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.

A Dietary Medium-Chain Fatty Acid, Decanoic Acid, Inhibits Recruitment of Nur77 to the HSD3B2 Promoter In Vitro and Reverses Endocrine and Metabolic Abnormalities in a Rat Model of Polycystic Ovary Syndrome.

Hyperandrogenism is the central feature of polycystic ovary syndrome (PCOS). Due to the intricate relationship between hyperandrogenism and insulin resistance in PCOS, 50%-70% of these patients also present with hyperinsulinemia. Metformin, an insulin sensitizer, has been used to reduce insulin resistance and improve fertility in women with PCOS. In previous work, we have noted that a dietary medium-chain fatty acid, decanoic acid (DA), improves glucose tolerance and lipid profile in a mouse model of diabetes. Here, we report for the first time that DA, like metformin, inhibits androgen biosynthesis in NCI-H295R steroidogenic cells by regulating the enzyme 3ß-hydroxysteroid dehydrogenase/Δ5-Δ4-isomerase type 2 (HSD3B2). The inhibitory effect on HSD3B2 and androgen production required cAMP stimulation, suggesting a mechanistic action via the cAMP-stimulated pathway. Specifically, both DA and metformin reduced cAMP-enhanced recruitment of the orphan nuclear receptor Nur77 to the HSD3B2 promoter, coupled with decreased transcription and protein expression of HSD3B2. In a letrozole-induced PCOS rat model, treatment with DA or metformin reduced serum-free testosterone, lowered fasting insulin, and restored estrous cyclicity. In addition, DA treatment lowered serum total testosterone and decreased HSD3B2 protein expression in the adrenals and ovaries. We conclude that DA inhibits androgen biosynthesis via mechanisms resulting in the suppression of HSD3B2 expression, an effect consistently observed both in vitro and in vivo. The efficacy of DA in reversing the endocrine and metabolic abnormalities of the letrozole-induced PCOS rat model are promising, raising the possibility that diets including DA could be beneficial for the management of both hyperandrogenism and insulin resistance in PCOS.

Antimüllerian hormone, antral follicle count and ovarian volume predict menstrual cycle length in healthy women.

OBJECTIVE: Although menstrual cycle length is one of the main concerns of women and may have important health consequences, little is known about its predictors. The aim of this study was to identify predictors of menstrual cycle length variability in healthy women. DESIGN: Prospective cross-sectional study. PATIENTS: Two hundred healthy women aged 21-45. MEASUREMENTS: A questionnaire was administered to determine lifestyle factors. Ovarian parameters, metabolic parameters, pituitary hormones, sex steroids and antimüllerian hormone (AMH) were measured. RESULTS: Women with long (≥35 days) and normal (25-34 days) menstrual cycles had >5-fold and >2-fold higher serum AMH levels, respectively, compared to those with short cycles (<25 days). Menstrual cycle length was associated with age but not lifestyle factors. Only one factor group (AMH, antral follicle count [AFC], ovarian volume, testosterone and LH) was significantly associated with menstrual cycle length. Within this factor group, only the ovarian parameters (AMH, AFC, ovarian volume) predicted menstrual cycle length. Each SD increase in AMH (32·9 pmol/l) and ovarian volume (2·29 cm(3) ) was associated with 2·80-fold (95% CI: 1·67-4·69) and 1·62-fold (95% CI: 1·08-2·43) increased risks, respectively, for longer menstrual cycles. CONCLUSIONS: AMH, AFC and ovarian volume are positively associated with menstrual cycle length in healthy women. Our identification of AMH as an independent predictor of menstrual cycle length puts forth a new notion of utilizing menstrual cycle length to predict possible AMH-dependent/-associated outcomes. In addition, this novel relationship may facilitate the interpretation of AMH levels and its clinico-pathological significance across different centres.