No abstract

Decreased total L-carnitine levels may be associated with hyperandrogenism and/or insulin resistance in non-obese women with PCOS. Long-term studies are needed to evaluate carnitine metabolism in PCOS, especially with regard to the molecular basis.

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The opposing actions of estrogen and progesterone during the menstrual cycle regulate the cyclical and predictable endometrial proliferation and differentiation that is required for implantation. Progesterone indirectly stimulates the expression of 17beta hydroxysteroid dehydrogenase type 2 (HSD17B2), which catalyzes the conversion of biologically potent estradiol to weakly estrogenic estrone in the endometrial epithelium. We previously demonstrated upregulation of the HSD17B2 gene in human endometrial epithelial cells by factors secreted from endometrial stromal cells in response to progesterone. We investigated the underlying mechanism by which these stroma-derived, progesterone-induced paracrine factors stimulate HSD17B2 expression. Here, we show that transcription factors SP1 and SP3 interact with specific motifs in HSD17B2 promoter to upregulate enzyme expression in human endometrial epithelial cell lines. Conditioned medium (CM) from progestin-treated stromal cells increased levels of SP1 and SP3 in endometrial epithelial cells and induced HSD17B2 mRNA expression. Mithramycin A, an inhibitor of SP1-DNA interaction, reduced epithelial HSD17B2 promoter activity in a dose-dependent manner. Serial deletion and site-directed mutants of the HSD17B2 promoter demonstrated that two overlapping SP1 motifs (nt -82/-65) are essential for induction of promoter activity by CM or overexpression of SP1/SP3. CM markedly enhanced, whereas anti-SP1/SP3 antibodies inhibited, binding of nuclear proteins to this region of the HSD17B2 promoter. In vivo, we demonstrated a significant spatiotemporal association between epithelial SP1/SP3 and HSD17B2 levels in human endometrial biopsies. Taken together, these data suggest that HSD17B2 expression in endometrial epithelial cells, and, therefore, estrogen inactivation, is regulated by SP1 and SP3, which are downstream targets of progesterone-dependent paracrine signals originating from endometrial stromal cells.

This study was designed to determine serum Fetuin-A levels and establish whether serum Fetuin-A level is related with insulin resistance, oxidative stress, ovarian hyperandrogenism and dyslipidemia in women with polycystic ovary syndrome (PCOS). Twenty-two patients with PCOS and twenty-one healthy control women were evaluated in this controlled clinical study. Serum Fetuin-A, lipid fractions, glucose, insulin, malondialdehyde (MDA), myeloperoxidase (MPO), glutathione (GSH), superoxide dismutase (SOD) and other hormone (gonadotropins, androgens) levels were measured. The estimate of insulin resistance was calculated by homeostasis model assessment (HOMA-R). The women with PCOS had significantly higher serum fasting glucose, insulin, luteinizing hormone (LH), MDA, Fetuin-A levels, and LH/follicle-stimulating hormone (FSH) ratio, free androgen index (FAI), HOMA-IR than healthy women. However, sex hormone-binding globulin (SHBG) and GSH levels were significantly lower in patients with PCOS compared with controls. Fetuin-A was positively correlated with insulin, HOMA-IR and FAI. Multiple regression analysis revealed that FAI was strong predictor of serum Fetuin-A level. Serum Fetuin-A level was related with insulin resistance and ovarian hyperandrogenism in women with PCOS. These results suggest that Fetuin-A may have a role in triggering the processes leading to insulin resistance and androgen excess in PCOS.