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绝经后女性通常需要补充雌激素±孕激素以改善绝经症状，但是可能增加乳腺癌的风险。美国国家卫生研究院于1991年发起的女性健康倡议研究包括3项随机对照干预研究和1项病例对照观察研究，入组了16万绝经后女性，随访超过15年。其中的随机对照研究发现，合用马雌激素＋醋酸甲羟孕酮的女性乳腺癌风险增加，不过令人惊讶的是，单用共轭马雌激素可以减少癌症风险。 2018年11月1日，国际抗癌联盟《国际癌症杂志》在线发表国家癌症研究所、哈佛大学医学院布列根妇女医院、布法罗大学、华盛顿大学弗雷德哈钦森癌症研究中心、爱因斯坦医学院、匹兹堡大学、威斯康星大学、希望之城国家医学中心、雷多斯生物医学研究中心弗雷德里克国家癌症研究实验室的女性健康倡议观察研究报告，调查了不同激素对绝经后女性乳腺癌风险的不同影响机制。 该研究利用女性健康倡议病例对照观察研究1864例女性的血清，测量了15种不同的雌激素代谢产物，以追踪共轭马雌激素的代谢途径。其中，609例当时正在合用雌激素＋孕激素者（351例合用共轭马雌激素＋醋酸甲羟孕酮）、272例单用雌激素（162例单用共轭马雌激素）。通过逆概率加权线性回归，对各种代谢产物、羟化途径（2-羟化、4-羟化、16-羟化）和途径浓度比例进行分析。 结果发现，单用雌激素者与合用雌激素＋孕激素者相比，所有雌激素代谢产物浓度较高，尤其非共轭雌酮、雌二醇、共轭雌二醇、2-甲氧雌酮、非共轭2-甲氧雌酮、4-甲氧雌酮、非共轭雌三醇。 对于接受不同绝经激素疗法的女性，2-羟化与4-羟化雌激素代谢产物相对浓度相似（2-羟化占15%、4-羟化<2%）；不过，单用雌激素女性的16-羟化雌激素代谢产物浓度显著较低（P=0.036）。 单用雌激素的女性与合用雌激素和孕激素的女性相比，2-、4-羟化雌激素代谢产物显著高于16-羟化雌激素代谢产物。单用共轭马雌激素的女性与合用共轭马雌激素＋醋酸甲羟化孕酮的女性相比，2-、4-羟化雌激素代谢产物高于16-羟化雌激素代谢产物，但是不显著。 对于单用雌激素的女性，2-羟化的代谢活性高于16-羟化，可以减少癌症风险。对于合用雌激素和孕激素的女性，16-羟化的代谢活性高于2-羟化，可以增加癌症风险。 因此，该研究结果表明，单用雌激素与合用雌激素＋孕激素的女性相比，2-羟化与16-羟化相比，代谢更广。这与流行病学证据一致，即与此代谢特征相关的绝经后乳腺癌风险减少，并且可能为女性健康倡议期间单用共轭马雌激素的乳腺癌风险减少提供线索。 Int J Cancer. 2018 Nov 1. [Epub ahead of print] Estrogen metabolism in menopausal hormone users in the Women's Health Initiative Observational Study: Does it differ between estrogen plus progestin and estrogen alone? Falk RT, Manson JE, Barnabei VM, Anderson GL, Brinton LA, Rohan TE, Cauley JA, Chen C, Coburn SB, Pfeiffer RM, Reding KW, Sarto GE, Wentzensen N, Chlebowski RT, Xu X, Trabert B. National Cancer Institute, Bethesda, MD; Brigham and Women's Hospital, Harvard Medical School, Boston, MA; University at Buffalo, Buffalo, NY; Fred Hutchinson Cancer Research Center, Seattle, WA; Albert Einstein College of Medicine, Bronx, NY; University of Pittsburgh, Pittsburgh, PA; University of Washington, Seattle, WA; University of Wisconsin, Madison, WI; City of Hope National Medical Center Duarte, CA; Leidos Biomedical Research, Inc, Frederick National Laboratory for Cancer Research, Frederick, MD.
The WHI found an unexpected reduced breast cancer risk in women using CEE alone. We hypothesized CEE alone induces estrogen hydroxylation along the 2-pathway rather than the competing 16-pathway, a pattern linked to reduced postmenopausal breast cancer risk. 1864 women in a WHIOS case-control study of estrogen metabolism and ovarian and endometrial cancer were studied of whom 609 were current E+P users (351 used CEE+MPA), while 272 used E alone (162 used CEE). Fifteen EM were measured, and analyses conducted for each metabolite, hydroxylation pathway (2-, 4-, or 16-pathway), and ratios of pathway concentrations using inverse probability weighted linear regression. Compared to E+P users, all EM were higher in E alone users (significant for unconjugated estrone, total/conjugated estradiol, total/unconjugated 2-methoxyestrone, 4-methoxyestrone and unconjugated estriol). The relative concentrations of 2- and 4-pathway EM did not differ between the MHT users (2-pathway EM comprised 15% and 4-pathway EM <2% of the total), but 16-pathway EM were lower in E alone users (p=0.036). Ratios of 2- and 4-pathway EM compared to 16-pathway EM were significantly higher in E alone compared to E+P users. Similar but not significant patterns were observed in CEE-alone and CEE+MPA users. Our data suggest that compared to E+P users, women using E alone have more extensive metabolism via the 2- versus the competing 16-pathway. This is consistent with epidemiologic evidence of reduced postmenopausal breast cancer risk associated with this metabolic profile and may provide a clue to the breast cancer risk reduction in CEE alone users during the WHI. KEYWORDS: Women's Health Initiative Observational Study; conjugated equine estrogens; conjugated equine estrogens plus medroxyprogesterone acetate; estrogen alone; estrogen metabolism; estrogen plus progestin PMID: 30183089 DOI: 10.1002/ijc.31851
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