绝经期激素疗法与乳腺癌发病风险
全世界流行病学研究证据荟萃分析
绝经期激素疗法，又称更年期激素疗法、激素替代疗法、激素补充疗法，可以改善绝经期女性卵巢功能衰退所致性激素内分泌减少引起的月经紊乱、潮热盗汗、心悸失眠、烦躁易怒等生理心理症状。不过，绝经期激素疗法与乳腺癌发病风险可能存在相关性。可是，已经发表的研究结果众说纷纭、莫衷一是，并且长期随访结果较少。
8月29日，国际四大医学期刊之一、英国《柳叶刀》正刊发表英国牛津大学代表国际乳腺癌内分泌因素研究协作组起草的研究报告，将全世界已经发表和尚未发表的绝经期激素疗法与乳腺癌发病风险相关性流行病学研究证据、随机对照研究证据进行了荟萃分析。
该荟萃分析对1992年1月1日～1月1日正式和非正式发表的研究进行定期检索，对所有符合条件的绝经期激素疗法类型和时间前瞻研究参与者信息完整个体数据进行分析。绝经期激素疗法随访时间最长达5年（平均1.4年）。根据逻辑回归模型分析，校正其他影响因素，对特定绝经期激素疗法使用者与从未使用者进行比较。
结果，前瞻随访期间，10万8647例绝经期女性发生乳腺癌，平均发病年龄65±7岁；其中5万5575例（51%）曾经用过绝经期激素疗法。
对于信息完整的女性，绝经时平均年龄为50±5岁、开始绝经期激素疗法时年龄为50±6岁，绝经期激素疗法平均持续时间：当时使用者为10±6年、过去使用者为7±6年。
除了阴道雌激素之外，各种类型的绝经期激素疗法使用者与从未使用者相比，乳腺癌发病风险都增加，并且随着治疗时间延长而持续增加，而且雌激素＋孕激素与仅用雌激素制剂相比，乳腺癌发病风险显著较高。
绝经期激素疗法当时使用者与从未使用者相比：
1～4年乳腺癌发病风险
雌激素＋孕激素：高1.60倍（95%置信区间：1.52～1.69）
仅用雌激素制剂：高1.17倍（95%置信区间：1.10～1.26）
5～乳腺癌发病风险
雌激素＋孕激素：高2.08倍（95%置信区间：2.02～2.15）
仅用雌激素制剂：高1.33倍（95%置信区间：1.28～1.37）
雌激素＋每天孕激素：高2.30倍（95%置信区间：2.21～2.40）
雌激素＋间歇孕激素：高1.93倍（95%置信区间：1.84～2.01）
对于相同制剂，入组当时使用者5～乳腺癌发病风险：
雌激素受体阳性肿瘤高于雌激素受体阴性肿瘤
40～44、45～49、50～54、55～59岁高于60岁之后开始绝经期激素疗法或肥胖女性（肥胖女性仅用雌激素的乳腺癌发病风险极低）
停止绝经期激素疗法之后，乳腺癌发病风险增加持续至少；该风险高低取决于既往绝经期激素疗法持续时间，绝经期激素疗法少于1年的乳腺癌发病风险增加极少。
因此，该荟萃分析结果表明，如果上述相关性存在因果关系，那么对于发达国家平均体重女性而言，从50岁开始，5年绝经期激素疗法可使50～69岁乳腺癌发病风险大约增加1/50（雌激素＋每天孕激素制剂）或1/70（雌激素＋间歇孕激素制剂）或1/200（仅用雌激素制剂），绝经期激素疗法对应乳腺癌发病风险大约增加两倍。
对此，加拿大多伦多大学发表同期评论：绝经期激素与乳腺癌的重磅证据。
Lancet. Aug 29. [Epub ahead of print]
Type and timing of menopausal hormone therapy and breast cancer risk: individual participant meta-analysis of the worldwide epidemiological evidence.
Collaborative Group on Hormonal Factors in Breast Cancer.
BACKGROUND: Published findings on breast cancer risk associated with different types of menopausal hormone therapy (MHT) are inconsistent, with limited information on long-term effects. We bring together the epidemiological evidence, published and unpublished, on these associations, and review the relevant randomised evidence.
METHODS: Principal analyses used individual participant data from all eligible prospective studies that had sought information on the type and timing of MHT use; the main analyses are of individuals with complete information on this. Studies were identified by searching many formal and informal sources regularly from Jan 1, 1992, to Jan 1, . Current users were included up to 5 years (mean 1.4 years) after last-reported MHT use. Logistic regression yielded adjusted risk ratios (RRs) comparing particular groups of MHT users versus never users.
FINDINGS: During prospective follow-up, 108647 postmenopausal women developed breast cancer at mean age 65 years (SD 7); 55575 (51%) had used MHT. Among women with complete information, mean MHT duration was 10 years (SD 6) in current users and 7 years (SD 6) in past users, and mean age was 50 years (SD 5) at menopause and 50 years (SD 6) at starting MHT. Every MHT type, except vaginal oestrogens, was associated with excess breast cancer risks, which increased steadily with duration of use and were greater for oestrogen-progestagen than oestrogen-only preparations. Among current users, these excess risks were definite even during years 1-4 (oestrogen-progestagen RR 1.60, 95% CI 1.52-1.69; oestrogen-only RR 1.17, 1.10-1.26), and were twice as great during years 5-14 (oestrogen-progestagen RR 2.08, 2.02-2.15; oestrogen-only RR 1.33, 1.28-1.37). The oestrogen-progestagen risks during years 5-14 were greater with daily than with less frequent progestagen use (RR 2.30, 2.21-2.40 vs 1.93, 1.84-2.01; heterogeneity p<0.0001). For a given preparation, the RRs during years 5-14 of current use were much greater for oestrogen-receptor-positive tumours than for oestrogen-receptor-negative tumours, were similar for women starting MHT at ages 40-44, 45-49, 50-54, and 55-59 years, and were attenuated by starting after age 60 years or by adiposity (with little risk from oestrogen-only MHT in women who were obese). After ceasing MHT, some excess risk persisted for more than 10 years; its magnitude depended on the duration of previous use, with little excess following less than 1 year of MHT use.
INTERPRETATION: If these associations are largely causal, then for women of average weight in developed countries, 5 years of MHT, starting at age 50 years, would increase breast cancer incidence at ages 50-69 years by about one in every 50 users of oestrogen plus daily progestagen preparations; one in every 70 users of oestrogen plus intermittent progestagen preparations; and one in every 200 users of oestrogen-only preparations. The corresponding excesses from 10 years of MHT would be about twice as great.
FUNDING: Cancer Research UK and the Medical Research Council
DOI: 10.1016/S0140-6736(19)31709-X
Lancet. Aug 29. [Epub ahead of print]
Menopausal hormones: definitive evidence for breast cancer.
Joanne Kotsopoulos.
Women"s College Research Institute, Women"s College Hospital, Toronto, ON, Canada; Dalla Lana School of Public Health, University of Toronto, Toronto, ON, Canada.
DOI: 10.1016/S0140-6736(19)31901-4
