40岁女人雌二醇412正常吗(女性雌二醇354正常吗)

近期发表在JAMA network open 2020, 3(4):e203645.的一篇文章，首次发现

绝经后女性，血液内源性孕酮水平高使乳腺癌风险增加16%。

对此，国际绝经学会组织此领域重要专家对这篇文章进行了分析与评价，因为激素与乳腺癌风险的研究是全球热点，国际绝经学会首次邀请2位专家从不同角度评价。

首都医科大学附属北京妇产医院内分泌科阮祥燕教授，作为国际绝经学会委员，在激素与乳腺癌风险研究有10余年经验，被国际绝经学会邀请对这篇文章进行评述，阮祥燕教授组织团队对这篇文章进行深入学习与分析，并邀请首都医科大学流行病学专家李星明教授一起讨论研究的设计，偏倚等问题。

我们的评述意见提交国际绝经学会，2020年6月29 日国际绝经学会官方发布。

详细内容请参中文翻译并附英文原文。

内源性孕酮水平与乳腺癌风险：

关于Trabert等 “绝经后女性血循环孕酮水平与乳腺癌风险关系”的不同专家观点

首都医科大学附属北京妇产科医院内分泌科阮向燕教授团队评价

原文概要

Trabert及其同事利用一项基于骨随访到骨折的干预试验（B-FIT，n=15595）进行了血液中内源性孕酮对绝经后乳腺癌发病率影响的前瞻性病例队列研究。

参与者在采血时没有接受外源性激素治疗（1992-1993） [1]。癌症发病率是基于问卷调查的结果，以及随后的医疗记录核实和/或临床中心癌症登记处注册的信息。

在病例队列研究中，排除了1811个病例。在剩余的13784 例符合条件的参与者中，从不同层级的临床中心中，随机抽取了年龄差在10岁以内的515例绝经后女性作为研究亚组。进一步排除后，在12年的随访中诊断乳腺癌的病例405例（n = 405例），从不同层级的临床中心中，随机抽取了年龄差在10岁以内的495例绝经后女性作为研究亚组。

2017年7月采用液相色谱-串联质谱法完成了对血清孕酮的测定。受试者抽血时的平均（SD）年龄为67.2（6.2）岁，大多数为非西班牙白人（384[94.8%]）。乳腺癌患者诊断时的平均（SD）年龄为73（6.4）岁（范围：56-89）。主要发现是孕酮浓度平均值（SD）为4.6（1.7）ng/ dL。血液孕酮水平较高的女性，孕激素水平每增加一个SD，绝经后乳腺癌的风险增加16%（HR 1.16；95%CI 1.00 -1.35，p = .048）。

作者结论：在绝经后妇女中，血液循环中孕酮水平升高与乳腺癌风险增加16%相关。

评论

关于绝经后激素治疗（menopause hormone therapy, MHT）与乳腺癌风险的争论一直是一个热点议题。

超过50项观察性研究表明激素治疗会增加乳腺癌的风险。从妇女健康倡议（WHI）的研究中，我们发现乳腺癌风险主要取决于孕激素成分[2]。一些大型的临床研究，包括E3N研究和芬兰队列研究均发现雌二醇联合孕酮或地屈孕酮在5-8年内乳腺癌的发病率低于其他合成孕激素[3,4]。

Mohammed及其同事发现孕酮抑制雌激素介导和ERα+乳腺癌移植瘤的生长，并可以增加抗增殖作用。与此同时，他们发现用他莫昔芬与黄体酮联合用药对肿瘤有最强的抑制作用 [5]。

我们团队多年来一直关注MHT和乳腺癌风险，从体外实验和体内动物实验中，我们发现一些合成孕激素在过度表达孕激素受体膜组分1（PGRMC1）的情况下可以促进乳腺癌细胞的增殖或肿瘤的生长，而天然孕激素黄体酮则没有这些作用[6-8]。许多其他研究也发现不同的孕激素有不同的作用。与合成孕激素相比，天然孕酮联合雌激素与乳腺癌风险增加无关。这篇文章[1]不能支持之前的研究结果。

此研究需要考虑一些混杂因素，如:

● （1）在B-FIT项目中，有64%的符合入组条件的妇女完成了调查问卷，是否存在抽样误差？

● （2）在12年的随访中，许多其他乳腺癌因素也可能影响乳腺癌的发病率，如环境和饮食、MHT治疗方案及药物类型。

● （3）本研究的血清标本在-20℃保存3年，然后在-70℃保存20年以上（27-28年），因此可能影响孕酮及其代谢物的稳定性[9]。

此外，即使不考虑上述潜在的混杂因素，HR也只有1.16，表明此研究检测到的一个非常微弱的关联力度不足。

总之，目前发表在《JAMA 2020》上的这篇论文很有趣，但作者应该非常谨慎地得出“绝经后女性较高的血液循环孕酮水平与乳腺癌风险增加有关”的结论。

附英文：

Endogenous progesterone levels and breast cancer risk: comparing opinions on"Association of Circulating Progesterone With Breast Cancer Risk Among Postmenopausal Women". by Trabert et al.

Is there a relationship between endogenous progesterone and postmenopausal breast cancer risk?

Summary

Trabert and colleagues investigated the influence of circulating endogenous progesterone on the incidence of postmenopausal breast cancer through a prospective case-cohort study based on a bone follow-up to the Fracture Intervention Trial (B-FIT, n=15595). Participants were not receiving exogenous hormone therapy at the time of blood sampling (1992-1993) [1]. Cancer incidence was based on questionnaire responses with subsequent requests from medical record verification and/or cancer registry linkage at clinical sites. One thousand eight hundred eleven cases were excluded from possible selection in the case-cohort study. Of the remaining 13784 eligible participants, 515 were randomly selected for the subcohort within a 10-year age and clinical center strata. After additional exclusions, 405 incident breast cancer cases diagnosed during 12 follow-up years and a subcohort of 495 postmenopausal women were randomly selected within a 10-year age and clinical center strata. Progesterone assays, using a liquid chromatography–tandem mass spectrometry assay were completed in July 2017. Participants’ mean (SD) age at blood draw was 67.2 (6.2) years, and most were non-Hispanic white (384 [94.8%]). Mean (SD) age for women with breast cancer was 73 (6.4) years at diagnosis (range, 56-89). The key findings were that progesterone concentrations displayed a mean (SD) of 4.6 (1.7) ng/dL. Women with higher circulating progesterone levels had a 16% increased risk of postmenopausal breast cancer per SD increase in progesterone (HR, 1.16; 95% CI,1.00-1.35; P=.048).

In conclusion, in postmenopausal women, elevated circulating progesterone levels were associated with a 16% increase in the risk of breast cancer.

Commentary

The debate between MHT and breast cancer risk has always been a hot topic. More than 50 observed studies have shown that hormone therapy can increase breast cancer risk. From the Women’s Health Initiative (WHI) study, we found the breast cancer risk mainly depends on the progestogen components [2]. Some large clinical studies, including the E3N study and Finnish study, found that estradiol combined with progesterone or dydrogesterone showed a lower breast cancer incidence than that of other synthetic progestogens within 5-8 years [3,4]. Mohammed and colleagues found progesterone inhibited estrogen-mediated growth and ERα+ breast tumour explants and had increased anti-proliferative effects. At the same time, they found that tamoxifen combination with progesterone had the highest degree of tumour inhibition [5]. Our team has also focused on MHT and breast cancer risk for many years; from in vitro experiments and in vivo animal experiments, we found some synthetic progestogens can promote the proliferation of breast cancer cells or growth of tumour if there is an overexpression of progesterone receptor membrane component 1 (PGRMC1), whereas natural progesterone does not have these effects [6-8]. Many other studies have also found that different progestogens have different effects. In contrast to synthetic progestogens, progesterone in combination with estrogen has not been associated with increased breast cancer risk. This publication [1] could not support previous findings.

Some confounding factors need to be considered in the present study, such as:

(1) In the B-FIT project, the questionnaire was completed by 64% of eligible women; was there a sampling bias？

(2) During a follow-up of 12 years, many other breast cancer factors could have affected the incidence of breast cancer, such as environment and diet, MHT regimens and types

(3) The serum samples of the study were stored at -20 °C for three years, then -70 °C for more than 20 years (27-28 years), therefore the stability of progesterone and its metabolites could have been affected [9].

Also, even without considering the above potential confounders, the HR is only 1.16, indicating this study was underpowered to detect a very weak association.

To summarize, the current paper from the JAMA 2020 is interesting but the authors should be very careful to conclude that in postmenopausal women, higher circulating progesterone levels are associated with increased risk of breast cancer.

参考文献：

[1]Trabert B, Bauer DC, Buist DSM, Cauley JA, Falk RT, Geczik AM, Gierach GL, Hada M, Hue TF, Lacey JV, Jr. et al: Association of Circulating Progesterone With Breast Cancer Risk Among Postmenopausal Women. JAMA network open 2020, 3(4):e203645.

https://pubmed.ncbi.nlm.nih.gov/32329771/

[2]Rossouw JE, Anderson GL, Prentice RL, LaCroix AZ, Kooperberg C, Stefanick ML, Jackson RD, Beresford SA, Howard BV, Johnson KC, et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women’s Health Initiative randomized controlled trial. JAMA 2002, 288(3):321-333.

https://pubmed.ncbi.nlm.nih.gov/12117397/

[3]Fournier A, Mesrine S, Boutron-Ruault MC, Clavel-Chapelon F. Estrogen-progestagen menopausal hormone therapy and breast cancer: does delay from menopause onset to treatment initiation influence risks? Journal of clinical oncology: official journal of the American Society of Clinical Oncology 2009, 27(31):5138-5143.

https://pubmed.ncbi.nlm.nih.gov/19752341/

[4]Lyytinen H, Pukkala E, Ylikorkala O. Breast cancer risk in postmenopausal women using estradiol-progestogen therapy. Obstetrics and gynecology, 2009, 113(1):65-73.

https://pubmed.ncbi.nlm.nih.gov/19104361/

[5]Mohammed H, Russell IA, Stark R, Rueda OM, Hickey TE, Tarulli GA, Serandour AA, Birrell SN, Bruna A, Saadi A et al. Progesterone receptor modulates ERα action in breast cancer. Nature 2015, 523(7560):313-317.

https://pubmed.ncbi.nlm.nih.gov/26153859/

[6]Cai G, Ruan X, Gu M, Zhao Y, Wang Y, Mueck AO. PGRMC1 in animal breast cancer tissue and blood is associated with increased tumor growth with norethisterone in contrast to progesterone and dydrogesterone: four-arm randomized placebo-controlled xenograft study. Gynecological Endocrinology: the official journal of the International Society of Gynecological Endocrinology 2020:1-4.

https://pubmed.ncbi.nlm.nih.gov/32208774/

[7]Zhao Y, Ruan X, Wang H, Li X, Gu M, Wang L, Li Y, Seeger H, Mueck AO. The presence of a membrane-bound progesterone receptor induces growth of breast cancer with norethisterone but not with progesterone: A xenograft model. Maturitas 2017, 102:26-33.

https://pubmed.ncbi.nlm.nih.gov/28610679/

[8]Zhang Y, Ruan X, Willibald M, Seeger H, Fehm T, Neubauer H, Mueck AO. May progesterone receptor membrane component 1 (PGRMC1) predict the risk of breast cancer? Gynecological endocrinology: the official journal of the International Society of Gynecological Endocrinology 2016, 32(1):58-60.

https://pubmed.ncbi.nlm.nih.gov/26303031/

[9]Holl K, Lundin E, Kaasila M, Grankvist K, Afanasyeva Y, Hallmans G, Lukanova A. Effect of long-term storage on hormone measurements in samples from pregnant women: the experience of the Finnish Maternity Cohort. Acta Oncol 2008, 47(3): 406-412.

https://pubmed.ncbi.nlm.nih.gov/17891670/