Dehydroepiandrosterone to induce murine models for the study of polycystic ovary syndrome

doi:10.1016/j.jsbmb.2010.02.015

The Journal of Steroid Biochemistry and Molecular Biology

Volume 119, Issues 3–5, April 2010, Pages 105-111

https://doi.org/10.1016/j.jsbmb.2010.02.015 Get rights and content

Abstract

During the last decade a battery of animal models used for the study of polycystic ovary syndrome (PCOS) have allowed a focus on different aspects of the pathology. Since dehydroepiandrosterone (DHEA) was found to be one of the most abundant circulating androgens in women with PCOS, a rodent model showing the salient features found in women with PCOS was developed by the injection of DHEA. Although insulin-sensitizing agents, such as biguanides, are clinically used in the treatment of diabetes and PCOS, the complete understanding of their mechanisms of action remains unknown. The present review discusses the molecular mechanisms involved in the development of PCOS by using the DHEA-PCOS murine model and analyzes the role of the biguanide metformin as treatment.

Introduction

The current diagnostic criteria for polycystic ovary syndrome (PCOS) are hyperandrogenism, oligo- or amenorrhea and anovulation [1]. In addition, PCOS is frequently associated with hyperinsulinemia, insulin resistance syndrome, increased cardiovascular risk and diabetes mellitus [1]. Despite its prevalence, little is known about the etiology and pathology of the syndrome. However, during the last decade several clues that may have significant repercussions in the treatment have emerged from human and animal studies. Mahesh and Greenblatt [2] were the first to isolate dehydroepiandrosterone (DHEA) from the ovaries of women with PCOS. After that, Roy et al. [3] produced an animal model for the study of PCOS by injecting DHEA. Subsequent studies established that the DHEA-PCOS murine model exhibits many of the salient features of human PCOS such as hyperandrogenism, insulin resistance, altered steroidogenesis, abnormal maturation of ovarian follicles and anovulation [4], [5], [6], [7], [8], [9], [10], [11], [12].

Multiple therapies have been applied in PCOS. Recent studies have investigated the role of a type of insulin-sensitizing agents: the biguanides. The use of N,N′-dimethyl-biguanide metformin is becoming increasingly accepted and widespread [[13], [14], [15], [16] among others]; however, metformin is being clinically used without a complete understanding of the mechanism involved. This review compiles some of the data on the endocrine and immune aspects that are altered in PCOS by using the DHEA-PCOS murine model and discusses the molecular mechanisms of metformin treatment.

Section snippets

Effects of prepubertal hyperandrogenism

In order to assess the effect of hyperandrogenism during the prepubertal stage a PCOS murine model can be obtained by daily injection of DHEA (6 mg/kg body weight: 0.75 mg DHEA per mouse) for 20 consecutive days in prepubertal BALB/c mice [9], [11]. This dose of DHEA ensures a hyperandrogenized status equivalent to that found in women with PCOS, which is 0.7 mg DHEA in total per day [4], [5], [6], [9], [10], [11]. Histological examination of prepubertal ovaries from the DHEA-treated mice reveals

Hyperandrogenism in early pregnancy induces embryo resorption

DHEA sulfate (DHEAS), the highest circulating steroid, is the precursor and reservoir of DHEA, which, in turn, produces sex steroids. [37]. During pregnancy, DHEAS is the major source for estrogen formation in the fetoplacental unit [38] and DHEA suppresses the immune reactions by regulating cytokine levels, thus ensuring the development of gestation [39], [40], [41]. The decrease in maternal DHEAS or abnormally increased levels of DHEA leads to an imbalance of the ovarian function which

Effects of hyperandrogenism in uterine tissue

It has been reported that increased levels of androgens induce detrimental effects on the endometrial response, resulting in miscarriage [42], [43], [44], and that women with PCOS have an increased risk to develop endometrial cancer [45]. These data suggest that an excess of androgens alters uterine tissue; however, the potential mechanisms underlying these disorders are complex and await their complete elucidation. For this reason, we designed experiments to study the mechanisms involved in

Role of metformin in the treatment of hyperandrogenism: molecular mechanisms involved

Insulin-sensitizing agents, such as biguanides are used in the treatment of PCOS, without a complete understanding by which metformin increases peripheral insulin. It has been reported that metformin reduces insulin resistance by restoring insulin sensitivity [50], [51], [52] and that it regulates ovarian steroidogenesis either directly or indirectly [53], [54]. However, controversial results have been reported with regards to metformin and its relationship with the immune system. In patients

Conclusions

The present study describes the mechanisms by which an excess of androgens impairs the endocrine and immune systems and induces metabolic alterations. The investigations were carried out during different stages of the reproductive period and aim to gain insights into the molecular mechanisms involved in each abnormal condition. We also demonstrated the role of metformin treatment in reversing the alterations induced by the excess of androgens.

Acknowledgements

This study was supported by PICTR 32529/2005 and PICT 949/2006 from Agencia Nacional de Promoción Científica y Tecnológica (ANPCyT).

References (113)

C.G. Luchetti et al.
Effects of dehydroepiandrosterone on ovarian cystogenesis and immune function
J. Reprod. Immunol.
(2004)
B. Halliwell et al.
Lipid peroxidation, oxygen radicals, cell damage, and antioxidant therapy
Lancet
(1984)
R.A. Star
Nitric oxide
Am. J. Med. Sci.
(1993)
A. Estevez et al.
Interleukin-1beta up-regulates nitrite production: effects on ovarian function
Nitric Oxide
(2004)
T. Sabuncu et al.
Oxidative stress in polycystic ovary syndrome and its contribution to the risk of cardiovascular disease
Clin. Biochem.
(2001)
N. Tagawa et al.
Serum concentrations of dehydroepiandrosterone and dehydroepiandrosterone sulfate and their relation to cytokine production during and after normal pregnancy
Clin. Chim. Acta
(2004)
M.A. Okon et al.
Serum androgen levels in women who have recurrent miscarriages and their correlation with markers of endometrial function
Fertil. Steril.
(1998)
E.M. Tuckerman et al.
Do androgens have a direct effect on endometrial function? An in vitro study
Fertil. Steril.
(2000)
R. Mansfield et al.
Metformin has direct effects on human ovarian steroidogenesis
Fertil. Steril.
(2003)
C. Ruat et al.
Tritiated thymidine incorporation does not enhance sensitivity of the popliteal lymph node assay
Toxicology
(2003)

D.T. Vandermolen et al.

Metformin increases the ovulation rate and pregnancy rate from clomiphene citrate in patients with polycystic ovary syndrome who are resistant to clomiphene citrate alone

Fertil. Steril.

(2001)

D. Tessier et al.

Effect of gliclazide versus metformin on the clinical profile and lipid peroxidation markers in type 2 diabetes

Metabolism

(1999)

D. Bonnefont-Rousselot et al.

An intracellular modulation of free radical production could contribute to the beneficial effects of metformin towards oxidative stress

Metabolism

(2003)

J.L. Sartoretto et al.

Metformin treatment restores the altered microvascular reactivity in neonatal streptozotocin-induced diabetic rats increasing NOS activity, but not NOS expression

Life Sci.

(2005)

M.H. Zou et al.

Activation of the AMP-activated protein kinase by the anti-diabetic drug metformin in vivo

J. Biol. Chem.

(2004)

M.F. McCarty

AMPK activation may suppress hepatic production of C-reactive protein by stimulating nitric oxide synthase

Med. Hypotheses

(2004)

J.M. Cacicedo et al.

AMPK Inhibits fatty acid-induced increases in NF-kappaB transactivation in cultured human umbilical vein endothelial cells

Biochem. Biophys. Res. Commun.

(2004)

D.N. Kiortsis et al.

The effects of orlistat on metabolic parameters and other cardiovascular risk factors

Diabetes Metab.

(2005)

L.G.D. Fryer et al.

The anti-diabetic drugs rosiglitazone and metformin stimulate AMP-activated protein kinase through distinct signalling pathways

J. Biol. Chem.

(2002)

M. Zang et al.

AMP-activated protein kinase is required for the lipid-lowering effect of metformin in insulin-resistant human HepG2 cells

J. Biol. Chem.

(2004)

S. Youssef et al.

Effect of diabetes and aminoguanidine therapy on renal advanced glycation end-product binding

Kidney Int.

(1999)

M.F. McCarty

Chronic activation of AMPK-activated kinase as a strategy for slowling aging

Med. Hypotheses

(2004)

B.E. Crute et al.

Functional domains of the alpha1 catalytic subunit of the AMP-activated protein kinase

J. Biol. Chem.

(1998)

S. Franks

Polycystic ovary syndrome

N. Engl. J. Med.

(1995)

V.B. Mahesh et al.

Isolation of dehydroepiandrosterone and 17-hydroxy-pregnenolone from polycystic ovaries of the Stein–Leventhal syndrome

J. Clin. Endocrinol. Metab.

(1962)

S. Roy et al.

Effect of dehydroepiandrosterone and androstenedione on the reproductive organs of female rats: production of cystic changes in the ovary

Nature

(1962)

M.T. Lee et al.

Changes in ovarian morphology and serum hormones in the rat after treatment with dehydroepiandrosterone

Anat. Rec.

(1991)

G.Y. Lee et al.

Multidrug resistance gene expression correlates with progesterone production in dehydroepiandrosterone-induced polycystic equine chorionic gonadotropin-stimulated ovaries of prepuberal rats

Biol. Reprod.

(1998)

H. Henmi et al.

Lysyl oxidase and MMP-2 expression in dehydroepiandrosterone-induced polycystic ovary in rats

Biol. Reprod.

(2001)

E. Anderson et al.

Cystogenesis of the ovarian antral follicle of the rat: ultrastructural changes and hormonal profile following the administration of dehydroepiandrosterone

Anat. Rec.

(1992)

E. Elia et al.

The mechanisms involved in the action of metformin in regulating ovarian function in hyperandrogenized mice

Mol. Hum. Reprod.

(2006)

V. Sander et al.

The influence of dehydroepiandrosterone on early pregnancy in mice

Neuroimmunomodulation

(2005)

V. Sander et al.

Role of the N,N′dimethylbiguanide metformin in the treatment of female prepuberal BALB/c mice hyperandrogenized with dehydroepiandrosterone

Reproduction

(2006)

M.E. Solano et al.

Metformin prevents embryonic resorption induced by hyperandrogenization with dehydroepiandrosterone in mice

Reprod. Fertil. Dev.

(2006)

S. Palomba et al.

Uterine effects of clomiphene citrate in women with polycystic ovary syndrome: a prospective controlled study

Hum. Reprod.

(2006)

F. Orio et al.

Improvement in endothelial structure and function after metformin treatment in young normal-weight women with polycystic ovary syndrome: results of a 6-month study

J. Clin. Endocrinol. Metab.

(2005)

R.S. Legro et al.

Clomiphene, metformin, or both for infertility in the polycystic ovary syndrome

N. Engl. J. Med.

(2007)

E. Diamanti-Kandarakis et al.

The effect of pharmaceutical intervention on lipid profile in polycystic ovary syndrome

Obes. Rev.

(2009)

M. Yilmaz et al.

Resistin and adiponectin levels in women with polycystic ovary syndrome

Gynecol. Endocrinol.

(2009)

V.B. Schini et al.

Role of the l-arginine-nitric oxide pathway in vascular smooth muscle

Eur. Heart J.

(1993)

A.B. Motta et al.

Dual effects of nitric oxide in functional and regressing rat corpus luteum

Mol. Hum. Reprod.

(2001)

H.Z. Wang et al.

The hormonal control of human luteal cells

R.F. Aten et al.

Regulation of ovarian antioxidant vitamins reduced glutathione and lipid peroxidation by luteinizing hormone and prostaglandin F2 alpha

Biol. Reprod.

(1992)

N. Sugino et al.

Suppression of intracellular superoxide dismutase activity by antisense oligonucleotides causes inhibition of luteal cells

Biol. Reprod.

(1999)

A. Maggioni et al.

Randomised study of systematic lymphadenectomy in patients with epithelial ovarian cancer macroscopically confined to the pelvis

Br. J. Cancer

(2006)

E.T. Samy et al.

The role of physiological self-antigen in the acquisition and maintenance of regulatory T-cell function

Immunol. Rev.

(2006)

V. Anaf et al.

Pain, mast cells, and nerves in peritoneal, ovarian, and deep infiltrating endometriosis

Fertil. Steril.

(2006)

J. Yang et al.

Islet-specific glucose-6-phosphatase catalytic subunit-related protein-reactive CD4+ T cells in human subjects

J. Immunol.

(2006)

Y.F. Zhang et al.

Elevated serum levels of interleukin-18 are associated with insulin resistance in women with polycystic ovary syndrome

Endocrine

(2006)

R. Wu et al.

Ovarian leukocyte distribution and cytokine/chemokine mRNA expression in follicular fluid cells in women with polycystic ovary syndrome

Hum. Reprod.

(2007)

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Polycystic ovary syndrome (PCOS) is a complex endocrine disease. Thioredoxin-interacting protein (TXNIP) promotes oxidative stress and triggers inflammation. Herein, we investigated the role and potential mechanism of TXNIP in PCOS. In a mouse model of dehydroepiandrosterone (DHEA)-induced PCOS, we found that TXNIP was upregulated in the ovaries, especially in granulosa cells (GCs). TXNIP was also upregulated in testosterone (T)-treated GCs in vitro. Knockdown of TXNIP by lentivirus-constructed shRNA attenuated T-induced GC injury and oxidative stress, as well as inflammation and the NLRP3 inflammasome. The mechanism by which TXNIP promotes inflammation may involve TXNIP dissociation from the TXNIP-TRX complex and binding to NLRP3 to form the inflammasome. Additionally, we verified that knockdown of TXNIP ameliorated ovarian injury and inflammation in mice with DHEA-induced PCOS in vivo. Collectively, we demonstrated that TXNIP is involved in GC inflammation by promoting NLRP3 inflammasome activation in PCOS.
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The ovarian histomorphological sections of the PCOS mice revealed more cysts and atretic follicles and fewer or no corpora lutea when compared with the control group. In a similar study, it was reported that the PCOS mouse model displayed most of the features seen in human PCOS patients including hyperandrogenism and abnormal follicular development leading to anovulation and infertility (Motta, 2010). Several circRNA, miRNA and long non-coding RNA expression profiling studies about PCOS have been carried out on different human components such as ovarian tissues, follicular fluids, uterine tissues, sera and adipose tissue (Fu et al., 2018; Gao et al., 2016; Zhang et al., 2019).
What is the expression pattern of inflammatory mRNA profiles of a dehydroepiandrosterone (DHEA) plus high-fat diet (HFD)-induced polycystic ovary syndrome (PCOS) mouse model?
RNA sequencing was performed to investigate the mRNA expression profiles in the ovarian tissues of a DHEA plus HFD-induced PCOS mouse model. Six samples were divided into two groups (control and PCOS), with three biological replicates in each group. This was followed by hierarchical clustering, gene ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses. The relative expression levels of nine inflammatory genes were validated via quantitative reverse-transcription polymerase chain reaction.
A total of 436 genes were differentially expressed between the control and PCOS mice. Out of these, 137 genes were up-regulated while 299 genes were down-regulated. Gene ontology analysis indicated that differentially expressed mRNA were associated with T cell-mediated cytotoxicity and homocysteine metabolic processes. Pathway analysis further showed that these abnormally expressed mRNA were associated with signalling pathways, such as NF-kB signalling, tyrosine metabolism and phenylalanine metabolism. All these pathways are involved in chronic inflammation and PCOS.
The differentially expressed genes are potentially involved in the inflammation that is evident in PCOS, and so could serve as therapeutic options against the disease. Nevertheless, prospective studies are needed to test this hypothesis.
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Polycystic ovary syndrome (PCOS) is a frequent gynecological endocrine disorder, and the majority of PCOS patients experience different degrees of insulin resistance (IR). Nevertheless, the functions of microRNAs (miRNAs) in IR of PCOS remain unclear. In this study, we desired to elucidate the mechanisms of miR-103 in IR of PCOS.
The ovarian pathological morphology of established PCOS rats was detected by HE staining. Following miR-103 expression determination in the ovarian tissues of PCOS rats, the relationship between its expression and IR was studied. A PCOS/IR cell model was established, and the effect of miR-103 on granulosa cells was determined by CCK-8 assay and flow cytometry. Through online website prediction and consulting related literatures, the target gene of miR-103 and the pathway regulated by the target genes were discovered, which was verified by further experiments.
PCOS rats showed polycystic changes in the ovary and a decrease in granulosa cells, and these symptoms were more pronounced in rats showed IR. miR-103 expressed highly in PCOS and was positively related to IR. miR-103 inhibitor led to improved PCOS-related symptoms. In addition, miR-103 directly targeted IRS1, which was poorly expressed in PCOS, and IRS1 silencing promoted PCOS development. Furthermore, miR-103 regulated the PI3K/AKT pathway by targeting IRS1, and PI3K/AKT pathway suppression reduced the therapeutic effect of miR-103 inhibitor.
This study indicates that miR-103 disrupts the PI3K/AKT pathway activation by targeting IRS1, thereby aggravating PCOS development. miR-103 inhibition may be a promising molecular target for treatment of PCOS.
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Moreover, it has been reported that PPARg modulates cyclooxygenase (COX)-2 expression, the limiting enzyme involved in the synthesis of prostaglandins (Zaree et al., 2015). Prenatal hyperandrogenization (PH) in females leads to the appearance of a PCOS phenotype in adulthood (Abbott et al., 2008; Motta, 2010; Padmanabhan and Veiga-Lopez, 2013; van Houten and Visser, 2014). These prenatally induced-PCOS animal models are usually permanent, due to specific developmental disturbances during the maturation and differentiation of the organs, leading to alterations of their structures and functions (Abbott et al., 2007).
Prenatal androgen excess is considered one of the main causes of the development of polycystic ovary syndrome. In this study, we investigated the effect of prenatal hyperandrogenization (PH) on the physiology of the adult uterine tissue using a murine model of fetal programming caused by androgen excess in adult female rats. Pregnant rats were hyperandrogenized with testosterone and female offspring were studied when adult. Our results showed that PH leads to hyperglycemia and hyperinsulinemia. Consequently, PH developed insulin resistance and a systemic inflammatory state reflected by increased C-reactive protein. In the uterine tissue, levels of PPAR gamma—an important metabolic sensor in the endometrium—were found to be impaired. Moreover, PH induced a pro-inflammatory and an unbalanced oxidative state in the uterus reflected by increased COX-2, lipid peroxidation, and NF-κB. In summary, our results revealed that PH leads to a compromised metabolic state likely consequence of fetal reprogramming.
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Many studies have also described the link between the endocrine and immune system in PCOS. For example, a positive correlation between hyperandrogenism and serum tumor necrosis factor alpha (TNF-α) has been demonstrated in patients with PCOS (Sayin et al., 2003; Ebejer, K and Calleja-Agius, 2013) and in DHEA- or DHT-induced PCOS animal models (Motta, 2010; Luchetti et al., 2004; Sander et al., 2005; Krishnan et al., 2020). Studies in DHT-treated rats have also shown the presence of necrotic lesions in the liver, multinucleated giant cells and lymphocytes in the ovary (Krishnan et al., 2020).
Polycystic ovary syndrome (PCOS) is associated with hyperandrogenemia and uterine abnormalities. Our aim was to investigate the uterine effects of PCOS that are mediated through the androgen receptor (AR). After weaning, female rats were treated with sesame oil (Control), dehydroepiandrosterone (DHEA), or DHEA + flutamide (FLU, an AR antagonist) for 20 consecutive days. On postnatal day 41, serum, ovarian and uterine tissues were collected. DHEA and DHEA + FLU rats showed increased testosterone levels. DHEA rats showed increased epithelial height, glandular density, subepithelial stroma and myometrial thickness, associated with decreased nuclei density. These rats also showed increased uterine water content, with decreased aquaporin (AQP) 3, 7 and 8 expression in the uterine epithelium and increased AQP8 expression in the myometrium. DHEA rats also showed decreased uterine collagen remodeling, decreased cell proliferation in the subepithelial stroma, and increased apoptosis in the luminal and glandular epithelium and in the myometrium. They also showed an increase in insulin-like growth factor-1 and a decrease in phosphatidylinositol-3,4,5-trisphosphate 3-phosphatase. The uterine stroma of DHEA rats showed no changes in progesterone receptor or estrogen receptor alpha (ERα) and increased AR expression. DHEA + FLU rats showed a smaller increase in the myometrial thickness, an increase in the uterine water content without AQP8 induction and a smaller decrease in collagen remodeling. These rats also showed no apoptosis induction and decreased proliferation in the myometrium, decreased ERα in the subepithelial stroma and myometrium and no modifications in AR. Our results demonstrate that the uterine cell turnover and collagen remodeling in DHEA rats are regulated through AR, directly or indirectly associated with ERα expression.
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ReviewDehydroepiandrosterone to induce murine models for the study of polycystic ovary syndrome

Abstract

Introduction

Section snippets

Effects of prepubertal hyperandrogenism

Hyperandrogenism in early pregnancy induces embryo resorption

Effects of hyperandrogenism in uterine tissue

Role of metformin in the treatment of hyperandrogenism: molecular mechanisms involved

Conclusions

Acknowledgements

J. Reprod. Immunol.

Lancet

Am. J. Med. Sci.

Nitric Oxide

Clin. Biochem.

Clin. Chim. Acta

Fertil. Steril.

Fertil. Steril.

Fertil. Steril.

Toxicology

Fertil. Steril.

Metabolism

Metabolism

Life Sci.

J. Biol. Chem.

Med. Hypotheses

Biochem. Biophys. Res. Commun.

Diabetes Metab.

J. Biol. Chem.

J. Biol. Chem.

Kidney Int.

Med. Hypotheses

J. Biol. Chem.

Polycystic ovary syndrome

N. Engl. J. Med.

Isolation of dehydroepiandrosterone and 17-hydroxy-pregnenolone from polycystic ovaries of the Stein–Leventhal syndrome

J. Clin. Endocrinol. Metab.

Effect of dehydroepiandrosterone and androstenedione on the reproductive organs of female rats: production of cystic changes in the ovary

Nature

Changes in ovarian morphology and serum hormones in the rat after treatment with dehydroepiandrosterone

Anat. Rec.

Multidrug resistance gene expression correlates with progesterone production in dehydroepiandrosterone-induced polycystic equine chorionic gonadotropin-stimulated ovaries of prepuberal rats

Biol. Reprod.

Lysyl oxidase and MMP-2 expression in dehydroepiandrosterone-induced polycystic ovary in rats

Biol. Reprod.

Cystogenesis of the ovarian antral follicle of the rat: ultrastructural changes and hormonal profile following the administration of dehydroepiandrosterone

Anat. Rec.

The mechanisms involved in the action of metformin in regulating ovarian function in hyperandrogenized mice

Mol. Hum. Reprod.

The influence of dehydroepiandrosterone on early pregnancy in mice

Neuroimmunomodulation

Role of the N,N′dimethylbiguanide metformin in the treatment of female prepuberal BALB/c mice hyperandrogenized with dehydroepiandrosterone

Reproduction

Metformin prevents embryonic resorption induced by hyperandrogenization with dehydroepiandrosterone in mice

Reprod. Fertil. Dev.

Uterine effects of clomiphene citrate in women with polycystic ovary syndrome: a prospective controlled study

Hum. Reprod.

Improvement in endothelial structure and function after metformin treatment in young normal-weight women with polycystic ovary syndrome: results of a 6-month study

J. Clin. Endocrinol. Metab.

Clomiphene, metformin, or both for infertility in the polycystic ovary syndrome

N. Engl. J. Med.

The effect of pharmaceutical intervention on lipid profile in polycystic ovary syndrome

Obes. Rev.

Resistin and adiponectin levels in women with polycystic ovary syndrome

Gynecol. Endocrinol.

Role of the l-arginine-nitric oxide pathway in vascular smooth muscle

Eur. Heart J.

Dual effects of nitric oxide in functional and regressing rat corpus luteum

Mol. Hum. Reprod.

The hormonal control of human luteal cells

Regulation of ovarian antioxidant vitamins reduced glutathione and lipid peroxidation by luteinizing hormone and prostaglandin F2 alpha

Biol. Reprod.

Suppression of intracellular superoxide dismutase activity by antisense oligonucleotides causes inhibition of luteal cells

Biol. Reprod.

Randomised study of systematic lymphadenectomy in patients with epithelial ovarian cancer macroscopically confined to the pelvis

Br. J. Cancer

The role of physiological self-antigen in the acquisition and maintenance of regulatory T-cell function

Immunol. Rev.

Pain, mast cells, and nerves in peritoneal, ovarian, and deep infiltrating endometriosis

Fertil. Steril.

Review
Dehydroepiandrosterone to induce murine models for the study of polycystic ovary syndrome