piperidines and Hyperandrogenism

Animal studies suggest that cannabinoid receptor-1 (CB-1) blockade reduces inflammation and neovascularization by decreasing vascular endothelial growth factor (VEGF) levels associated with a reduction in inflammatory markers, thereby potentially reducing cardiovascular risk.. To determine the impact of CB1 antagonism by rimonabant on VEGF and inflammatory markers in obese PCOS women.. Randomized, open-labelled parallel study.. Endocrinology outpatient clinic in a referral centre.. Twenty patients with PCOS (PCOS) and biochemical hyperandrogenaemia with a body mass index of ≥30 kg/m. Post hoc review to detect VEGF and pro-inflammatory cytokines TNF-α, IL-1β, IL-1ra, IL-2, IL6, IL-8, IL-10 and MCP-1 before and after 12 weeks of treatment.. After 12 weeks of rimonabant treatment, there was a significant increase in VEGF (99·2 ± 17·6 vs 116·2 ± 15·8 pg/ml, P < 0·01) and IL-8 (7·4 ± 11·0 vs 18·1 ± 13·2 pg/ml, P < 0·05) but not after metformin (VEGF P = 0·7; IL-8 P = 0·9). There was no significant difference in the pro-inflammatory cytokines TNF-α, IL-1β, IL-1ra, IL-2, IL6, IL-8, IL-10 and MCP-1 following either treatment.. This study suggests that rimonabant CB-I blockade paradoxically raised VEGF and the cytokine IL-8 in obese women with PCOS that may have offset the potential benefit associated with weight loss.

Topics: Biomarkers; Cannabinoid Receptor Antagonists; Cytokines; Female; Humans; Hyperandrogenism; Inflammation; Interleukin-8; Metformin; Obesity; Piperidines; Polycystic Ovary Syndrome; Pyrazoles; Rimonabant; Vascular Endothelial Growth Factor A; Weight Loss

Weight loss and metformin therapy are reported to be beneficial in improving the biochemical hyperandrogenaemia and insulin resistance of polycystic ovary syndrome (PCOS). Rimonabant has been found to reduce weight and improve the metabolic profile in patients with obesity, type 2 diabetes and metabolic syndrome.. To compare the effects of insulin sensitization with metformin to weight reduction by rimonabant on biochemical hyperandrogenaemia and insulin resistance in patients with PCOS.. A randomized, open-label parallel study.. Endocrinology outpatient clinic in a referral centre.. Twenty patients with PCOS and biochemical hyperandrogenaemia with a body mass index (BMI) >or= 30 kg/m(2) were recruited.. Patients were randomized to 1.5 g daily of metformin or 20 mg daily of rimonabant.. The primary end-point of the study was a change in total testosterone.. After 12 weeks of rimonabant there was a significant reduction (mean +/- SEM) in weight (104.6 +/- 4.6 vs. 98.4 +/- 4.7 kg, P < 0.01), waist circumference (116.0 +/- 3.3 vs. 109.2 +/- 3.7 cm, P < 0.01), hip circumference (128.5 +/- 4.0 vs. 124.1 +/- 4.2 cm, P < 0.03), waist-hip ratio (0.90 +/- 0.02 vs. 0.88 +/- 0.01, P < 0.01) free androgen index (FAI) (26.6 +/- 6.1 vs. 16.6 +/- 4.1, P < 0.01), testosterone [4.6 +/- 0.4 vs. 3.1 +/- 0.3 nmol/l (132.7 +/- 11.5 vs. 89.4 +/- 8.65 ng/dl), P < 0.01] and insulin resistance as measured by the homeostasis model assessment (HOMA) method (4.4 +/- 0.5 vs. 3.4 +/- 0.4, P = 0.05). There was no change in any of these parameters in the metformin-treated group.. This study suggests that the weight loss through rimonabant therapy may be of use in patients with PCOS and appears superior to insulin sensitization by metformin in reducing the FAI and insulin resistance in obese PCOS patients treated over a 12-week period.

Topics: Adult; Female; Humans; Hyperandrogenism; Insulin Resistance; Metformin; Piperidines; Polycystic Ovary Syndrome; Pyrazoles; Rimonabant; Testosterone; Weight Loss

Polycystic ovary syndrome is a common reproductive disorder in the female of reproductive age, which is characterized by hyperandrogenism, insulin resistance, cystic ovary and infertility. The level of pro-inflammatory adipokine, visfatin is elevated in PCOS conditions in human and animal. In this study, letrozole induced hyperandrogenised PCOS mice model have been used to unravel the effects of visfatin inhibition. The results showed that letrozole induced hyperandrogenisation significantly (p < 0.05) elevates ovarian visfatin concentration from 66.03 ± 1.77 to 112.08 ± 3.7 ng/ml, and visfatin expression to 2.5 fold (p < 0.05) compared to control. Visfatin inhibition in PCOS by FK866 has significantly (p < 0.05) suppressed the secretion of androgens, androstenedione (from 0.329 ± 0.07 to 0.097 ± 0.01 ng/ml) and testosterone levels (from 0.045 ± 0.003 to 0.014 ± 0.0009 ng/ml). Ovarian histology showed that visfatin inhibition suppressed cyst formation and promotes corpus luteum formation. Visfatin inhibition has suppressed apoptosis and increases the expression of BCL2 along with increase in the proliferation (GCNA expression elevated). Visfatin inhibition has increased ovarian glucose content (from 167.05 ± 8.5 to 210 ± 7 mg/dl), along with increase in ovarian GLUT8 expression. In vitro study has also supported the in vivo findings where FK866 treatment significantly (p < 0.05) suppressed testosterone (control-3.84 ± 0.44 ng/ml, 1 nM FK866-2.02 ± 0.048 ng/ml, 10 nM FK866-1.74 ± 0.20 ng/ml) and androstenedione (control-4.68 ± 0.91 ng/ml, 1 nM FK866-3.38 ± 0.27 ng/ml, 10 nM FK866-4.55 ± 0.83 ng/ml) production from PCOS ovary. In conclusion, this is first report, which showed that visfatin inhibition by FK866 in hyperandrogenised mice ameliorates pathogenesis of PCOS. Thus, it may be suggested that visfatin inhibition could have a therapeutic potential in PCOS management along with other intervention.

Topics: Acrylamides; Androgens; Animals; Blood Glucose; Cytokines; Disease Models, Animal; Female; Hyperandrogenism; Insulin Resistance; Letrozole; Mice; Nicotinamide Phosphoribosyltransferase; Piperidines; Polycystic Ovary Syndrome