Polycystic ovarian syndrome: a second-take on flutamide

In this month’s Fertility and Sterility, Dumesic et al. (1Dumesic D.A. Winnett C. Lu G. Randomized clinical trial: effect of low-dose flutamide on abdominal adipogenic function in normal-weight polycystic ovary syndrome women.Fertil Steril. 2023; 119: 116-126Abstract Full Text Full Text PDF Scopus (3) Google Scholar) published their findings from a randomized controlled trial about the effect of low dose flutamide on abdominal adipocyte function in women with polycystic ovarian syndrome (PCOS). Polycystic ovarian syndrome is the most common endocrinopathy diagnosed in females that increases the lifelong risk of developing diabetes and cardiovascular disease. Although reproductive and gynecologic concerns are usually addressed with prescriptions of hormonal contraceptives or agents for ovulation induction, the lifelong consequences of PCOS are poorly understood; therefore, the other clinical sequalae of the disease may be neglected. Dumesic et al. (1Dumesic D.A. Winnett C. Lu G. Randomized clinical trial: effect of low-dose flutamide on abdominal adipogenic function in normal-weight polycystic ovary syndrome women.Fertil Steril. 2023; 119: 116-126Abstract Full Text Full Text PDF Scopus (3) Google Scholar) examined whether the actions of flutamide, an androgen receptor blocker, may be of use in combating processes of lipid accumulation which likely contribute to the development of metabolic diseases that so often plagues these patients throughout their life. This pilot study included 12 women diagnosed with PCOS, based on the National Institutes of Health criteria, who were randomized to receive either placebo or flutamide for a duration of 6 months. The use of National Institutes of Health-defined criteria by the investigators identifies women with the highest risk of developing metabolic disorders. Women with PCOS were also matched to controls to ensure that the study population included women with characteristics unique to PCOS (increased androgens and adiposity) despite similar age and normal body mass index. Including only women with a normal body mass index may capture the “low risk” patients with PCOS that are not often encountered (and perhaps misdiagnosed) in the clinical practice. Even in this population of normal weight women with PCOS, flutamide decreased abdominal fat deposition and lowered low-density lipoprotein without differences in luteinizing hormone and androgen levels among the placebo and treatment groups. Intriguingly, the actions of flutamide were not necessarily tied to the changes in systemic androgen levels. A previous study found that flutamide improved lipid profiles in women with PCOS regardless of obesity and Dumesic et al. (1Dumesic D.A. Winnett C. Lu G. Randomized clinical trial: effect of low-dose flutamide on abdominal adipogenic function in normal-weight polycystic ovary syndrome women.Fertil Steril. 2023; 119: 116-126Abstract Full Text Full Text PDF Scopus (3) Google Scholar) provides a possible mechanism of its action in the patient with PCOS and exposes a pathway that can be potentially manipulated to prevent metabolic disease (2Diamanti-Kandarakis E. Mitrakou A. Raptis S. Tolis G. Duleba A.J. The effect of a pure antiandrogen receptor blocker, flutamide, on the lipid profile in the polycystic ovary syndrome.J Clin Endocrinol Metab. 1998; 83: 2699-2705Crossref PubMed Scopus (138) Google Scholar). Of course, this adds an additional narrative to the story but, as always with PCOS, we are still left searching for more information. Now this study does not provide evidence that flutamide should be prescribed to the patients with PCOS to decrease cardiovascular disease but does encourage more research of its kind. The main limitation is the small number of participants. In addition, the long-term safety of flutamide is also in question owing to the risk of hepatotoxicity and teratogenicity. What it should be is a springboard for future studies: PCOS deserves more attention to the whole spectrum of the disease and not just the reproductive manifestations. The pathogenesis of PCOS has always been a case of which came first- the chicken or the egg? We accept the fact that insulin resistance and androgen excess are the main culprits; however, genetics and environment are also contributors to this complex endocrinopathy. Because cardiovascular disease is the number one cause of morbidity and mortality in women, further understanding of this high-risk population will provide opportunities in the future to improve their long-term health and decrease future diagnoses of hypertension, diabetes, and hyperlipidemia. Our protocol for initiating treatment in patients is still rather old-fashioned. Physicians promote healthy habits (of course); however, preventive medicine is really the key. Investigating how we can reverse critical pathways that lead to disease progression should be of critical importance. In addition, Black women with PCOS are at an increased risk of metabolic syndrome and cardiovascular disease compared with White woman and so future studies are needed that are inclusive of all populations (3Hillman J.K. Johnson N.C. Limaye M. Feldman R.A. Sammel M. Dokras A. Black women with polycystic ovarian syndrome (PCOS) have increased risk for metabolic syndrome and cardiovascular disease compared with white women with PCOS.Fertil Steril. 2013; 2: 530-535Google Scholar). In the future, women with PCOS may have more therapeutic options to decrease the risk of metabolic diseases and physicians will hopefully have a better understanding of the endocrine disease they encounter most commonly in clinical practice. Randomized clinical trial: effect of low-dose flutamide on abdominal adipogenic function in normal-weight women with polycystic ovary syndromeFertility and SterilityVol. 119Issue 1PreviewTo examine whether low-dose flutamide administration to normal-weight women with polycystic ovary syndrome (PCOS) reduces abdominal fat deposition, attenuates accelerated lipid accumulation in newly formed adipocytes derived from subcutaneous (SC) abdominal adipose stem cells (ASCs), and/or alters glucose-lipid metabolism. Full-Text PDF Open Access