{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T23:46:33Z","timestamp":1792194393800,"version":"4.4.0"},"reference-count":39,"publisher":"Oxford University Press (OUP)","issue":"5","license":[{"start":{"date-parts":[[2021,1,17]],"date-time":"2021-01-17T00:00:00Z","timestamp":1610841600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001505","name":"Health Research Council of New Zealand","doi-asserted-by":"publisher","award":["18-671"],"award-info":[{"award-number":["18-671"]}],"id":[{"id":"10.13039\/501100001505","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Swedish Society of Medicine and the Uppsala University Hospital"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2021,4,20]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>STUDY QUESTION<\/jats:title>\n                  <jats:p>Is anti-androgen treatment during adolescence associated with an improved probability of spontaneous conception leading to childbirth in women with polycystic ovary syndrome (PCOS)?<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>SUMMARY ANSWER<\/jats:title>\n                  <jats:p>Early initiation of anti-androgen treatment is associated with an increased probability of childbirth after spontaneous conception among women with PCOS.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>WHAT IS KNOWN ALREADY<\/jats:title>\n                  <jats:p>PCOS is the most common endocrinopathy affecting women of reproductive age. Hyperandrogenism and menstrual irregularities associated with PCOS typically emerge in early adolescence. Previous work indicates that diagnosis at an earlier age (&amp;lt;25\u2009years) is associated with higher fecundity compared to a later diagnosis.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>STUDY DESIGN, SIZE, DURATION<\/jats:title>\n                  <jats:p>This population-based study utilized five linked Swedish national registries. A total of 15\u00a0106 women with PCOS and 73\u00a0786 control women were included. Women were followed from when they turned 18\u2009years of age until the end of 2015, leading to a maximum follow-up of 10\u2009years. First childbirth after spontaneous conception was the main outcome, as identified from the Medical Birth Registry.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>PARTICIPANTS\/MATERIALS, SETTING, METHODS<\/jats:title>\n                  <jats:p>Participants included all women born between 1987 and 1996 with a diagnosis of PCOS in the Swedish Patient Registry and randomly selected non-PCOS controls (ratio 1:5). Information on anti-androgenic treatment was retrieved from the Swedish Prescribed Drug Registry with the use of Anatomic Therapeutic Chemical (ATC) codes. Women with PCOS who were not treated with any anti-androgenic medication were regarded as normo-androgenic, while those treated were regarded as hyperandrogenic. Women were further classified as being mildly hyperandrogenic if they received anti-androgenic combined oral contraceptive (aaCOC) monotherapy, or severely hyperandrogenic if they received other anti-androgens with or without aaCOCs. Early and late users comprised women with PCOS who started anti-androgenic treatment initiated either during adolescence (\u2264 18\u2009years of age) or after adolescence (&amp;gt;18\u2009years), respectively. The probability of first childbirth after spontaneous conception was analyzed with the use of Kaplan\u2013Meier hazard curve. The fecundity rate (FR) and 95% confidence interval for the time to first childbirth that were conceived spontaneously were calculated using Cox proportional hazards regression models, with adjustment for obesity, birth year, country of birth and education level.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>MAIN RESULTS AND THE ROLE OF CHANCE<\/jats:title>\n                  <jats:p>The probability of childbirth after spontaneous conception in the PCOS group compared to non-PCOS controls was 11% lower among normo-androgenic (adjusted FR 0.68 (95% CI 0.64\u20130.72)), and 40% lower among hyperandrogenic women with PCOS (adjusted FR 0.53 (95% CI 0.50\u20130.57)). FR was lowest among severely hyperandrogenic women with PCOS compared to normo-androgenic women with PCOS (adjusted FR 0.60 (95% CI 0.52\u20130.69)), followed by mildly hyperandrogenic women with PCOS (adjusted FR 0.84 (95% CI 0.77\u20130.93)). Compared to early anti-androgenic treatment users, late users exhibited a lower probability of childbirth after spontaneous conception (adjusted FR 0.79 (95% CI 0.68\u20130.92)).<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>LIMITATIONS, REASONS FOR CAUTION<\/jats:title>\n                  <jats:p>We lacked direct information on the intention to conceive and the androgenic biochemical status of the PCOS participants, applying instead the use of anti-androgenic medications as a proxy of hyperandrogenism. The duration of anti-androgenic treatment utilized is not known, only the age at prescription. Results are not adjusted for BMI, but for obesity diagnosis. The period of follow-up (10\u2009years) was restricted by the need to include only those women for whom data were available on the dispensing of medications during adolescence (born between 1987 and 1996). Women with PCOS who did not seek medical assistance might have been incorrectly classified as not having the disease. Such misclassification would lead to an underestimation of the true association between PCOS and outcomes.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>WIDER IMPLICATIONS OF THE FINDINGS<\/jats:title>\n                  <jats:p>Early initiation of anti-androgen treatment is associated with better spontaneous fertility rate. These findings support the need for future interventional randomized prospective studies investigating critical windows of anti-androgen treatment.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>STUDY FUNDING\/COMPETING INTEREST(S)<\/jats:title>\n                  <jats:p>This study was funded by the Health Research Council of New Zealand (18-671), the Swedish Society of Medicine and the Uppsala University Hospital. Evangelia Elenis has, over the past year, received lecture fee from Gedeon Richter outside the submitted work. Inger Sundstr\u00f6m Poromaa has, over the past 3\u2009years, received compensation as a consultant and lecturer for Bayer Schering Pharma, MSD, Gedeon Richter, Peptonics and Lundbeck A\/S. The other authors declare no competing interests.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>TRIAL REGISTRATION NUMBER<\/jats:title>\n                  <jats:p>N\/A<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/humrep\/deaa357","type":"journal-article","created":{"date-parts":[[2020,12,3]],"date-time":"2020-12-03T12:38:30Z","timestamp":1606999110000},"page":"1427-1435","source":"Crossref","is-referenced-by-count":21,"title":["Early initiation of anti-androgen treatment is associated with increased probability of spontaneous conception leading to childbirth in women with polycystic ovary syndrome: a population-based multiregistry cohort study in Sweden"],"prefix":"10.1093","volume":"36","author":[{"given":"E","family":"Elenis","sequence":"first","affiliation":[{"name":"Department of Women\u2019s and Children\u2019s Health, Uppsala University, Uppsala 751 85, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"E","family":"Desroziers","sequence":"additional","affiliation":[{"name":"Centre for Neuroendocrinology & Department of Physiology, School of Biomedical Sciences, Otago University, Dunedin 9054, New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S","family":"Persson","sequence":"additional","affiliation":[{"name":"Department of Women\u2019s and Children\u2019s Health, Uppsala University, Uppsala 751 85, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"I","family":"Sundstr\u00f6m Poromaa","sequence":"additional","affiliation":[{"name":"Department of Women\u2019s and Children\u2019s Health, Uppsala University, Uppsala 751 85, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"R E","family":"Campbell","sequence":"additional","affiliation":[{"name":"Centre for Neuroendocrinology & Department of Physiology, School of Biomedical Sciences, Otago University, Dunedin 9054, New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2021,1,17]]},"reference":[{"key":"2021042107340760500_deaa357-B1","doi-asserted-by":"crossref","first-page":"930","DOI":"10.1016\/j.fertnstert.2019.06.018","article-title":"Body-image distress is increased in women with polycystic ovary syndrome and mediates depression and anxiety","volume":"112","author":"Alur-Gupta","year":"2019","journal-title":"Fertil Steril"},{"key":"2021042107340760500_deaa357-B2","doi-asserted-by":"crossref","first-page":"2283","DOI":"10.1523\/JNEUROSCI.2304-17.2018","article-title":"Prepubertal development of GABAergic transmission to gonadotropin-releasing hormone (GnRH) neurons and postsynaptic response are altered by prenatal androgenization","volume":"38","author":"Berg","year":"2018","journal-title":"J Neurosci"},{"key":"2021042107340760500_deaa357-B3","doi-asserted-by":"crossref","first-page":"375","DOI":"10.1089\/met.2010.0039","article-title":"Polycystic ovary syndrome in the pediatric population","volume":"8","author":"Bremer","year":"2010","journal-title":"Metab Syndr Relat Disord"},{"key":"2021042107340760500_deaa357-B4","doi-asserted-by":"crossref","first-page":"1210","DOI":"10.1111\/j.1471-0528.2006.01008.x","article-title":"PCOS according to the Rotterdam consensus criteria: change in prevalence among WHO-II anovulation and association with metabolic factors","volume":"113","author":"Broekmans","year":"2006","journal-title":"BJOG"},{"key":"2021042107340760500_deaa357-B5","first-page":"84","article-title":"The role of the brain in the pathogenesis and physiology of polycystic ovary syndrome (PCOS)","volume":"7","author":"Coutinho","year":"2019","journal-title":"Med Sci (Basel)"},{"key":"2021042107340760500_deaa357-B6","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1210\/jcem.83.1.4500","article-title":"Hormonal effects of flutamide in young women with polycystic ovary syndrome","volume":"83","author":"De Leo","year":"1998","journal-title":"J Clin Endocrinol Metab"},{"key":"2021042107340760500_deaa357-B7","doi-asserted-by":"crossref","first-page":"815","DOI":"10.1016\/j.tem.2018.09.005","article-title":"Central obesity, faster maturation, and \u2018PCOS\u2019 in girls","volume":"29","author":"de Zegher","year":"2018","journal-title":"Trends Endocrinol Metab"},{"key":"2021042107340760500_deaa357-B8","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1055\/s-2003-43308","article-title":"Polycystic ovary syndrome in adolescence","volume":"21","author":"Driscoll","year":"2003","journal-title":"Semin Reprod Med"},{"key":"2021042107340760500_deaa357-B9","first-page":"4047","article-title":"Polycystic ovarian syndrome: evidence that flutamide restores sensitivity of the gonadotropin-releasing hormone pulse generator to inhibition by estradiol and progesterone","volume":"85","author":"Eagleson","year":"2000","journal-title":"J Clin Endocrinol Metab"},{"key":"2021042107340760500_deaa357-B10","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1002\/tera.1420250305","article-title":"Teratogenic effects of cyproterone acetate and medroxyprogesterone treatment during the pre- and postimplantation period of mouse embryos. II. Cyproterone acetate and medroxyprogesterone acetate treatment before implantation in vivo and in vitro","volume":"25","author":"Eibs","year":"1982","journal-title":"Teratology"},{"key":"2021042107340760500_deaa357-B11","doi-asserted-by":"crossref","first-page":"371","DOI":"10.1159\/000479371","article-title":"An international consortium update: pathophysiology, diagnosis, and treatment of polycystic ovarian syndrome in adolescence","volume":"88","author":"Ib\u00e1\u00f1ez","year":"2017","journal-title":"Horm Res Paediatr"},{"key":"2021042107340760500_deaa357-B12","first-page":"37","article-title":"Oral spironolactone in post-teenage female patients with acne vulgaris: practical considerations for the clinician based on current data and clinical experience","volume":"5","author":"Kim","year":"2012","journal-title":"J Clin Aesthet Dermatol"},{"key":"2021042107340760500_deaa357-B13","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1016\/j.jad.2019.05.006","article-title":"Body image and its relationships with sexual functioning, anxiety, and depression in women with polycystic ovary syndrome","volume":"253","author":"Kogure","year":"2019","journal-title":"J Affect Disord"},{"key":"2021042107340760500_deaa357-B14","doi-asserted-by":"crossref","first-page":"2134","DOI":"10.1093\/humrep\/den136","article-title":"Fecundability and spontaneous abortions in women with self-reported oligo-amenorrhea and\/or hirsutism: Northern Finland Birth Cohort 1966 Study","volume":"23","author":"Koivunen","year":"2008","journal-title":". Hum Reprod"},{"key":"2021042107340760500_deaa357-B15","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1016\/j.fertnstert.2016.05.003","article-title":"Criteria, prevalence, and phenotypes of polycystic ovary syndrome","volume":"106","author":"Lizneva","year":"2016","journal-title":"Fertil Steril"},{"key":"2021042107340760500_deaa357-B16","doi-asserted-by":"crossref","first-page":"450","DOI":"10.1186\/1471-2458-11-450","article-title":"External review and validation of the Swedish national inpatient register","volume":"11","author":"Ludvigsson","year":"2011","journal-title":"BMC Public Health"},{"key":"2021042107340760500_deaa357-B17","doi-asserted-by":"crossref","first-page":"659","DOI":"10.1007\/s10654-009-9350-y","article-title":"The Swedish personal identity number: possibilities and pitfalls in healthcare and medical research","volume":"24","author":"Ludvigsson","year":"2009","journal-title":"Eur J Epidemiol"},{"key":"2021042107340760500_deaa357-B18","doi-asserted-by":"crossref","first-page":"544","DOI":"10.1093\/humrep\/dep399","article-title":"The prevalence of polycystic ovary syndrome in a community sample assessed under contrasting diagnostic criteria","volume":"25","author":"March","year":"2010","journal-title":"Hum Reprod"},{"key":"2021042107340760500_deaa357-B19","doi-asserted-by":"crossref","first-page":"796","DOI":"10.1210\/en.2012-1954","article-title":"Estradiol negative and positive feedback in a prenatal androgen-induced mouse model of polycystic ovarian syndrome","volume":"154","author":"Moore","year":"2013","journal-title":"Endocrinology"},{"key":"2021042107340760500_deaa357-B20","doi-asserted-by":"crossref","first-page":"596","DOI":"10.1073\/pnas.1415038112","article-title":"Enhancement of a robust arcuate GABAergic input to gonadotropin-releasing hormone neurons in a model of polycystic ovarian syndrome","volume":"112","author":"Moore","year":"2015","journal-title":"Proc Natl Acad Sci USA"},{"key":"2021042107340760500_deaa357-B21","doi-asserted-by":"crossref","first-page":"391","DOI":"10.1007\/s12350-019-01624-z","article-title":"Landmark analysis: a primer","volume":"26","author":"Morgan","year":"2019","journal-title":"J Nucl Cardiol"},{"key":"2021042107340760500_deaa357-B22","author":"National Board of Health and Welfare [Socialstyrelsen]","year":"2020"},{"key":"2021042107340760500_deaa357-B23","doi-asserted-by":"crossref","first-page":"391","DOI":"10.3109\/09513590.2012.754876","article-title":"Ovulatory effects of flutamide in the polycystic ovary syndrome","volume":"29","author":"Paradisi","year":"2013","journal-title":"Gynecol Endocrinol"},{"key":"2021042107340760500_deaa357-B24","doi-asserted-by":"crossref","first-page":"2052","DOI":"10.1093\/humrep\/dez159","article-title":"Fecundity among women with polycystic ovary syndrome (PCOS)-a population-based study","volume":"34","author":"Persson","year":"2019","journal-title":"Hum Reprod"},{"key":"2021042107340760500_deaa357-B25","doi-asserted-by":"crossref","first-page":"698","DOI":"10.1097\/MOP.0000000000000945","article-title":"Current concepts of polycystic ovary syndrome pathogenesis","volume":"32","author":"Rosenfield","year":"2020","journal-title":"Curr Opin Pediatr"},{"key":"2021042107340760500_deaa357-B26","doi-asserted-by":"crossref","first-page":"467","DOI":"10.1210\/er.2015-1104","article-title":"The pathogenesis of polycystic ovary syndrome (PCOS): the hypothesis of PCOS as functional ovarian hyperandrogenism revisited","volume":"37","author":"Rosenfield","year":"2016","journal-title":"Endocr Rev"},{"key":"2021042107340760500_deaa357-B27","doi-asserted-by":"crossref","first-page":"2230","DOI":"10.1210\/en.2019-00428","article-title":"Neuroendocrine impairments of polycystic ovary syndrome","volume":"160","author":"Ruddenklau","year":"2019","journal-title":"Endocrinology"},{"key":"2021042107340760500_deaa357-B28","doi-asserted-by":"crossref","first-page":"1734","DOI":"10.1210\/en.2017-03218","article-title":"Antiandrogen treatment ameliorates reproductive and metabolic phenotypes in the letrozole-induced mouse model of PCOS","volume":"159","author":"Ryan","year":"2018","journal-title":"Endocrinology"},{"key":"2021042107340760500_deaa357-B29","doi-asserted-by":"crossref","first-page":"e99405","DOI":"10.1172\/jci.insight.99405","article-title":"Ontogeny and reversal of brain circuit abnormalities in a preclinical model of PCOS","volume":"3","author":"Silva","year":"2018","journal-title":"JCI Insight"},{"key":"2021042107340760500_deaa357-B30","doi-asserted-by":"crossref","first-page":"7129","DOI":"10.1073\/pnas.0308058101","article-title":"Prenatal androgens alter GABAergic drive to gonadotropin-releasing hormone neurons: implications for a common fertility disorder","volume":"101","author":"Sullivan","year":"2004","journal-title":"Proc Natl Acad Sci USA"},{"key":"2021042107340760500_deaa357-B31","first-page":"14","author":"Swedish Medical Products Agency [L\u00e4kemedelsverket]","year":"2014"},{"key":"2021042107340760500_deaa357-B32","author":"Swedish Public Health Agency [Folkh\u00e4lsomyndigheten]","year":"2019"},{"key":"2021042107340760500_deaa357-B33","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1186\/1741-7015-8-41","article-title":"Polycystic ovary syndrome: a complex condition with psychological, reproductive and metabolic manifestations that impacts on health across the lifespan","volume":"8","author":"Teede","year":"2010","journal-title":"BMC Med"},{"key":"2021042107340760500_deaa357-B34","doi-asserted-by":"crossref","first-page":"1602","DOI":"10.1093\/humrep\/dey256","article-title":"Recommendations from the international evidence-based guideline for the assessment and management of polycystic ovary syndrome","volume":"33","author":"Teede","year":"2018","journal-title":"Hum Reprod"},{"key":"2021042107340760500_deaa357-B35","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/j.fertnstert.2003.10.004","article-title":"Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome","volume":"81","author":"The Rotterdam ESHRE\/ASRM-SPCWG","year":"2004","journal-title":"Fertil Steril"},{"key":"2021042107340760500_deaa357-B36","doi-asserted-by":"crossref","first-page":"628","DOI":"10.1093\/humrep\/det437","article-title":"The impact of self-reported oligo-amenorrhea and hirsutism on fertility and lifetime reproductive success: results from the Northern Finland Birth Cohort 1966","volume":"29","author":"West","year":"2014","journal-title":"Hum Reprod"},{"key":"2021042107340760500_deaa357-B37","doi-asserted-by":"crossref","first-page":"1545","DOI":"10.1210\/js.2019-00078","article-title":"Polycystic ovary syndrome: pathophysiology, presentation, and treatment with emphasis on adolescent girls","volume":"3","author":"Witchel","year":"2019","journal-title":"J Endocr Soc"},{"key":"2021042107340760500_deaa357-B38","doi-asserted-by":"crossref","first-page":"2589","DOI":"10.3390\/ijerph15112589","article-title":"Geographical prevalence of polycystic ovary syndrome as determined by region and race\/ethnicity","volume":"15","author":"Wolf","year":"2018","journal-title":"Int J Environ Res Public Health"},{"key":"2021042107340760500_deaa357-B39","first-page":"377","volume-title":"Polycystic Ovary Syndrome","author":"Zawadski","year":"1992"}],"container-title":["Human Reproduction"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/academic.oup.com\/humrep\/article-pdf\/36\/5\/1427\/37216007\/deaa357.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/academic.oup.com\/humrep\/article-pdf\/36\/5\/1427\/37216007\/deaa357.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,4,21]],"date-time":"2021-04-21T18:59:25Z","timestamp":1619031565000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/humrep\/article\/36\/5\/1427\/6102682"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,1,17]]},"references-count":39,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2021,1,17]]},"published-print":{"date-parts":[[2021,4,20]]}},"URL":"https:\/\/doi.org\/10.1093\/humrep\/deaa357","relation":{},"ISSN":["0268-1161","1460-2350"],"issn-type":[{"value":"0268-1161","type":"print"},{"value":"1460-2350","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2021,5,1]]},"published":{"date-parts":[[2021,1,17]]}}}