The effect of metformin treatment in vivo on acute and long-term energy metabolism and progesterone production in vitro by granulosa cells from women with polycystic ovary syndrome

STUDY QUESTION What are the consequences of polycystic ovary syndrome (PCOS) pathology and metformin-pretreatment in vivo in women with PCOS on the metabolism and steroid production of follicular phenotype- and long-term cultured-granulosa cells (GC)? SUMMARY ANSWER PCOS pathology significantly comp...

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Published in:	Human reproduction (Oxford) 2014-10, Vol.29 (10), p.2302-2316
Main Authors:	Maruthini, D, Harris, S.E, Barth, J.H, Balen, A.H, Campbell, B.K, Picton, H.M
Format:	Article
Language:	eng
Subjects:	Adult Case-Control Studies Cell Proliferation - drug effects Cells, Cultured Female Follicular Fluid - metabolism Glucose - metabolism Granulosa Cells - drug effects Granulosa Cells - metabolism Humans Insulin - metabolism Lactic Acid - biosynthesis Metformin - pharmacology Metformin - therapeutic use Original Ovarian Follicle - anatomy & histology Ovarian Follicle - drug effects Ovarian Follicle - metabolism Polycystic Ovary Syndrome - drug therapy Polycystic Ovary Syndrome - metabolism Polycystic Ovary Syndrome - pathology Progesterone - biosynthesis Pyruvic Acid - metabolism
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Summary:	STUDY QUESTION What are the consequences of polycystic ovary syndrome (PCOS) pathology and metformin-pretreatment in vivo in women with PCOS on the metabolism and steroid production of follicular phenotype- and long-term cultured-granulosa cells (GC)? SUMMARY ANSWER PCOS pathology significantly compromised glucose metabolism and the progesterone synthetic capacity of follicular- and long-term cultured-GCs and the metabolic impact of PCOS on GC function was alleviated by metformin-pretreatment in vivo. WHAT IS KNOWN ALREADY Granulosa cells from women with PCOS have been shown to have an impaired insulin-stimulated glucose uptake and lactate production in vitro. However, these results were obtained by placing GCs in unphysiological conditions in culture medium containing high glucose and insulin concentrations. Moreover, existing data on insulin-responsive steroid production in vitro by PCOS GCs vary. STUDY DESIGN, SIZE AND DURATION Case-control experimental research comparing glucose uptake, pyruvate and lactate production and progesterone production in vitro by GCs from three aetiological groups, all undergoing IVF; healthy control women (Control, n = 12), women with PCOS treated with metformin in vivo (Metformin, n = 8) and women with PCOS not exposed to metformin (PCOS, n = 8). The study was conducted over a period of 3 years between 2007 and 2010. PARTICIPANTS/MATERIALS, SETTING, METHODS Rotterdam criteria were used for the diagnosis of PCOS; all subjects were matched for age, BMI and baseline FSH. Individual patient cultures were undertaken with cells incubated in a validated, physiological, serum-free culture medium containing doses of 0–6 mM glucose and 0–100 ng/ml insulin for 6 h and 144 h to quantify the impact of treatments on acute and long-term metabolism, respectively, and progesterone production. The metabolite content of spent media was measured using spectrophotometric plate reader assay. The progesterone content of spent media was measured by enzyme-linked immunosorbent assay. Viable GC number was quantified after 144 h of culture by the vital dye Neutral Red uptake assay. MAIN RESULTS AND THE ROLE OF CHANCE Granulosa cells from women with PCOS pathology revealed reduced pyruvate production and preferential lactate production in addition to their reduced glucose uptake during cultures (P < 0.05). Metformin pretreatment alleviated this metabolic lesion (P < 0.05) and enhanced cell proliferation in vitro (P < 0.05), but cells retained a signi
ISSN:	0268-1161 1460-2350