Flutamide-Metformin plus Ethinylestradiol-Drospirenone for Lipolysis and Antiatherogenesis in Young Women with Ovarian Hyperandrogenism: The Key Role of Metformin at the Start and after More than One Year of Therapy

Abstract

Flutamide (Flu)-metformin (Met) with ethinylestradiol-drospirenone is a combination therapy that reduces the total and abdominal fat excess, diminishes the lean mass deficit, and attenuates the dysadipocytokinemia of young and nonobese women with ovarian hyperandrogenism, a variant of polycystic ovary syndrome. We have now questioned the need: 1) to add Met at the start of Flu plus ethinylestradiol-drospirenone; and 2) to maintain Met after more than 1 yr on full combination therapy. The additive effects of Met (850 mg/d) were assessed in studies A and B, over 3 months, in young patients with hyperinsulinemic hyperandrogenism. In study A, all participants [n = 31; age approximately 16 yr; body mass index approximately 22 kg/m(2)] started on Flu (62.5 mg/d) and an oral contraceptive (ethinyl-estradiol + drospirenone), and they were randomized to receive Met in addition or not. In study B, all participants (n = 42; age approximately 19 yr; body mass index approximately 22 kg/m(2)) had been treated with Flu-Met plus the same contraceptive for a mean duration of 17 months, and they were randomized for discontinuation of Met or not. Fasting blood glucose, serum insulin, testosterone, lipid profile, adiponectin, and IL-6 were determined at the start and after 3 months, together with body composition, by dual energy x-ray absorptiometry. The results of studies A and B complemented each other; the addition of Met was found to have consistently (more) normalizing effects on IL-6 and adiponectin, on lean mass (mean Met benefit of +1.2 kg in study A and +0.6 kg in study B), and in particular on abdominal fat excess [Met benefit of -0.7 kg (A) and -0.3 kg (B)]. In conclusion, Met proved to be a pivotal component of a prime combination therapy that attenuates the dysadipocytokinemia, the lean mass deficit, and the central adiposity of young patients with polycystic ovary syndrome.

Determinants of Interleukin-6 and C-Reactive Protein Vary in Polycystic Ovary Syndrome, as Do Effects of Short- and Long-Term Metformin Therapy

“…Finally, our results are in accordance with data from recent studies that have shown improvement in endothelial structure and function after metformin treatment in PCOS [22, 44, 45] and effects on inflammatory markers and adipokines in patients with PCOS [45,46,47], IGT [48] or T2DM [49,50,51] and metabolic syndrome [52]. In vitro studies have shown that the novel anti-inflammatory actions of metformin were probably attributed to the inhibition of cytokine-induced nuclear factor ĸB activation via the activation of AMPK [53, 54].…”

Circulating inflammatory markers in polycystic ovary syndrome: a systematic review and metaanalysis

“…An additional 16 studies were excluded for the following reasons: 1) Less than 25 PCOS patients were included in 8 studies (54,78,82,118,121,158,174,176); 2) No controls were included in 6 studies (126,143,154,160, 161,164); 3) Patients and controls were also included in ulterior extended series by the same authors in 1 study (178); 4) Serum IL-6 was measured in only 8 controls in 1 study (180). …”

Effect of metformin on serum interleukin-6 levels in polycystic ovary syndrome: a systematic review

“…The six remaining studies evaluated the effect of metformin on IL-6 levels in PCOS patients. One study was excluded because it did not meet the objective of the present systematic review; this study by Ibáñez et al [15] evaluated the influence of metformin combined with flutamide to IL-6 levels (Figure 1). …”