Mina Amiri1, Fatemeh Nahidi2, Razieh Bidhendi-Yarandi1,3, Davood Khalili4, Maryam Tohidi4, Fahimeh Ramezani Tehrani1. 1. Reproductive Endocrinology Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran. 2. Department of Midwifery and Reproductive Health, Faculty of Nursing and Midwifery, Shahid Beheshti University of Medical Sciences, Tehran, Iran. 3. School of Public Health, Department of Epidemiology and biostatistics, Tehran University of Medical Sciences, Tehran, Iran. 4. Prevention of Metabolic Disorders Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University, Tehran, Iran.
Abstract
STUDY QUESTION: Do oral contraceptives (OCs) containing progestins with low androgenic or antiandrogenic activities have different effects to those containing levonorgestrel (LNG) on clinical, androgenic and metabolic manifestations of polycystic ovarian syndrome (PCOS)? SUMMARY ANSWER: The three OCs tested had similar effects on clinical findings of hyperandrogenism (HA), whereas products containing LNG were less effective on androgenic profiles and had detrimental effects on lipid profiles. WHAT IS KNOWN ALREADY: Despite data available on the effects of OCs, the superiority of products with low androgenic or antiandrogenic progesterone components in comparison with older products used in women with PCOS has not been clarified. STUDY DESIGN, SIZE, DURATION: This study is a crossover randomized controlled six-arm trial, with all six arms including two 6-month treatment periods, one period with OCs containing LNG, and the other with one of three OCs containing desogestrel (DSG), cyproterone acetate (CPA) or drospirenone (DRSP). The trial was conducted between February 2016 and January 2018 and enrolled 200 patients with PCOS. PARTICIPANTS/MATERIALS, SETTING, METHODS: Two hundred women with PCOS (ages 18-45 years) were recruited at the endocrine outpatient clinic of the Research Institute for Endocrine Sciences (RIES) of the Shahid Beheshti University of Medical Sciences, Tehran, Iran. A blocking or stratification random allocation (block size = 6) using a computer-based random number generator was prepared to assign participants to treatment groups. Both the clinical examiner and data analyst were blinded to participants during the trial. Outcomes of interest, including anthropometric and clinical manifestations and hormonal, and biochemical parameters were assessed at baseline, after 3 and 6 months of each treatment and after the washout period. MAIN RESULTS AND THE ROLE OF CHANCE: This study detected a higher decrease in free-androgen index (FAI) levels after 3 months of treatment with OCs containing DSG (95% CI: -2.3, -1.0), CPA (95% CI: -2.4, -1.1) and DRSP (95% CI: -2.6, -1.4), compared with products containing LNG (P < 0.001). Use of OCs containing DSG (95% CI: -3.6, -1.5), CPA (95% CI: -3.1, -0.8) and DRSP (95% CI: -3.4, -1.1) for 6 months was associated with more decrease in FAI, compared with products containing LNG (P < 0.001). The study showed that use of OCs containing DSG, CPA and DRSP for 3-6 months was associated with a higher increase of sex hormone-binding globulin (SHBG), compared with products containing LNG (P < 0.001). We also observed more decrease in dehydroepiandrosterone sulfate levels after use of OCs containing DSG (P = 0.003), CPA (P = 0.012) and DRSP (P < 0.001) for 6 months, compared with products containing LNG. Our results showed that the use of OCs containing DRSP for 6 months was associated with more improvement in acne, compared with products containing LNG (P = 0.007). Women treated with OCs containing CPA, and DRSP for 3 months had higher TG and HDL levels and lower LDL levels, compared with those treated with products containing LNG (P < 0.05). After 6 months of treatment, patients treated with OCs containing DRSP had a sharper decline in LDL levels and more increase in HDL levels, compared to those treated with products containing LNG (P = 0.001). LIMITATIONS, REASONS FOR CAUTION: Considering this trial was conducted in women diagnosed with Androgen Excess Society criteria, the results may not be generalizable for mild phenotypes diagnosed using Rotterdam criteria. Other limitations of the study include the high dropout rate, the lack of a gold standard androgen assay and the multiple end points. WIDER IMPLICATIONS OF THE FINDINGS: Our results support the views of clinicians, who suggest an OC with a low androgenic or antiandrogenic progestin, if available, to treat PCOS. STUDY FUNDING/COMPETING INTEREST(S): This study was supported by the RIES, Shahid Beheshti University of Medical Sciences, Tehran, Iran. There are no conflicts of interest. TRIAL REGISTRATION NUMBER: IRCT201702071281N2. TRIAL REGISTRATION DATE: 21 February 2017. DATE OF FIRST PATIENT’S ENROLMENT: 21 March 2017.
STUDY QUESTION: Do oral contraceptives (OCs) containing progestins with low androgenic or antiandrogenic activities have different effects to those containing levonorgestrel (LNG) on clinical, androgenic and metabolic manifestations of polycystic ovarian syndrome (PCOS)? SUMMARY ANSWER: The three OCs tested had similar effects on clinical findings of hyperandrogenism (HA), whereas products containing LNG were less effective on androgenic profiles and had detrimental effects on lipid profiles. WHAT IS KNOWN ALREADY: Despite data available on the effects of OCs, the superiority of products with low androgenic or antiandrogenic progesterone components in comparison with older products used in women with PCOS has not been clarified. STUDY DESIGN, SIZE, DURATION: This study is a crossover randomized controlled six-arm trial, with all six arms including two 6-month treatment periods, one period with OCs containing LNG, and the other with one of three OCs containing desogestrel (DSG), cyproterone acetate (CPA) or drospirenone (DRSP). The trial was conducted between February 2016 and January 2018 and enrolled 200 patients with PCOS. PARTICIPANTS/MATERIALS, SETTING, METHODS: Two hundred women with PCOS (ages 18-45 years) were recruited at the endocrine outpatient clinic of the Research Institute for Endocrine Sciences (RIES) of the Shahid Beheshti University of Medical Sciences, Tehran, Iran. A blocking or stratification random allocation (block size = 6) using a computer-based random number generator was prepared to assign participants to treatment groups. Both the clinical examiner and data analyst were blinded to participants during the trial. Outcomes of interest, including anthropometric and clinical manifestations and hormonal, and biochemical parameters were assessed at baseline, after 3 and 6 months of each treatment and after the washout period. MAIN RESULTS AND THE ROLE OF CHANCE: This study detected a higher decrease in free-androgen index (FAI) levels after 3 months of treatment with OCs containing DSG (95% CI: -2.3, -1.0), CPA (95% CI: -2.4, -1.1) and DRSP (95% CI: -2.6, -1.4), compared with products containing LNG (P < 0.001). Use of OCs containing DSG (95% CI: -3.6, -1.5), CPA (95% CI: -3.1, -0.8) and DRSP (95% CI: -3.4, -1.1) for 6 months was associated with more decrease in FAI, compared with products containing LNG (P < 0.001). The study showed that use of OCs containing DSG, CPA and DRSP for 3-6 months was associated with a higher increase of sex hormone-binding globulin (SHBG), compared with products containing LNG (P < 0.001). We also observed more decrease in dehydroepiandrosterone sulfate levels after use of OCs containing DSG (P = 0.003), CPA (P = 0.012) and DRSP (P < 0.001) for 6 months, compared with products containing LNG. Our results showed that the use of OCs containing DRSP for 6 months was associated with more improvement in acne, compared with products containing LNG (P = 0.007). Women treated with OCs containing CPA, and DRSP for 3 months had higher TG and HDL levels and lower LDL levels, compared with those treated with products containing LNG (P < 0.05). After 6 months of treatment, patients treated with OCs containing DRSP had a sharper decline in LDL levels and more increase in HDL levels, compared to those treated with products containing LNG (P = 0.001). LIMITATIONS, REASONS FOR CAUTION: Considering this trial was conducted in women diagnosed with Androgen Excess Society criteria, the results may not be generalizable for mild phenotypes diagnosed using Rotterdam criteria. Other limitations of the study include the high dropout rate, the lack of a gold standard androgen assay and the multiple end points. WIDER IMPLICATIONS OF THE FINDINGS: Our results support the views of clinicians, who suggest an OC with a low androgenic or antiandrogenic progestin, if available, to treat PCOS. STUDY FUNDING/COMPETING INTEREST(S): This study was supported by the RIES, Shahid Beheshti University of Medical Sciences, Tehran, Iran. There are no conflicts of interest. TRIAL REGISTRATION NUMBER: IRCT201702071281N2. TRIAL REGISTRATION DATE: 21 February 2017. DATE OF FIRST PATIENT’S ENROLMENT: 21 March 2017.
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