Síndrome del ovario poliquístico y factores de riesgo cardiovascular asociados. Modificación de los mismos tras el tratamiento con un sensibilizador de insulina, la metformina, o una combinación de etinilestradiol más acetato de ciproterona (Diane35 Diario) e influencia de la presencia de obesidad

Resum

Background: The polycystic ovary syndrome (PCOS) is a common and etiologically complex endocrine disorder of women. PCOS is characterized by hyperandrogenism and ovulatory dysfunction and, in a significant proportion of patients, by the presence of insulin resistance and obesity. Cardiovascular risk factors and subclinical atherosclerosis cluster in PCOS patients. The relative contribution of hyperandrogenism, insulin resistance and/or obesity, to the metabolic and cardiovascular abnormalities present in these women is still matter of intense debate. On the one hand, we have here aimed to delineate the metabolic and cardiovascular risk profile of PCOS women and, on the other hand, we have compared the effects of an antiandrogenic contraceptive pill with those of the insulin sensitizer drug metformin, on several biochemical markers and tests of cardiovascular performance. Objectives. 1) To determine the presence of classic and non-classic cardiovascular risk markers, as well as endothelial dysfunction and subclinical atherosclerosis, in PCOS patients compared with non-hyperandrogenic control women, while evaluating the impact of obesity, insulin resistance and hyperandrogenism on the associations observed. 2) To confirm the influence of insulin resistance and hyperandrogenism on these cardiovascular risk factors by antagonizing their effects by administering an insulin sensitizer drug, metformin, or an antiandrogenic contraceptive pill containing ethinyl estradiol plus cyproterone acetate, while evaluating the possible interference of obesity on the response to both drugs. Material and methods: Cross-sectional study: Forty unselected hyperandrogenic PCOS patients (age 25.6 ± 6.0 yr, 15 – 42 yr; body mass index 29.4 ± 6.3, range 18.8 – 47.5 kg/m2) diagnosed on the basis of the presence of clinical and/or biochemical hyperandrogenism, oligo-ovulation and exclusion of secondary aetiologies, were recruited. PCOS patients were compared with a control group composed by non-hyperandrogenic women (age 25.6 ± 6.0 yr, 13-38 yr; body mass index 29.4 ± 6.9, range 19.8 – 49.2 kg/m2) who had regular menstrual cycles every 26 – 34 days and who were selected in order to be similar in terms of age and body mass index with the patients. Patients and controls were submitted to a complete evaluation that included anthropometrical, laboratory and hormonal measurements, a 75g oral glucose tolerance test with measurement of serum insulin and plasma glucose every 30 minutes for 2 hours, an ambulatory monitoring of blood pressure during 24 hours, and Doppler sonography evaluation of endothelial dysfunction and of carotid intima-media thickness as a marker of subclinical atherosclerosis. Clinical Trial: Thirty-four of the 40 PCOS patients included in the case-control study agreed to articipate in a randomized controlled clinical trial addressing the effects of treatment with an antiandrogenic oral contraceptive compared with the insulin sensitizer metformin on many classic and non-classic cardiovascular risk factors evaluated in the former study. Patients were randomized to receive 35 µg of ethinyl-estradiol plus 2 mg of cyproterone acetate (Diane35 Diario) or 850 mg of metformin twice a day for 24 weeks, and were instructed to maintain a diet containing 25 – 30 Kcal per kg of body weight and day and moderate physical activity throughout the trial. The evaluation performed at baseline was repeated after 12 and 24 weeks of treatment. Results were evaluated by a repeated-measures general lineal model, introducing the changes observed along the study as within-subjects effect, and the arm of treatment as between-subjects effects. Results: Cross-sectional study: In our young PCOS women, obesity was the main determinant of abnormalities in glucose metabolism, dyslipidemia, hyperuricemia, and abnormalities of blood pressure, whereas the increased carotid intima-media thickness observed in PCOS women, which correlates with cardiovascular events in healthy general population, was directly related to androgen excess suggesting that hyperandrogenism also contributes to atherosclerosis and cardiovascular risk in these women. Patients were less insulin sensitive compared with non-hyperandrogenic controls, and had specific abnormalities in the physiological nocturnal decrease of blood pressure and laboratory findings suggestive of a subclinical proinflammatory and prothrombotic state. Nevertheless, all these abnormalities were boosted by the presence of obesity. Clinical trial: Diane35 Diario appears to be superior to metformin for the control of cutaneous signs and menstrual dysfunction independently of the grade of obesity. The tolerance of Diane35 Diario was excellent showing a safe cardiovascular profile; although it showed a minimal impact on glucose metabolism, Diane35 Diario improved the lipid profile, decreased serum uric acid levels, increased serum adiponectin concentrations, and even induced a small decrease in the carotid intima-media thickness of PCOS patients. Nevertheless, Diane35 Diario resulted in a mild increase of daytime blood pressure parameters and worsened several clotting tests. These facts should be considered when we prescribe contraceptive pills to these women. The administration of metformin induced only a mild improvement of hirsutism and restored menstrual regularity in less than 50% of patients yet this drug clearly outperforms Diane35 Diario in improving insulin resistance. Tolerance of metformin was poor. Of note, metformin resulted in a mild decrease of inflammation markers such as IL-6 and C-reactive protein in obese PCOS women, improved blood pressure parameters during daytime, and induced a significant reduction of ferritin concentrations. These beneficial effects should favour the use of metformin in PCOS patients who present with a personal or family history of abnormalities of glucose metabolism, high ferritin levels and /or hypertension. Conclusion: The cardiovascular risk associated with PCOS has a multifactorial origin, where obesity, insulin resistance and hyperandrogenemia contribute, some times in an independent manner, to the clustering of cardiovascular risk factors and markers of subclinical atherosclerosis present in PCOS women. Therefore, both antiandrogenic contraceptive pills and insulin sensitizers could be used in these women, and the choice of antiandrogenic oral contraceptives or insulin sensitizer must be tailored to meet the expectations of the individual PCOS patient, and her particular clinical characteristics.