Animal Model Of Polycystic Ovary Syndrome Research Articles

Cangfudaotan Decoction Alleviates Insulin Resistance and Improves Follicular Development in Rats with Polycystic Ovary Syndrome via IGF-1-PI3K/Akt-Bax/Bcl-2 Pathway.

Polycystic ovary syndrome (PCOS) is the most common endocrine and metabolic disorder prevalent in females of reproductive age; insulin resistance (IR) is the major pathogenic driver. Pharmacology is a basic option for PCOS therapy; traditional Chinese medicine (TCM), as a significant part of complementary and alternative medicine, has a long history in the clinical management of PCOS. Cangfudaotan decoction (CFD) has been used clinically for gynaecological diseases especially PCOS. In this study, first, chemical components in CFD were clarified using UPLC-Q/TOF-MS analysis. Then, an animal model of PCOS was established, granular cells were also isolated from the rats with PCOS, and CFD was administrated at different dosages in PCOS rats and granular cells, to investigate the therapeutic effect and mechanisms of CFD for PCOS treatment. The result showed that CFD treatment is effective in PCOS rats and granulosa cells. CFD was able to improve IR, restore the serum hormone levels, inhibit the inflammatory cytokines in PCOS rat, and alleviate ovary morphological injury and apoptosis in PCOS rats. In granulosa cells of PCOS, the result showed that the cell viability was improved, and cell apoptosis was inhibited after CFD administration. Further experiments suggested that CDF improves IR, follicular development, cell apoptosis, and inflammatory microenvironment, and this was associated to the regulation of IGF-1-PI3K/Akt-Bax/Bcl-2 pathway-mediated gene expression. Given that CFD sufficiently suppresses insulin resistance and improves follicular development in this study, exploring these mechanisms might help to optimize the therapeutic treatment of CFD in PCOS patients.

Options for generating polycystic ovary syndrome based on experimental findings in animal models

Polycystic ovary syndrome (PCOS) is a common endocrine pathology that affects 814% of women of reproductive age. The leading signs of the disease are hyperandrogenism, ovulatory dysfunction, and polycystic ovarian morphology. Over the past decades, a variety of animal models have been developed to study the etiology and pathogenesis of PCOS, including chemical, hormonal, and genetic interventions. However, a large number of experimental techniques differ even in the framework of a single model. In this review article, we summarized PCOS animal models using both direct hormonal effects and indirect methods.

Cardiac function and tolerance to ischemia/reperfusion injury in a rat model of polycystic ovary syndrome during the postmenopausal period

AimsThere is much controversy regarding whether cardiovascular events increase in women with polycystic ovary syndrome (PCOS) with aging. Considering the lack of possibility of certain investigations in humans, animal models of PCOS may be suitable resources to obtain the useful data needed. In this study; we aimed to investigate whether cardiac function and tolerance to ischemia/reperfusion (I/R) injury worsen in postmenopausal rats, who had PCOS at younger ages, compared to controls. Main methodsThe hearts of aged rats with a history of PCOS and their controls were isolated and perfused in a Langendorff apparatus. Values of hemodynamic parameters, including left ventricular systolic pressure (LVSP), left ventricular developed pressure (LVDP), rate pressure product (RPP) and peak rates of positive and negative changes in left ventricular pressure (±dp/dt) were recorded using a power lab system. Blood serum levels of total testosterone (TT) and estradiol (E2) were determined by ELISA kits. Generalized Estimating Equation Model and t-student unpaired test results were used to compare the findings documented between two groups. Key findingsNo statistically significant differences were observed in hemodynamic parameters of the heart including, LVSP, LVDP, RPP and ±dp/dt, between the rats of two groups of study, at baseline or before ischemia and after I/R. Nor were any significant differences observed in the levels of two hormones between the two groups (p > 0.05). SignificanceHistory of PCOS during reproductive ages should not be considered an important risk factor for reduction in cardiac contractile function or less tolerance to I/R injury during the postmenopausal period.

The Role of the Brain in the Pathogenesis and Physiology of Polycystic Ovary Syndrome (PCOS).

Polycystic ovary syndrome (PCOS) is a common reproductive endocrine disorder, affecting at least 10% of women of reproductive age. PCOS is typically characterized by the presence of at least two of the three cardinal features of hyperandrogenemia (high circulating androgen levels), oligo- or anovulation, and cystic ovaries. Hyperandrogenemia increases the severity of the condition and is driven by increased luteinizing hormone (LH) pulse secretion from the pituitary. Indeed, PCOS women display both elevated mean LH levels, as well as an elevated frequency of LH pulsatile secretion. The abnormally high LH pulse frequency, reflective of a hyperactive gonadotropin-releasing hormone (GnRH) neural circuit, suggests a neuroendocrine basis to either the etiology or phenotype of PCOS. Several studies in preclinical animal models of PCOS have demonstrated alterations in GnRH neurons and their upstream afferent neuronal circuits. Some rodent PCOS models have demonstrated an increase in GnRH neuron activity that correlates with an increase in stimulatory GABAergic innervation and postsynaptic currents onto GnRH neurons. Additional studies have identified robust increases in hypothalamic levels of kisspeptin, another potent stimulator of GnRH neurons. This review outlines the different brain and neuroendocrine changes in the reproductive axis observed in PCOS animal models, discusses how they might contribute to either the etiology or adult phenotype of PCOS, and considers parallel findings in PCOS women.

Therapeutic effects of isoflavone-aglycone fraction from soybean (Glycine max L. Merrill) in rats with estradiol valerate-induced polycystic ovary syndrome as an inflammatory state

Polycystic ovary syndrome (PCOS) is a proinflammatory/oxidative state resulting in metabolic dysregulation and ovarian dysfunction. Isoflavones in soybean seed possess anti-inflammatory/antioxidant properties. So, in this study, the effects of soybean isoflavone-aglycones on tissue inflammation, oxidative status, and ovarian histology in an animal model of PCOS were considered to achieve a novel therapeutic agent. Thirty-two female Wistar rats were divided into four groups (n = 8): a control group receiving the vehicle (CON−); a group with PCOS receiving no treatment (PCOS); and two groups of PCOS rats treated with soybean isoflavone-aglycone fraction (SISAF) at 50 and 100 mg/kg (SISAF50 and SISAF100). PCOS was induced by injecting a single dose of estradiol valerate (4 mg/kg, IM) dissolved in 0.2 ml of sesame oil following 60 days for the full development of polycystic ovaries. The SISAF treatments were administered orally once a day for 21 days. Then, the ovaries were harvested for the assessment of oxidative/antioxidative parameters, interleukin (IL)-6, and tumor necrosis factor (TNF)-α levels concomitant with histological studies. Treatment with SISAF reduced the number of cystic follicles and thickness of the theca layer, as well as increasing the number of corpora lutea and granulosa cells in PCOS rats. Also, SISAF treatment significantly decreased ovarian tissue IL-6 and TNF-α levels, and improved total oxidative/antioxidative status compared to the PCOS group. Isoflavones may provide therapeutic effects in PCOS owing to the antioxidant and anti-inflammatory properties.

Rodent models of mental illness in polycystic ovary syndrome: the potential role of hypothalamic-pituitary-adrenal dysregulation and lessons for behavioral researchers.

Polycystic ovary syndrome (PCOS) is the most commonly diagnosed endocrine disorder in women of reproductive age, with phenotypes including ovarian and metabolic dysfunctions. Women with PCOS also show increased rates of mental illness, dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, and altered responsiveness to stressors that may contribute to the higher rates of mental illness, specifically depression and anxiety. Animal models of PCOS have provided insight into the ovarian and metabolic mechanisms that underlie the syndrome, and several models have been used to study the behavioral consequences associated with PCOS in the laboratory. Several studies in rodent models of PCOS demonstrate changes in anxiety-like behavior, but researchers often neglect to report procedural details or behavioral data crucial to interpreting the differences observed in those studies. Additionally, the impact of potential HPA dysregulation in animal models of PCOS may influence behavioral findings, although only three studies to date have examined this. As such, researchers should consider and report stress-associated variables (e.g., time of day, light/dark cycle, light intensity, housing, and procedures to control experimenter and litter effects) that may influence depression- and anxiety-like behaviors in rodents. This review will summarize the behavioral and HPA-related studies in women with PCOS and rodent models of the disease, and provide considerations for future studies.

Prenatal Androgenization of Ewes as a Model of Hirsutism in Polycystic Ovary Syndrome.

The main clinical feature associated with hyperandrogenism in polycystic ovary syndrome (PCOS) in humans is hirsutism, where hair increases its length, pigmentation, and particularly its diameter. Currently, it is not known whether PCOS animal models also exhibit changes in the hair. Therefore, the aim of this study was to explore the wool characteristics in sheep prenatally androgenized (PA) with testosterone propionate. After 4 and 13 months of life, wool was collected from the top of the shoulder of both females and males (both androgenized and controls). The offspring sheep were followed for up to 19 months of life to evaluate testosterone and androstenedione serum levels by ultra-high-performance liquid chromatography-tandem mass spectrometry, determine insulin and glucose response to intravenous glucose tolerance test, and address estrus cyclicity during the second breeding season. PA male animals showed a reduction in wool fiber diameter at 4 months of age compared with controls (P = 0.02) but not at 13 months, whereas PA females showed increased hair diameter at 13 months (P = 0.002), with no difference at 4 months. No substantial changes in other hair parameters (length, color, and medullation) were identified. In addition, increased levels of serum testosterone were observed in PA female sheep compared with controls at 12 months (P = 0.03). Our results indicate for the first time, to our knowledge, that changes in wool fiber diameter observed in PA ewes replicate, at the translational level, the increase in hair diameter in hirsute women with PCOS.

How to choose the suitable animal model of polycystic ovary syndrome?

Polycystic ovary syndrome (PCOS) is a gynecological metabolic and endocrine disorder with uncertain etiology. To understand the etiology of PCOS or the evaluation of various therapeutic agents, different animal models have been introduced. Considering this fact that is difficult to develop an animal model that mimics all aspects of this syndrome, but, similarity of biological, anatomical, and/or biochemical features of animal model to the human PCOS phenotypes can increase its application. This review paper evaluates the recently researched animal models and introduced the best models for different research purposes in PCOS studies. During January 2013 to January 2017, 162 studies were identified which applied various kinds of animal models of PCOS including rodent, primate, ruminant and fish. Between these models, prenatal and pre-pubertal androgen rat models and then prenatal androgen mouse model have been studied in detail than others. The comparison of main features of these models with women PCOS demonstrates higher similarity of these three models to human conditions. Thereafter, letrozole models can be recommended for the investigation of various aspects of PCOS. Interestingly, similarity of PCOS features of post-pubertal insulin and human chorionic gonadotropin rat models with women PCOS were considerable which can make it as a good choice for future investigations.

Hyperandrogenemia reduces endothelium-derived hyperpolarizing factor-mediated relaxation in mesenteric artery of female rats†

Women with polycystic ovary syndrome (PCOS) are often presented with hyperandrogenemia along with vascular dysfunction and elevated blood pressure. In animal models of PCOS, anti-androgen treatment decreased blood pressure, indicating a key role for androgens in the development of hypertension. However, the underlying androgen-mediated mechanism that contributes to increased blood pressure is not known. This study determined whether elevated androgens affect endothelium-derived hyperpolarizing factor (EDHF)-mediated vascular relaxation responses through alteration in function of gap junctional proteins. Female rats were implanted with placebo or dihydrotestosterone (DHT) pellets (7.5 mg, 90-day release). After 12 weeks of DHT exposure, blood pressure was assessed through carotid arterial catheter and endothelium-dependent mesenteric arterial EDHF relaxation using wire myograph. Connexin expression in mesenteric arteries was also examined. Elevated DHT significantly increased mean arterial pressure and decreased endothelium-dependent EDHF-mediated acetylcholine relaxation. Inhibition of Cx40 did not have any effect, while inhibition of Cx37 decreased EDHF relaxation to a similar magnitude in both controls and DHT females. On the other hand, inhibition of Cx43 significantly attenuated EDHF relaxation in mesenteric arteries of controls but not DHT females. Elevated DHT did not alter Cx37 or Cx40, but decreased Cx43 mRNA and protein levels in mesenteric arteries. In vitro exposure of DHT to cultured mesenteric artery smooth muscle cells dose-dependently downregulated Cx43 expression. In conclusion, increased blood pressure in hyperandrogenic females is due, at least in part, to decreased EDHF-mediated vascular relaxation responses. Decreased Cx43 expression and activity may play a role in contributing to androgen-induced decrease in EDHF function.

A Novel Letrozole Model Recapitulates Both the Reproductive and Metabolic Phenotypes of Polycystic Ovary Syndrome in Female Mice.

Polycystic ovary syndrome (PCOS) pathophysiology is poorly understood, due partly to lack of PCOS animal models fully recapitulating this complex disorder. Recently, a PCOS rat model using letrozole (LET), a nonsteroidal aromatase inhibitor, mimicked multiple PCOS phenotypes, including metabolic features absent in other models. Given the advantages of using genetic and transgenic mouse models, we investigated whether LET produces a similar PCOS phenotype in mice. Pubertal female C57BL/6N mice were treated for 5 wk with LET, which resulted in increased serum testosterone and normal diestrus levels of estradiol, similar to the hyperandrogenemia and follicular phase estrogen levels of PCOS women. As in PCOS, ovaries from LET mice were larger, polycystic, and lacked corpora lutea versus controls. Most LET females were acyclic, and all were infertile. LET females displayed elevated serum LH levels and higher Lhb mRNA in the pituitary. In contrast, serum FSH and Fshb were significantly reduced in LET females, demonstrating differential effects on gonadotropins, as in PCOS. Within the ovary, LET females had higher Cyp17, Cyp19, and Fsh receptor mRNA expression. In the hypothalamus, LET females had higher kisspeptin receptor mRNA expression but lower progesterone receptor mRNA levels. LET females also gained more weight than controls, had increased abdominal adiposity and adipocyte size, elevated adipose inflammatory mRNA levels, and impaired glucose tolerance, mirroring the metabolic phenotype in PCOS women. This is the first report of a LET paradigm in mice that recapitulates both reproductive and metabolic PCOS phenotypes and will be useful to genetically probe the PCOS condition.

Can Animal Models of PCOS Help Point the Way Towards Early and Effective Therapeutic Intervention in Women With the Syndrome?

Polycystic ovary syndrome (PCOS) is a major cause of reproductive and metabolic dysfunction in women, but it remains an enigmatic condition whose treatment is necessarily empirical (1). It is the principal cause of menstrual irregularity, anovulatory infertility and the distressing cutaneous manifestations of hirsutism and persistent acne, as well being a significant risk factor for development of type 2 diabetes mellitus. The etiology of the syndrome clearly involves both genetic and environmental factors, but there is still much work to be done in identification of the key genes and getting a clearer understanding of the nature of the interaction between genes and environment. Animal models of PCOS have provided valuable insight into the pathogenesis of the syndrome (2–7), particularly large animals, sheep or rhesus monkeys (3–5, 7), which, as predominantly monoovulatory species, most resemble humans. These animals, exposed in utero to very high concentrations of androgens, develop both reproductive and metabolic abnormalities that resemble clinical PCOS, suggesting that the syndrome arises, at least in part, as a result of androgen programming of fetal and postnatal development (6, 8). They also offer, as illustrated by the article by Padmanabhan et al (23) in this issue of Endocrinology, the prospect of testing therapeutic options that are targeted at reversing, or at least attenuating, during puberty or before, the adverse effects of PCOS and thereby altering the natural progression of the syndrome into adult life. From a clinical viewpoint, it is a constant frustration that management of the reproductive and metabolic sequelae of PCOS is more a matter of controlling symptoms than preventing or attenuating the development of the disorder. PCOS is usually first manifest during adolescence and, indeed, there may even be biochemical clues about susceptibility to development of the syndrome in premenarchal girls (9, 10). So an important question to be answered is: if we can intervene therapeutically to reduce hyperandrogenemia and/or improve insulin sensitivity when symptoms first appear during adolescence, can we reduce the impact of the syndrome on menstrual function, fertility, hirsutism and risk of type 2 diabetes mellitus? This very question was posed in the last millennium by Dan Apter in an article entitled “How possible is the prevention of polycystic ovary syndrome development in adolescent patients with early onset of hyperandrogenism?” (11). He concludes: “Well controlled, long-term follow-up studies are needed on the role of prepubertal hyperandrogenism, hyperinsulinemia, gonadotropins, and ovarian morphological aspects in the development of PCOS, and possibilities of prevention.” Unfortunately, we still lack definitive interventional studies. There is good evidence, from the small number of randomized clinical trials, that diet and lifestyle changes in overweight girls (12, 13), and drugs that improve insulin sensitivity, particularly metformin (14, 15), have a positive effect on both ovarian and metabolic function, which is unsurprising given the results from studies in older women. Antiandrogens alone or in combination with insulin sensitizers or combined oral contraceptives appear beneficial in selected subjects (16–19). And there are tantalizing hints that these therapies may be more effective (in terms of preventing progression of symptoms) in adolescent girls than in later

Cardiac Nitric Oxide Synthases and Na⁺/K⁺-ATPase in the Rat Model of Polycystic Ovary Syndrome Induced by Dihydrotestosterone.

Nitric oxide synthases (NOSs) and Na(+)/K(+)-ATPase are enzymes essential for regular functioning of the heart. Since both enzymes are under insulin and androgen regulation and since insulin action and androgen level were disturbed in polycystic ovary syndrome (PCOS), we hypothesized that cardiac nitric oxide (NO) production and sodium/potassium transport would be deteriorated in PCOS. To test our hypothesis we introduced animal model of PCOS based on dihydrotestosterone (DHT) treatment of female Wistar rats and analyzed protein expression, phosphorylation or subcellular localization of endothelial NOS (eNOS), inducible NOS (iNOS) and alpha subunits of Na(+)/K(+)-ATPase in the heart. Obtained results indicate that DHT treatment significantly decreased cardiac eNOS protein level and activating phosphorylation at serine 1,177, while inhibitory phosphorylation at threonine 495 was increased. In contrast to expression of eNOS, iNOS protein level in the heart of DHT-treated rats was significantly elevated. Furthermore, cardiac protein level of alpha 1 subunit of the ATPase, as well as its plasma membrane content, were decreased in rats with PCOS. In line with this, alpha 2 subunit protein level in fraction of plasma membranes was also significantly below control level. In conclusion, DHT treatment impaired effectiveness of NOSs and Na(+)/K(+)-ATPase in the female rat heart. Regarding the importance of NO production and sodium/potassium transport in the cardiac contraction and blood flow regulation, it implicates strong consequences of PCOS for heart functioning.

Cardiac fatty acid uptake and metabolism in the rat model of polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is associated with an altered plasma lipid profile and increased risk for cardiovascular diseases. We hypothesized that molecular mechanisms underlying cardiac pathology in PCOS involve changes in expression and subcellular localization of several key proteins involved in cardiac lipid transport and metabolism, such as fatty acid transporter CD36, lipin 1, peroxisome proliferator-activated receptor α (PPARα), peroxisome proliferator-activated receptor γ coactivator-1 (PGC1), and carnitine palmitoyltransferase 1 (CPT1). We used the animal model of PCOS obtained by treating female rats with dihydrotestosterone (DHT). Protein levels of CD36, lipin 1, PPARα, PGC1, and antioxidative enzymes were assessed by Western blot in different cardiac cell compartments. Cardiac triglycerides (TG) and lipid peroxidation were also measured. The content of CD36 was decreased in both the cardiac plasma membranes and intracellular pool. On the other hand, total content of cardiac lipin 1 in DHT-treated rats was elevated, in contrast to decreased microsomal lipin 1 content. An increase in nuclear content of lipin 1 was observed together with elevation of nuclear PPARα and PGC1, and an increase in CPT1 expression. However, lipid peroxidation was reduced in the heart, without alterations in antioxidative enzymes expression and cardiac TG content. The results indicate that treatment of female rats with DHT is accompanied by a decrease of fatty acid uptake and a reduction of lipid peroxidation in the heart. The observed elevation of lipin 1, PPARα, PGC1, and CPT1 expression suggests that cardiac fatty acid metabolism is shifted toward mitochondrial beta oxidation.

Dihydrotestosterone deteriorates cardiac insulin signaling and glucose transport in the rat model of polycystic ovary syndrome

It is supposed that women with polycystic ovary syndrome (PCOS) are prone to develop cardiovascular disease as a consequence of multiple risk factors that are mostly related to the state of insulin resistance and consequent hyperinsulinemia. In the present study, we evaluated insulin signaling and glucose transporters (GLUT) in cardiac cells of dihydrotestosterone (DHT) treated female rats as an animal model of PCOS. Expression of proteins involved in cardiac insulin signaling pathways and glucose transporters, as well as their phosphorylation or intracellular localization were studied by Western blot analysis in DHT-treated and control rats. Treatment with DHT resulted in increased body mass, absolute mass of the heart, elevated plasma insulin concentration, dyslipidemia and insulin resistance. At the molecular level, DHT treatment did not change protein expression of cardiac insulin receptor and insulin receptor substrate 1, while phosphorylation of the substrate at serine 307 was increased. Unexpectedly, although expression of downstream Akt kinase and its phosphorylation at threonine 308 were not altered, phosphorylation of Akt at serine 473 was increased in the heart of DHT-treated rats. In contrast, expression and phosphorylation of extracellular signal regulated kinases 1/2 were decreased. Plasma membrane contents of GLUT1 and GLUT4 were decreased, as well as the expression of GLUT4 in cardiac cells at the end of androgen treatment. The obtained results provide evidence for alterations in expression and especially in functional characteristics of insulin signaling molecules and glucose transporters in the heart of DHT-treated rats with PCOS, indicating impaired cardiac insulin action.

Developmental Origin of Reproductive and Metabolic Dysfunctions: Androgenic Versus Estrogenic Reprogramming

Polycystic ovary syndrome (PCOS) is one of the most common fertility disorders, affecting several million women worldwide. Women with PCOS manifest neuroendocrine, ovarian, and metabolic defects. A large number of animal models have evolved to understand the etiology of PCOS. These models provide support for the contributing role of excess steroids during development in programming the PCOS phenotype. However, considerable phenotypic variability is evident across animal models, depending on the quality of the steroid administered and the perinatal time of treatment relative to the developmental trajectory of the fetus/offspring. This review focuses on the reproductive and metabolic phenotypes of the various PCOS animal models that have evolved in the last decade to delineate the relative roles of androgens and estrogens in relation to the timing of exposure in programming the various dysfunctions that are part and parcel of the PCOS phenotype. Furthermore, the review addresses the contributory role of the postnatal metabolic environment in exaggerating the severity of the phenotype, the translational relevance of the various animal models to PCOS, and areas for future research.

Radiolabeling, biodistribution and gamma scintigraphy of noscapine hydrochloride in normal and polycystic ovary induced rats.

BackgroundNoscapine, an alkaloid from Papaver somniferum, widely used as an antitussive, is being clinically studied in the treatment of polycystic ovary syndrome (PCOS) and a few other cancers primarily because of its anti-angiogenesis properties. With the advent of diverse application of noscapine, we sought to determine whether the radiolabeling method can be useful in studying uptake and kinetics of the molecule in-vivo. Specific objectives of this study were to radiolabel noscapine with Technetium-99m (Tc-99m), to determine its organ biodistribution in rat model and study its uptake kinetics in PCOS model.MethodsA method for radiolabeling noscapine with Tc-99m was standardized using stannous reduction method and its in vitro and in vivo stability parameters were studied. The radiopharmaceutical was also evaluated for blood kinetics and biodistribution profile. An animal model of PCOS was created by using antiprogesterone RU486 and uptake of 99mTc-noscapine in normal and PCOS ovaries was compared using gamma scintigraphy.ResultsNoscapine hydrochloride was successfully radiolabeled with Tc-99m with high labeling efficiency and in vitro stability. Most of the blood clearance of the drug (80%) took place in first hour after intravascular injection with maximum accumulation being observed in liver, spleen, kidney followed by the ovary. At 4 hours post injection, radiolabeled complex accumulation doubled in PCOS ovaries in rats (0.9 ± 0.03% ID/whole organ) compared to normal cyclic rats (0.53 ± 0.01% ID/whole organ). This observation was further strengthened by scintigraphic images of rats taken at different time intervals (1 h, 2 h, 4 h, and 24 h) where SPECT images suggested discrete accumulation in the PCOS ovaries.ConclusionThrough our study we report direct radiolabeling of noscapine and its biodistribution in various organs and specific uptake in PCOS that may show its utility for imaging ovarian pathology. The increased ovarian uptake in PCOS may be related to its receptor binding suggesting possible role of 99mTc-noscapine in PCOS diagnostics and therapeutics.

A Unique Rodent Model of Cardiometabolic Risk Associated with the Metabolic Syndrome and Polycystic Ovary Syndrome

Polycystic ovary syndrome (PCOS) is characterized by hyperandrogenism, oligo-/anovulation and polycystic ovarian morphology, and is a complex endocrine disorder that also presents with features of the metabolic syndrome, including obesity, insulin resistance and dyslipidemia. These latter symptoms form cardiometabolic risk factors predisposing individuals to the development of type-2 diabetes and cardiovascular disease (CVD). To date, animal models to study PCOS in the context of the metabolic syndrome and CVD risk have been lacking. The aim of this study was to investigate the JCR:LA-cp rodent as an animal model of PCOS associated with the metabolic syndrome. Metabolic indices were measured at 6 and 12 wks, and reproductive parameters including ovarian morphology and estrous cyclicity were assessed at 12 wks or adulthood. At 6 wks of age, the cp/cp genotype of the JCR:LA-cp strain developed visceral obesity, IR, dyslipidemia (hypertriglyceridemia and hypercholesterolemia) compared to control animals. Serum testosterone (T) concentrations were not significantly different between groups at 6 wks of age. However at 12 wks, the cp/cp genotype had higher serum T concentrations, compared to control animals, and presented with oligo-ovulation, a decreased number of corpora lutea and an increased number of total follicles, in particular atretic and cystic follicles. The cardiometabolic risk factors in the cp/cp animals were exacerbated at 12 wks including obesity, insulin resistance and dyslipidemia. The results of this study demonstrate that the JCR:LA-cp rodent may be a useful PCOS-like model to study early mechanisms involved in the etiology of cardiometabolic risk factors in the context of both PCOS and the metabolic syndrome.

The Ossabaw Pig as a Model of Polycystic Ovary Syndrome

Polycystic ovary syndrome (PCOS) is not only a gynecological condition, but a comprehensive syndrome with a variety of associated metabolic disorders. Our objective was to characterize endocrine parameters of female Ossabaw pigs to establish their suitability as an animal model of PCOS. Hyperandrogenism is a hallmark of PCOS, but is not associated with the metabolic syndrome in the absence of PCOS. Blood was collected from domestic pigs, Ossabaw females maintained on a low fat diet, and Ossabaw females fed a high fat, high cholesterol diet. Excess fat and cholesterol feeding elicits profound obesity, insulin resistance, increased plasma LDL/HDL cholesterol and triglycerides and coronary disease in Ossabaw swine, all characteristics of the metabolic syndrome (Dyson et al. FASEB J. 19:A191, 2005). Serum androstenedione was 4-fold greater (P<0.05) in Ossabaw females fed excess fat. Lean Ossabaw females had 4-fold greater circulating testosterone than lean domestic females. Ossabaw females fed excess fat, which exhibited the metabolic syndrome, showed 8-fold greater testosterone than lean domestic females. Androstenedione production in cultured theca cells, in response to insulin and LH stimulation, was ~2-fold greater in Ossabaw than domestic gilts. In conclusion, PCOS-driven hyperandrogenism is present in Ossabaw swine, similar to humans. (Support: NIH RR13223, HL62552, and ADA to M.S.).