Veena:

The critical key to understanding the seeming paradox is to appreciate that not only, as is well-recognized, that tamoxifen shows "endocrine duality", that is, both estrogenic (agonist) and/or antiestrogenic (antagonist) properties, but - less well known - that tamoxifen can also act as a PR (progesterone receptor)-promoter (PR-promoter) and possibly synergize the well-known beneficial response to progestin therapy in endometrial carcinomas.

So it is well-established that tamoxifen (TAM) can stimulate the proliferation of certain EC cell lines, engendering an excess risk of EC for women taking TAM (as compared with controls), and that TAM causes endometrial changes (benign polyps and hyperplasia) in a large number of cases (up to 40% as the ACOG Committee determined). But it needs to be appreciated that It remains unclear and a matter of continuing controversy as to whether TAM, because of its estrogenic / agonistic properties, induces the formation of EC, or whether it ssimply accelerates the growth of pre-existing EC.

We now have both preclinical and clinical data suggesting that TAM, when bound to the cytoplasmic ER, can stimulate the production of PRs (progesterone receptors) and therefore possibly potentiate the activity of progestin therapy [1], since in human breast cancer cells TAM halts estrogen-promoted growth, yet at some concentrations increases progesterone receptors [2,3]. And in early studies, tamoxifen (40 mg daily for 5 to 7 days) caused an increase of the progesterone receptor concentration in most tumors, a finding also observed in patients with metastatic breast cancers [5]. Thus, independent of its estrogen-based activities (both estrogenic (agonist) and antiestrogenic (antagonist)), the evidence to date suggests that TAM has a promoting effect on progesterone receptor (PR), of potential use in some patients with advanced or metastatic endometrial carcinoma, and may in addition might potentiate the response to progestin therapy, and it further appears that this PR-promotion effect, in endometrial cancer, dominates any estrogen-based activities to yield a clinically significant overall benefit [6 - 14].

In this connection, see the ingenious recent study from researchers at UCLA [15] which suggests that stromal-PR is necessary and sufficient for progesterone antitumor effects in EC, so that stromal expression of PR (stromal-PR) may be a reliable biomarker in predicting response to hormonal therapy in EC. This is an exciting development given that up to now we have had no consistently reliable indicator to differentiate and select who is hormonally-responsive and hence a candidate for hormonal interventions in, especially, advanced and metastatic EC, and we await confirmation in human clinical trials.

REFERENCES

1. Emons G, Fleckenstein G, Hinney B, Huschmand A, Heyl W. Hormonal interactions in endometrial cancer. [Review] Endocr Relat Cancer 2000; 7(4):227-42.

2. Lippman. M., Bolan, G., and Huff, K. The effects of estrogens and antiestrogens on hormone responsive human breast cancer in long-term tissue culture. Cancer Res.. 35 4595-4601, 1976.

3. Mortel R, Levy C, Wolff JP, et al. Female sex steroid receptors in postmenopausal endometrial carcinoma and biochemical response to an antiestrogen. Cancer Res 1981;41:1140-1147.

4. Mortel R, Levy C, Wolff JP, Nicolas JC, Robel P, Baulieu EE. Female sex steroid receptors in postmenopausal endometrial carcinoma and biochemical response to an antiestrogen. Cancer Res 1981; 41(3):1140-7.

5. Namer. M., Lalanne. C.. and Baulieu. E. E. Increase of progesterone receptor by tamoxifen as a hormonal challenge test in breast cancer. Cancer Res., 40: 1750-1752, 1980.

6. Carlson JA Jr., Allegra JC, Day TG Jr., et al. Tamoxifen and endometrial carcinoma: Alterations in estrogen and progesterone receptors in untreated patients and combination hormonal therapy in advanced neoplasia. Am J Obstet Gynecol 1984;149:149-153.

7. Thigpen T, Brady MF, Homesley HD, et al. Tamoxifen in the treatment of advanced or recurrent endometrial carcinoma: A Gynecologic Oncology Group study. J Clin Oncol 2001;19:364-367.

8. Moore TD, Phillips PH, Nerenstone SR, et al. Systemic treatment of advanced and recurrent endometrial carcinoma: Current status and future directions. J Clin Oncol 1991;9:1071-1088.

9. Decruze SB, Green JA. Hormone therapy in advanced and recurrent endometrial cancer: A systematic review. Int J Gynecol Cancer 2007;17:964-978.

10. Lentz SS, Brady MF, Major FJ, et al. High-dose megestrol acetate in advanced or recurrent endometrial carcinoma: A Gynecologic Oncology Group Study. J Clin Oncol 1996;14:357-361.

11. Pandya KJ, Yeap BY, Weiner LM, et al. Megestrol and tamoxifen in patients with advanced endometrial cancer: An Eastern Cooperative Oncology Group study (E4882). Am J Clin Oncol 2001;24:43-46.

12. Fiorca JV, Brunetto VL, Hanjani P, et al. A phase II study of recurrent and advanced endometrial carcinoma treated with alternating courses of megestrol acetate (Megace) and tamoxifen citrate (Nolvadex) [abstract 1499]. Proc Am Soc Clin Oncol 2000;19.

13. Whitney CW, Brunetto VL, Zaine RJ, et al. Phase II study of medroxyprogesterone acetate plus tamoxifen in advanced endometrial carcinoma: A Gynecologic Oncology Group study. Gynecol Oncol 2004;92:4-9.

14. Rauh-Hain JA, Del Carmen MG. Treatment for advanced and recurrent endometrial carcinoma: combined modalities. Oncologist 2010; 15(8):852-61.

15. Janzen DM, Rosales MA, Paik DY, et al. Progesterone receptor signaling in the microenvironment of endometrial cancer influences its response to hormonal therapy. Cancer Res 2013 Aug 1; 73(15):4697-710.

Constantine Kaniklidis

Director of Medical Research

No Surrender Breast Cancer Foundation (NSBCF)

Thanks Constantine.

Tamoxifen is a weak estrogenic receptor agonist so it may initiate hyperplasia. But in cases of metastatic advanced endometrial cancer may be used after prolonged progesterone therapy as its receptors are depleted so it is used to stimulate synthesis of receptors to reuse progesterone again.

Tamoxifen causes Endometrial hyperplasia because of its weak Estrogenic agonist activity.In the advanced cases of carcinoma Endometrium tamoxifen can be used to stimulate the synthesis of the  receptorse which will help for the effective use of the progesterone therapy.