专家观点 | 绝经后女性血内源性孕酮水平与乳腺癌风险相关吗？
绝经后女性血内源性孕酮水平与乳腺癌风险相关吗？
阮祥燕
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，同期也发表了另外一位意大利专家的述评。
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医院阮祥燕教授团队评价
内源性孕酮与绝经后乳腺癌风险有关系吗?
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。
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关联力度非常微弱，不足以证明血循环中的孕酮水平高与乳腺癌风险增加有关。
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/
循环血中的内源性孕酮水平与绝经后妇女的乳腺癌风险有关吗？
Nicoletta Biglia MD, PhD
Associate Professor of Obstetrics and Gynaecology, The University of Torino School of Medicine
Director, Academic Division of Obstetrics and Gynaecology, Mauriziano Umberto I Hospital, Torino, Ital
原文概括最近，Trabert和他的同事[1]发表了一篇论文，旨在通过应用“高效液相色谱-串联质谱法”检测较低浓度的孕酮及其代谢物来揭示这个问题，该方法比以前使用的方法灵敏得多。
作者利用一个骨随访到骨折的干预试验（FIT），采用巢式病例队列研究[2]，量化了孕酮及其代谢物的预诊断血清含量，特别是抑癌的4-孕烯（如3α-二氢孕酮[3αHP]）和促癌的5α-孕烷（如5α-二氢孕酮[5 - a - P]）。他们发现，除在循环雌二醇最低的五分位组的女性外，血液循环中孕酮水平较高的女性患乳腺癌的风险也较高，且两者之间呈线性相关。与预期相反，5αP相对于3αHP的比率与乳腺癌的风险无关。5αP相对于3αHP的比率与孕酮相对于雌二醇的比率之间的关联也为零。年龄、体重指数及先前应用口服避孕药并未改变孕酮与乳腺癌的关联以及5αP/3αHP与乳腺癌的关联。
2014年[3]的一项研究评估了同一队列中循环血中内源性雌激素及其代谢物对乳腺癌风险的影响。正如预期的那样，循环中雌二醇水平的升高与乳腺癌风险的增加有关。而内源性孕酮的作用可能由于绝经后女性体内几乎无法检测到其循环水平，尚不清楚。在2004年发表的唯一一项关于内源性孕激素与绝经后乳腺癌风险的研究中，孕激素水平与乳腺癌风险[4]之间没有联系。然而，当时采用检测方法的低灵敏度（30%的样品检测不到黄体酮水平）可能限制了研究发现关联的能力。报道更年期雌激素加孕激素治疗增加乳腺癌风险的研究并未提供内源性孕酮与这种风险之间潜在关联的直接证据。事实上，他们评估了外源性合成孕激素的应用增加乳腺癌风险[5,6,7]，这些激素具有抗雄激素、促雄激素、糖皮质激素和抗盐皮质激素的作用[8]。研究报道，应用雌激素加天然孕酮与乳腺癌风险的关联性弱很多[9-10]。Trabert的研究首次提示绝经后妇女的孕酮水平与乳腺癌风险可能存在关联，前提是她们的循环雌二醇水平至少为中度至高度。有趣的是，在循环雌二醇最低的五分位组中，乳腺癌风险随着循环孕酮水平的增加而降低，而在循环雌二醇最高的五分位组中，乳腺癌风险随着循环孕酮水平的增加而增加。
鉴于研究中的女性抽血前至少四个月未应用外源性激素，此研究建议可能受循环雌二醇水平的调节，孕酮在生理水平上有不同作用。
这个观察还需要进一步证实，但增加了我们对雌激素和孕激素的协同作用的认识，即使在非常低的水平上，对乳腺细胞也是如此。
原作者的结论是：“还需要进一步的研究来评估孕酮代谢物的作用以及孕酮和雌二醇之间的相互作用与乳腺癌的风险。”
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, LaCroix AZ, Tice JA, Xu X, Dallal CM, Brinton LA. Association of Circulating Progesterone With Breast Cancer Risk Among Postmenopausal Women. JAMA Netw Open. 2020 Apr 1;3(4): e203645.https://pubmed.ncbi.nlm.nih.gov/32329771/2. Black DM, Reiss TF, Nevitt MC, Cauley J, Karpf D, Cummings SR. Design of the Fracture Intervention Trial. Osteoporos Int. 1993;3 Suppl 3:S29-S39.https://pubmed.ncbi.nlm.nih.gov/8298200/3. Dallal CM, Tice JA, Buist DS, et al. Estrogen metabolism and breast cancer risk among postmenopausal women: a case-cohort study within B~FIT. Carcinogenesis. 2014;35(2):346-355.https://pubmed.ncbi.nlm.nih.gov/24213602/4. Missmer SA, Eliassen AH, Barbieri RL, Hankinson SE. Endogenous estrogen, androgen, and progesterone concentrations and breast cancer risk among postmenopausal women. J Natl Cancer Inst. 2004;96(24):1856-1865.https://pubmed.ncbi.nlm.nih.gov/15601642/5. Collaborative Group on Hormonal Factors in Breast Cancer. Breast cancer and hormone replacement therapy: collaborative reanalysis of data from 51 epidemiological studies of 52,705 women with breast cancer and 108,411 women without breast cancer. Nov 15;350(9089):1484.https://pubmed.ncbi.nlm.nih.gov/10213546/6. Rossouw JE, Anderson GL, Prentice RL, 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/12117397/7. Beral V; Million Women Study Collaborators. Breast cancer and hormone-replacement therapy in the Million Women Study [published correction appears in Lancet. 2003 Oct 4;362(9390):1160]. Lancet. 2003;362(9382):419-427.https://pubmed.ncbi.nlm.nih.gov/12927427/8. Stanczyk FZ, Hapgood JP, Winer S, Mishell DR Jr. Progestogens used in postmenopausal hormone therapy: differences in their pharmacological properties, intracellular actions, and clinical effects. Endocr Rev. 2013;34(2):171-208.https://pubmed.ncbi.nlm.nih.gov/23238854/9. Gompel A, Plu-Bureau G. Progesterone, progestins and the breast in menopause treatment. Climacteric. 2018;21(4):326-332.https://pubmed.ncbi.nlm.nih.gov/29852797/10. Stute P, Wildt L, Neulen J. The impact of micronized progesterone on breast cancer risk: a systematic review. Climacteric. 2018;21(2):111-122.
以下为原文：
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.
Department of Gynecological Endocrinology, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing, China.
Are circulating endogenous progesterone levels associated with breast cancer risk in postmenopausal women?
Summary
A recent paper by Trabert and coworkers[1] aimed at shedding some light on this issue by looking at minimal concentrations of progesterone and metabolites with “high-performance liquid chromatography-tandem mass spectrometry” assay, which is much more sensitive than methods used in previous studies.
The Authors, in a case-cohort study nested within the Breast and Bone Follow-up to the Fracture Intervention Trial (FIT)[2], were able to quantify prediagnostic serum levels of progesterone and progesterone metabolites, in particular the cancer-inhibiting 4-pregnenes (e.g., 3α-dihydroprogesterone[3αHP]) and cancer-promoting 5α-pregnanes (e.g., 5α-dihydroprogesterone[5αP]). They found that women with higher circulating progesterone levels were at increased risk for breast cancer with a linear association between levels and risk, except for women in the lowest quintile of estrogen levels. Contrary to expectations, the ratio of 5αP relative to 3αHP was not associated with the risk of breast cancer. The associations between the ratio of 5αP relative to 3αHP, and progesterone relative to estradiol were also null. Age, body mass index or prior oral contraceptive use did not modify progesterone associations with breast cancer and 5αP/3αHP- associations with breast cancer.
Commentary
A previous study in 2014[3] evaluated the effect of circulating endogenous estrogens and their metabolites on breast cancer risk in the same cohort. As expected, elevated circulating estradiol levels were associated with increased breast cancer risk. The effect of endogenous progesterone, possibly because of the almost undetectable circulating levels in postmenopausal women, is much less clear. In the only previous study of endogenous progesterone and postmenopausal breast cancer risk, published in 2004, there was no association between progesterone levels and breast cancer risk[4]. However, the low sensitivity of the assay available at the time (30% of the samples had undetectable levels of progesterone) may have limited the study’s ability to find an association. Studies reporting increased breast cancer risk with menopausal estrogen plus progestin therapy, do not provide direct evidence as to the potential association between endogenous progesterone and this risk. Indeed, they evaluated the use of exogenous synthetic progestogens[5,6,7], which can have anti-androgenic, pro-androgenic, glucocorticoid, and anti-mineralocorticoid effects[8]. The studies reporting on the use of estrogens plus natural progesterone found a much weaker association.[9-10] The study by Trabert is the first suggesting a possible association of progesterone levels and breast cancer risk in postmenopausal women, provided that they have at least moderate to high circulating total estradiol levels. Interestingly, in the lowest quintile of circulating estradiol, the breast cancer risk decreased with increasing levels of circulating progesterone, whereas, in the higher quintiles of circulating estradiol, the breast cancer risk increased with increasing levels of circulating progesterone.
Given that the women in the study were not using exogenous hormones since at least four months from the blood draw, this study suggests a differential role of progesterone at physiologic levels, possibly modulated by the level of circulating estradiol.
This observation needs to be confirmed but adds to our knowledge on the synergistic activity of estrogens and progesterone, even at very low levels, on breast cells.
The authors conclude: “Further research is also needed to evaluate the role of progesterone metabolites and the interaction between progesterone and estradiol with breast cancer risk.”
Nicoletta Biglia MD,
PhDAssociate Professor of Obstetrics and Gynaecology, The University of Torino School of Medicine
Director, Academic Division of Obstetrics and Gynaecology, Mauriziano Umberto I Hospital, Torino, Italy
References
Is there a relationship between endogenous progesterone and postmenopausal breast cancer risk?
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/
Are circulating endogenous progesterone levels associated with breast cancer risk in postmenopausal women?
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