Cellular and Animal Studies: Insights into Pathophysiology and Therapy of PCOS.
Basic science studies have advanced our understanding of the role of key enzymes in the steroidogenesis pathway and those that affect the pathophysiology of PCOS. Studies with ovarian theca cells taken from women with PCOS have demonstrated increased androgen production due to increased CYP17A1 and HSD3B2 enzyme activities. Furthermore, overexpression of DENND1A variant 2 in normal theca cells resulted in a PCOS phenotype with increased androgen production. Notably, cellular steroidogenesis models have facilitated the understanding of the mechanistic effects of pharmacotherapies, including insulin sensitizers (e.g., pioglitazone and metformin) used for the treatment of insulin resistance in PCOS, on androgen production. In addition, animal models of PCOS have provided a critical platform to study the effects of therapeutic agents in a manner closer to the physiological state. Indeed, recent breakthroughs have demonstrated that natural derivatives such as the dietary medium-chain fatty acid decanoic acid (DA) can restore estrous cyclicity and lower androgen levels in an animal model of PCOS, thus laying the platform for novel therapeutic developments in PCOS. This chapter reviews the current understanding on the pathways modulating androgen biosynthesis, and the cellular and animal models that form the basis for preclinical research in PCOS, and sets the stage for clinical research.
Department of Obstetrics & Gynaecology, National University of Singapore, NUHS Tower Block, Level 12, 1E Kent Ridge Road, Singapore 119228, Singapore. Electronic address: phciri@nus.edu.sg.
Inthrani Raja
IR
Indran
Department of Obstetrics & Gynaecology, National University of Singapore, NUHS Tower Block, Level 12, 1E Kent Ridge Road, Singapore 119228, Singapore. Electronic address: baohui.lee@u.nus.edu.
Bao Hui
BH
Lee
Department of Obstetrics & Gynaecology, National University of Singapore, NUHS Tower Block, Level 12, 1E Kent Ridge Road, Singapore 119228, Singapore. Electronic address: eu_leong_yong@nuhs.edu.sg.
Eu-Leong
EL
Yong
D000728:Androgens / Q000096:biosynthesis*; D000818:Animals; D053418:Death Domain Receptor Signaling Adaptor Proteins / Q000378:metabolism; D003652:Decanoic Acids / Q000627:therapeutic use; D004195:Disease Models, Animal; D005260:Female; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism; D006801:Humans; D017588:Hyperandrogenism / Q000188:drug therapy / Q000378:metabolism*; D007004:Hypoglycemic Agents / Q000627:therapeutic use; D066298:In Vitro Techniques; D007333:Insulin Resistance; D008687:Metformin / Q000627:therapeutic use; D000077205:Pioglitazone; D011085:Polycystic Ovary Syndrome / Q000188:drug therapy / Q000378:metabolism*; D011375:Progesterone Reductase / Q000378:metabolism; D013254:Steroid 17-alpha-Hydroxylase / Q000378:metabolism; D013799:Theca Cells / Q000378:metabolism*; D045162:Thiazolidinediones / Q000627:therapeutic use
D000728:Androgens; C571984:DENND1A protein, human; D053418:Death Domain Receptor Signaling Adaptor Proteins; D003652:Decanoic Acids; D020662:Guanine Nucleotide Exchange Factors; D007004:Hypoglycemic Agents; D045162:Thiazolidinediones; C031071:decanoic acid; D008687:Metformin; C533068:3 beta-hydroxysteroid dehydrogenase type II; D011375:Progesterone Reductase; C501892:CYP17A1 protein, human; D013254:Steroid 17-alpha-Hydroxylase; D000077205:Pioglitazone
androgen; animal models; polycystic ovarian syndrome; steroidogenesis