María L Sánchez-Ferrer1,2, Jaime Mendiola2,3,4, Ana I Hernández-Peñalver1, Shiana Corbalán-Biyang1, Ana Carmona-Barnosi1, María T Prieto-Sánchez1,2, Aníbal Nieto1,2, Alberto M Torres-Cantero2,3,4,5. 1. Department of Obstetrics and Gynecology, 'Virgen de la Arrixaca' University Clinical Hospital, 30120 El Palmar (Murcia), Spain. 2. Institute for Biomedical Research of Murcia, IMIB-Arrixaca, 30120 El Palmar (Murcia), Spain. 3. Division of Preventive Medicine and Public Health, Department of Public Health Sciences, University of Murcia School of Medicine, 30100 Espinardo (Murcia), Spain. 4. CIBER Epidemiología y Salud Pública (CIBERESP), Instituto de Salud Carlos III, 28029 Madrid, Spain. 5. Department of Preventive Medicine, 'Virgen de la Arrixaca' University Clinical Hospital, 30120 El Palmar (Murcia), Spain.
Abstract
STUDY QUESTION: Is polycystic ovary syndrome (PCOS) associated with anogenital distance (AGD), a biomarker of fetal androgen exposure, in adult Mediterranean women? SUMMARY ANSWER: Longer AGD is associated with PCOS in adult Mediterranean women. WHAT IS KNOWN ALREADY: AGD is a biomarker of prenatal androgen milieu. Human observational studies have reported that associations between AGD and reproductive parameters in both sexes. Exposure of the female fetus to intrauterine androgens may be a risk factor for PCOS in adulthood. STUDY DESIGN, SIZE, DURATION: This was a case-control study of 126 women with PCOS and 159 controls between September 2014 and May 2016. PARTICIPANTS/MATERIALS, SETTING, METHODS: Cases were attending the gynecology unit of the 'Virgen de la Arrixaca' University Clinical Hospital (Murcia, Spain), and were diagnosed following the Rotterdam criteria. Phenotypic subtypes of PCOS were also assessed. Both prevalent and incident (newly diagnosed) cases were included. Controls were women without PCOS attending the gynecological outpatient clinic for routine gynecological exams. All women completed health questionnaires, and underwent physical and gynecological examinations, including transvaginal ultrasound and blood draw. We obtained measures from the anterior clitoral surface to the upper verge of the anus (AGDAC), and from the posterior fourchette to the upper verge of the anus (AGDAF). Gynecologists performing the AGD measures were blind to the status of the patients. We used unconditional multiple logistic regression to evaluate the association between AGD measurements and PCOS while accounting for relevant covariates and confounders, such as BMI, age and episiotomy. MAIN RESULTS AND THE ROLE OF CHANCE: Cases showed significantly longer AGDAF and AGDAC compared to controls in bivariate analyses (P-values < 0.05). In the final adjusted models, AGDAC, but not AGDAF, was associated with the presence of PCOS (P-values = 0.002-0.008). Women with AGDAC in the upper compared to the lowest tertile were 2.9-times (95% CI 1.4-5.9; P-trend = 0.008) more likely to have PCOS. AGDAC measures were also significantly associated with all of the different phenotypic subtypes of PCOS (ORs = 3.1-5.1; P-values < 0.05). LIMITATIONS REASONS FOR CAUTION: We took into account known and suspected covariates and confounders, but the possibility of chance findings or residual confounding should be noted. As with all observational studies, causal inference is limited, and study selection and information bias should not be ruled out. WIDER IMPLICATIONS OF THE FINDINGS: Our results support the hypothesis that PCOS has an intrauterine origin, and that the hormonal environment in which the fetus develops may be highly relevant. STUDY FUNDING/COMPETING INTEREST: This work was supported by the Ministry of Economy and Competitiveness, Instituto de Salud Carlos III (ISCIII) (AES, Acción Estratégica en Salud), grant No. PI13/01237, and The Seneca Foundation, Murcia Regional Agency of Science and Technology, grant No. 19443/PI/14. There are no competing interests. TRIAL REGISTRATION NUMBER: Not applicable.
STUDY QUESTION: Is polycystic ovary syndrome (PCOS) associated with anogenital distance (AGD), a biomarker of fetal androgen exposure, in adult Mediterranean women? SUMMARY ANSWER: Longer AGD is associated with PCOS in adult Mediterranean women. WHAT IS KNOWN ALREADY: AGD is a biomarker of prenatal androgen milieu. Human observational studies have reported that associations between AGD and reproductive parameters in both sexes. Exposure of the female fetus to intrauterine androgens may be a risk factor for PCOS in adulthood. STUDY DESIGN, SIZE, DURATION: This was a case-control study of 126 women with PCOS and 159 controls between September 2014 and May 2016. PARTICIPANTS/MATERIALS, SETTING, METHODS: Cases were attending the gynecology unit of the 'Virgen de la Arrixaca' University Clinical Hospital (Murcia, Spain), and were diagnosed following the Rotterdam criteria. Phenotypic subtypes of PCOS were also assessed. Both prevalent and incident (newly diagnosed) cases were included. Controls were women without PCOS attending the gynecological outpatient clinic for routine gynecological exams. All women completed health questionnaires, and underwent physical and gynecological examinations, including transvaginal ultrasound and blood draw. We obtained measures from the anterior clitoral surface to the upper verge of the anus (AGDAC), and from the posterior fourchette to the upper verge of the anus (AGDAF). Gynecologists performing the AGD measures were blind to the status of the patients. We used unconditional multiple logistic regression to evaluate the association between AGD measurements and PCOS while accounting for relevant covariates and confounders, such as BMI, age and episiotomy. MAIN RESULTS AND THE ROLE OF CHANCE: Cases showed significantly longer AGDAF and AGDAC compared to controls in bivariate analyses (P-values < 0.05). In the final adjusted models, AGDAC, but not AGDAF, was associated with the presence of PCOS (P-values = 0.002-0.008). Women with AGDAC in the upper compared to the lowest tertile were 2.9-times (95% CI 1.4-5.9; P-trend = 0.008) more likely to have PCOS. AGDAC measures were also significantly associated with all of the different phenotypic subtypes of PCOS (ORs = 3.1-5.1; P-values < 0.05). LIMITATIONS REASONS FOR CAUTION: We took into account known and suspected covariates and confounders, but the possibility of chance findings or residual confounding should be noted. As with all observational studies, causal inference is limited, and study selection and information bias should not be ruled out. WIDER IMPLICATIONS OF THE FINDINGS: Our results support the hypothesis that PCOS has an intrauterine origin, and that the hormonal environment in which the fetus develops may be highly relevant. STUDY FUNDING/COMPETING INTEREST: This work was supported by the Ministry of Economy and Competitiveness, Instituto de Salud Carlos III (ISCIII) (AES, Acción Estratégica en Salud), grant No. PI13/01237, and The Seneca Foundation, Murcia Regional Agency of Science and Technology, grant No. 19443/PI/14. There are no competing interests. TRIAL REGISTRATION NUMBER: Not applicable.
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