孕6周雌二醇111正常吗(孕6周雌二醇111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。

2020年6月29 日国际绝经学会官方发布，这是发表的一位意大利专家的述评。

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, Italy

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，除雌激素水平最低的五分之一的女性外，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。

评论

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。

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。”

附英文：

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.”

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.