Department of Women's and Children's Health, Uppsala University, Uppsala 751 85, Sweden.
Centre for Neuroendocrinology & Department of Physiology, School of Biomedical Sciences, Otago University, Dunedin 9054, New Zealand.
Hum Reprod. 2021 Apr 20;36(5):1427-1435. doi: 10.1093/humrep/deaa357.
Is anti-androgen treatment during adolescence associated with an improved probability of spontaneous conception leading to childbirth in women with polycystic ovary syndrome (PCOS)?
Early initiation of anti-androgen treatment is associated with an increased probability of childbirth after spontaneous conception among women with PCOS.
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 (<25 years) is associated with higher fecundity compared to a later diagnosis.
STUDY DESIGN, SIZE, DURATION: This population-based study utilized five linked Swedish national registries. A total of 15 106 women with PCOS and 73 786 control women were included. Women were followed from when they turned 18 years of age until the end of 2015, leading to a maximum follow-up of 10 years. First childbirth after spontaneous conception was the main outcome, as identified from the Medical Birth Registry.
PARTICIPANTS/MATERIALS, SETTING, METHODS: 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 (≤ 18 years of age) or after adolescence (>18 years), respectively. The probability of first childbirth after spontaneous conception was analyzed with the use of Kaplan-Meier 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.
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 0.64-0.72)), and 40% lower among hyperandrogenic women with PCOS (adjusted FR 0.53 (95% CI 0.50-0.57)). FR was lowest among severely hyperandrogenic women with PCOS compared to normo-androgenic women with PCOS (adjusted FR 0.60 (95% CI 0.52-0.69)), followed by mildly hyperandrogenic women with PCOS (adjusted FR 0.84 (95% CI 0.77-0.93)). Compared to early anti-androgenic treatment users, late users exhibited a lower probability of childbirth after spontaneous conception (adjusted FR 0.79 (95% CI 0.68-0.92)).
LIMITATIONS, REASONS FOR CAUTION: 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 years) 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.
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.
STUDY FUNDING/COMPETING INTEREST(S): 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 Sundström Poromaa has, over the past 3 years, 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.
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青春期使用抗雄激素治疗是否与多囊卵巢综合征（PCOS）女性自发受孕后生育的可能性增加有关？
早期开始抗雄激素治疗与 PCOS 女性自发受孕后生育的可能性增加有关。
PCOS 是影响育龄妇女最常见的内分泌疾病。与 PCOS 相关的高雄激素血症和月经不规律通常在青春期早期出现。先前的研究表明，与较晚诊断相比，<25 岁时的诊断与更高的生育能力相关。
研究设计、规模、持续时间：这项基于人群的研究利用了五个瑞典国家注册中心。共纳入了 15106 名患有 PCOS 的女性和 73786 名对照女性。女性从 18 岁开始随访，直到 2015 年底，最长随访时间为 10 年。首次自发受孕后的分娩是主要结局，通过医疗出生登记确定。
参与者/材料、地点、方法：参与者包括在瑞典患者登记处被诊断为 PCOS 的所有 1987 年至 1996 年出生的女性和随机选择的非 PCOS 对照者（比例为 1:5）。使用解剖治疗化学（ATC）代码从瑞典处方药物登记处获取抗雄激素治疗信息。未接受任何抗雄激素治疗的 PCOS 女性被视为正常雄激素，而接受治疗的女性被视为高雄激素。如果接受抗雄激素联合口服避孕药（aaCOC）单药治疗，则被归类为轻度高雄激素血症，如果接受其他抗雄激素药物联合或不联合 aaCOC 治疗，则被归类为重度高雄激素血症。青春期（≤18 岁）或青春期后（>18 岁）开始抗雄激素治疗的 PCOS 女性分别被归类为早期和晚期使用者。使用 Kaplan-Meier 风险曲线分析自发受孕后首次分娩的概率。使用 Cox 比例风险回归模型计算自发受孕的生育率（FR）和首次分娩的时间（95%置信区间），调整了肥胖、出生年份、出生国和教育水平。
与非 PCOS 对照组相比，PCOS 组中自发受孕后的分娩概率在正常雄激素血症女性中低 11%（调整后的 FR 0.68（95%CI 0.64-0.72）），在高雄激素血症 PCOS 女性中低 40%（调整后的 FR 0.53（95%CI 0.50-0.57））。与正常雄激素血症的 PCOS 女性相比，重度高雄激素血症的 PCOS 女性的 FR 最低（调整后的 FR 0.60（95%CI 0.52-0.69）），其次是轻度高雄激素血症的 PCOS 女性（调整后的 FR 0.84（95%CI 0.77-0.93））。与早期抗雄激素治疗使用者相比，晚期使用者自发受孕后生育的概率较低（调整后的 FR 0.79（95%CI 0.68-0.92））。
局限性、谨慎的原因：我们缺乏 PCOS 参与者受孕意图和雄激素生化状态的直接信息，而是使用抗雄激素药物的使用作为高雄激素血症的替代指标。抗雄激素治疗的持续时间未知，仅知道处方年龄。结果未根据 BMI 进行调整，而是根据肥胖症诊断进行调整。随访期（10 年）受到限制，因为仅包括那些在青春期（1987 年至 1996 年出生）期间有药物配药数据的女性。未寻求医疗帮助的 PCOS 女性可能被错误地归类为没有该疾病。这种错误分类会导致对 PCOS 与结局之间真实关联的低估。
早期开始抗雄激素治疗与更好的自发生育能力相关。这些发现支持未来需要进行干预性随机前瞻性研究，以调查抗雄激素治疗的关键窗口期。
研究资金/利益冲突：本研究由新西兰健康研究委员会（18-671）、瑞典医学协会和乌普萨拉大学医院资助。Evangelia Elenis 在过去一年中因在提交的工作之外担任讲师而获得了盖顿·里希特的演讲费。Inger Sundström Poromaa 在过去 3 年中，作为顾问和讲师，从拜耳先灵制药、默沙东、盖顿·里希特、佩通尼克斯和灵北制药公司获得了报酬。其他作者没有利益冲突。
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