossRef]
  70. Kafali H, Iriadam M, Ozardalı I, Demir N. Letrozole-induced polycystic ovaries in the rat: A new model for cystic ovarian disease. Arch Med Res. 2004; 35: 103-108. [CrossRef]
  71. Jin J, Hu QY, Xu WW, Zhu WJ, Liu B, Liu J, et al. Tanshinone IIA attenuates estradiol‑induced polycystic ovarian syndrome in mice by ameliorating FSHR expression in the ovary. Exp Ther Med. 2019; 17: 3501-3508. [CrossRef]
  72. Pournaderi PS, Yaghmaei P, Khodaei H, Noormohammadi Z, Hejazi SH. The effects of 6-Gingerol on reproductive improvement, liver functioning and Cyclooxygenase-2 gene expression in estradiol valerate–Induced polycystic ovary syndrome in Wistar rats. Biochem Biophys Res Commun. 2017; 484: 461-466. [CrossRef]
  73. Azin F, Khazali H. Neuropeptide galanin and its effects on metabolic and reproductive disturbances in female rats with estradiol valerate (EV)-induced polycystic ovary syndrome (PCOS). Neuropeptides. 2020; 80: 102026. [CrossRef]
  74. Barzegar MH, Khazali H, Kalantar SM, Khoradmehr A. Effect of Citrullus colocynthis hydro-alcoholic extract on hormonal and folliculogenesis process in estradiol valerate-induced PCOs rats model: An experimental study. Int J Reprod BioMed. 2017; 15: 661. [CrossRef]
  75. Mirabolghasemi G, Kamyab Z. Changes of the uterine tissue in rats with polycystic ovary syndrome induced by estradiol valerate. Int J Fertil Steril. 2017; 11: 47.
  76. Ghafurniyan H, Azarnia M, Nabiuni M, Karimzadeh L. The effect of green tea extract on reproductive improvement in estradiol valerate-induced polycystic ovarian syndrome in rat. Iran J Pharm Res. 2015; 14: 1215.
  77. Karimzadeh L, Nabiuni M, Kouchesfehani HM, Adham H, Bagheri A, Sheikholeslami A. Effect of bee venom on IL-6, COX-2 and VEGF levels in polycystic ovarian syndrome induced in Wistar rats by estradiol valerate. J Venom Anim Toxins Incl Trop Dis. 2013; 19: 32. [CrossRef]
  78. Li X, Wang S, Zhang L, Zhang L, Liu J, Luo H, et al. Amitriptyline plays important roles in modifying the ovarian morphology and improving its functions in rats with estradiol valerate-induced polycystic ovary. Arch Pharm Res. 2019; 42: 344-358. [CrossRef]
  79. Miri M, Jashni HK, Alipour F. Effect of exercise intensity on weight changes and sexual hormones (androstenedione and free testosterone) in female rats with estradiol valerate-induced PCOS. J Ovarian Res. 2014; 7: 37. [CrossRef]
  80. Gode F, Karagoz C, Posaci C, Saatli B, Uysal D, Secil M, et al. Alteration of cardiovascular risk parameters in women with polycystic ovary syndrome who were prescribed to ethinyl estradiol–cyproterone acetate. Arch Gynecol Obstet. 2011; 284: 923-929. [CrossRef]
  81. Daneasa A, Cucolas C, Lenghel LM, Olteanu D, Orasan R, Filip GA. Letrozole vs estradiol valerate induced PCOS in rats: Glycemic, oxidative and inflammatory status assessment. Reproduction. 2016; 151: 401-409. [CrossRef]
  82. Mesbah F, Moslem M, Vojdani Z, Mirkhani H. Does metformin improve in vitro maturation and ultrastructure of oocytes retrieved from estradiol valerate polycystic ovary syndrome-induced rats. J Ovarian Res. 2015; 8: 74. [CrossRef]
  83. Deshpande R, Chapman J, Michael S, Deshpande R, Chang M. Alteration of cytokine production in follicular cystic ovaries induced in mice by neonatal estradiol injection. Am J Reprod Immunol. 2000; 44: 80-88. [CrossRef]
  84. Kondo M, Osuka S, Iwase A, Nakahara T, Saito A, Nakamura T, et al. Increase of kisspeptin-positive cells in the hypothalamus of a rat model of polycystic ovary syndrome. Metab Brain Dis. 2016; 31: 673-681. [CrossRef]
  85. Priyadarshani A. Effects of opium alkaloid, noscapine in RU486 induced experimental model of polycystic ovary syndrome. Indian J Biochem Biophys. 2022; 59: 468-478.
  86. Priyadarshani A. Relevance of an opioid, noscapine in reducing cystogeneses in rat experimental model of polycystic ovary syndrome. J Endocrinol Investig. 2009; 32: 837-843. [CrossRef]
  87. Ruiz A, Aguilar R, Tébar M, Gaytán F, Sánchez-Criado JE. RU486-treated rats show endocrine and morphological responses to therapies analogous to responses of women with polycystic ovary syndrome treated with similar therapies. Biol Reprod. 1996; 55: 1284-1291. [CrossRef]
  88. Sánchez-Criado JE, Sánchez A, Ruiz A, Gaytán F. Endocrine and morphological features of cystic ovarian condition in antiprogesterone RU486-treated rats. Eur J Endocrinol. 1993; 129: 237-245. [CrossRef]
  89. Park E, Choi CW, Kim SJ, Kim YI, Sin S, Chu JP, et al. Hochu-ekki-to treatment improves reproductive and immune modulation in the stress-induced rat model of polycystic ovarian syndrome. Molecules. 2017; 22: 978. [CrossRef]
  90. Baravalle C, Salvetti N, Mira G, Lorente J, Ortega H. The role of ACTH in the pathogenesis of polycystic ovarian syndrome in rats: Hormonal profiles and ovarian morphology. Physiol Res. 2007; 56: 67-78. [CrossRef]
  91. He Y, Li X, Li Y, Kuai D, Zhang H, Wang Y, et al. Dehydroepiandrosterone with a high-fat diet treatment at inducing polycystic ovary syndrome in rat model. Steroids. 2024; 206: 109424. [CrossRef]
  92. Nooranizadeh MH, Rahmanifar F, Ahmadloo S, Shaaban Z, Shirazi MRJ, Tamaddon A. Enhancement of melanocortin-4 receptor (MC4R) and constancy of Kiss1 mRNAs expression in the hypothalamic arcuate nucleus in a model of polycystic ovary syndrome rat. Galen Med J. 2018; 7: 1070. [CrossRef]
  93. Kang X, Jia L, Shen X. Manifestation of hyperandrogenism in the continuous light exposure-induced PCOS rat model. Biomed Res Int. 2015; 2015: 943694. [CrossRef]
  94. Takahashi M, Ford JJ, Yoshinaga K, Greep RO. Ovulation in light-estrous rats induced by darkness. Endocrinol Jpn. 1977; 24: 89-96. [CrossRef]
  95. Singh KB. Rat models of polycystic ovary syndrome. In: Sourcebook of models for biomedical research. Totowa, NJ: Springer; 2008. pp. 405-410. [CrossRef]
  96. Yang H, Lee SR, Jo SL, Kim AH, Kim ER, Qu F, et al. The Improvement Effect of D-Chiro-Inositol and Ecklonia cava K. in the Rat Model of Polycystic Ovarian Syndrome. Front Pharmacol. 2022; 13: 905191. [CrossRef]
  97. Bevilacqua A, Dragotto J, Lucarelli M, Di Emidio G, Monastra G, Tatone C. High doses of D-chiro-inositol alone induce a PCO-like syndrome and other alterations in mouse ovaries. Int J Mol Sci. 2021; 22: 5691. [CrossRef]
  98. Abramovich D, Irusta G, Bas D, Cataldi NI, Parborell F, Tesone M. Angiopoietins/TIE2 system and VEGF are involved in ovarian function in a DHEA rat model of polycystic ovary syndrome. Endocrinology. 2012; 153: 3446-3456. [CrossRef]
  99. Wang F, Yu B, Yang W, Liu J, Lu J, Xia X. Polycystic ovary syndrome resembling histopathological alterations in ovaries from prenatal androgenized female rats. J Ovarian Res. 2012; 5: 15. [CrossRef]
  100. Liu W, Liu W, Fu Y, Wang Y, Zhang Y. Bak Foong pills combined with metformin in the treatment of a polycystic ovarian syndrome rat model. Oncol Lett. 2015; 10: 1819-1825. [CrossRef]
  101. Lee MT, Anderson E, Lee GY. Changes in ovarian morphology and serum hormones in the rat after treatment with dehydroepiandrosterone. Anat Rec. 1991; 231: 185-192. [CrossRef]
  102. Yarak S, Bagatin E, Hassun KM, Parada MO, Talarico Filho S. Hiperandrogenismo e pele: Síndrome do ovário policístico e resistência periférica à insulina. An Bras Dermatol. 2005; 80: 395-410. [CrossRef]
  103. King AJ, Bari Olivier N, MohanKumar PS, Lee JS, Padmanabhan V, Fink GD. Hypertension caused by prenatal testosterone excess in female sheep. Am J Physiol Endocrinol Metab. 2007; 292: E1837-E1841. [CrossRef]
  104. Tehrani FR, Noroozzadeh M, Zahediasl S, Piryaei A, Azizi F. Introducing a rat model of prenatal androgen‐induced polycystic ovary syndrome in adulthood. Exp Physiol. 2014; 99: 792-801. [CrossRef]
  105. Wu XY, Li ZL, Wu CY, Liu YM, Lin H, Wang SH, et al. Endocrine traits of polycystic ovary syndrome in prenatally androgenized female Sprague-Dawley rats. Endocr J. 2010; 57: 201-209. [CrossRef]
  106. Di F, Liu J, Li S, Yao G, Hong Y, Chen ZJ, et al. ATF4 contributes to ovulation via regulating COX2/PGE2 expression: A potential role of ATF4 in PCOS. Front Endocrinol. 2018; 9: 669. [CrossRef]
  107. Ota H, Fukushima M, Maki M. Formation of polycystic ovary in mature rats by the long-term administration of human chorionic gonadotropin. Tohoku J Exp Med. 1987; 151: 33-40. [CrossRef]
  108. Rosa-e-Silva A, Guimaraes MA, Padmanabhan V, Lara HE. Prepubertal administration of estradiol valerate disrupts cyclicity and leads to cystic ovarian morphology during adult life in the rat: Role of sympathetic innervation. Endocrinology. 2003; 144: 4289-4297. [CrossRef]
  109. Luza S, Lizama L, Burgos R, Lara H. Hypothalamic changes in norepinephrine release in rats with estradiol valerate-induced polycystic ovaries. Biol Reprod. 1995; 52: 398-404. [CrossRef]
  110. Yun MH, Lee DN, Seo IB, Kim HJ. Effects of Gaeullijin-tang on the progression of the estradiol valerate-induced polycystic ovaries in rats. J Korean Obstet Gynecol. 2010; 23: 1-19.
  111. Manneras L, Cajander S, Holmäng A, Seleskovic Z, Lystig T, Lönn M, et al. A new rat model exhibiting both ovarian and metabolic characteristics of polycystic ovary syndrome. Endocrinology. 2007; 148: 3781-3791. [CrossRef]
  112. Wu C, Lin F, Qiu S, Jiang Z. The characterization of obese polycystic ovary syndrome rat model suitable for exercise intervention. PloS One. 2014; 9: e99155. [CrossRef]
  113. Osuka S, Iwase A, Nakahara T, Kondo M, Saito A, Nakamura T, et al. Kisspeptin in the hypothalamus of 2 rat models of polycystic ovary syndrome. Endocrinology. 2017; 158: 367-377.
  114. Matsuzaki T, Tungalagsuvd A, Iwasa T, Munkhzaya M, Yanagihara R, Tokui T, et al. Kisspeptin mRNA expression is increased in the posterior hypothalamus in the rat model of polycystic ovary syndrome. Endocr J. 2017; 64: 7-14. [CrossRef]
  115. Baravalle C, Salvetti NR, Mira GA, Pezzone N, Ortega HH. Microscopic characterization of follicular structures in letrozole-induced polycystic ovarian syndrome in the rat. Arch Med Res. 2006; 37: 830-839. [CrossRef]
  116. Li D, Li C, Xu Y, Xu D, Li H, Gao L, et al. Differential expression of microRNAs in the ovaries from letrozole-induced rat model of polycystic ovary syndrome. DNA Cell Biol. 2016; 35: 177-183. [CrossRef]
  117. Brawer JR, Munoz M, Farookhi R. Development of the polycystic ovarian condition (PCO) in the estradiol valerate-treated rat. Biol Reprod. 1986; 35: 647-655. [CrossRef]
  118. Stener-Victorin E, Ploj K, Larsson B-M, Holmäng A. Rats with steroid-induced polycystic ovaries develop hypertension and increased sympathetic nervous system activity. Reprod Biol Endocrinol. 2005; 3: 44. [CrossRef]
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