Pharmacological Mechanism of Tamoxifen and Its Influence on Ovary Function_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

 LIXiao-shi ,  LÜQing , CHENJie , DUZheng-gui , TANQiu-wen , ZHANGDi , XIONGBing-jun

Department of Thyroid and Breast Surgery, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China;

Corresponding author：

LÜQing, Email: lqlq1963@163.com

Keywords：

Tamoxifen; Drug metabolism; Estrogen receptor; Ovary; Sex hormone

DOI：

10.7507/1007-9424.20150367

Video：

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Objective To summarize the relevant studies of pharmacological mechanism of tamoxifen and its influence on ovary function in order to provide information and evidence for the therapy of breast cancer. Methods Papers published from January 1950 to January 2014, were retrieved in MedLine, OVID, CBM, CNKI databases using the keywords on tamoxifen, drug metabolism, ovary, sex hormone, etc, 1286 papers were retrieved in English literatures, and 621 in Chinese literatures. Criteria of paper adoption:①The clinical and basic studies about metabolism of tamoxifen, metabolic effect of tamoxifen, and gene polymorphism of CYP2D6.②The role played by estrogen receptor and protein cofactors in tamoxifen effect.③The clinical and basic studies about tamoxifen induced ovulation, caused endometrial thickening, changed sex hormone levels. According to the above criteria, 152 papers were selected, and 77 papers out of them were finally analyzed and reviewed. Results ①The tamoxifen metabolite 4-OH-N-tamoxifen was the main working component, the decreased levels could predict the poor prognosis.②The CYP2D6 gene polymorphism could affect the metabolic effect of tamoxifen and the therapeutic effect of patients with breast cancer.③The metabolic effect of tamoxifen needed the participation of the estrogen receptors and protein cofactors.④Tamoxifen could affect the reproductive system function through the estrogen receptor of H-P-O axis, ovary, and endometrium. Conclusions Metabolic effect of tamoxifen is regulated by gene, it could affect reproductive system functions through estrogen receptor. the mechanism that tamoxifen cowld affect the hormone levels and wherther it could reflect the ovarian function by monitering the hormone levels continuously for patients with breast cancer need to be researched.

Citation： LIXiao-shi, LÜQing, CHENJie, DUZheng-gui, TANQiu-wen, ZHANGDi, XIONGBing-jun. Pharmacological Mechanism of Tamoxifen and Its Influence on Ovary Function. CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY, 2015, 22(11): 1397-1404. doi: 10.7507/1007-9424.20150367 Copy

1.	von Ahsen N, Binder C, Brockmöller J, et al. CYP2D6 und tamoxifen:pharmakogenetische neuentdeckung eines etablierten medikaments?/CYP2D6 and tamoxifen:pharmacogenetic reinvention of an established drug? Lab Med, 2009, 33(5):293-302.
2.	Berliere M, Duhoux FP, Dalenc F, et al. Tamoxifen and ovarian function. PLoS One, 2013, 8(6):e66616.
3.	Harper MJ, Walpole AL. Contrasting endocrine activities of cis and trans isomers in a series of substituted triphenylethylenes. Nature, 1966, 212(5057):87.
4.	Skidmore J, Walpole AL, Woodburn J. Effect of some triphenylethylenes on oestradiol binding in vitro to macromolecules from uterus and anterior pituitary. J Endocrinol, 1972, 52(2):289-298.
5.	Jordan VC. Tamoxifen (ICI46, 474) as a targeted therapy to treat and prevent breast cancer. Br J Pharmacol, 2006, 147 Suppl 1:S269-S276.
6.	Meirow D, Raanani H, Maman E, et al. Tamoxifen co-administration during controlled ovarian hyperstimulation for in vitro fertilization in breast cancer patients increases the safety of fertility-preservation treatment strategies. Fertil Steril, 2014, 102(2):488-495.e3.
7.	龙馄.临床药物手册.北京:金盾出版社, 1992:193.
8.	Irvin WJ, Walko CM, Weck KE, et al. Genotype-guided tamoxifen dosing increases active metabolite exposure in women with reduced CYP2D6 metabolism:a multicenter study. J Clin Oncol, 2011, 29(24):3232-3239.
9.	Reid JM, Goetz MP, Buhrow SA, et al. Pharmacokinetics of endoxifen and tamoxifen in female mice:implications for comparative in vivo activity studies. Cancer Chemother Pharmacol, 2014, 74(6):1271-1278.
10.	Gjerde J, Kisanga ER, Hauglid M, et al. Identification and quantification of tamoxifen and four metabolites in serum by liquid chromatography-tandem mass spectrometry. J Chromatogr A, 2005, 1082(1):6-14.
11.	Borges S, Desta Z, Li L, et al. Quantitative effect of CYP2D6 genotype and inhibitors on tamoxifen metabolism:implication for optimization of breast cancer treatment. Clin Pharmacol Ther, 2006, 80(1):61-74.
12.	Newman WG, Hadfield KD, Latif A, et al. Impaired tamoxifen metabolism reduces survival in familial breast cancer patients. Clin Cancer Res, 2008, 14(18):5913-5918.
13.	Eichelbaum M, Ingelman-Sundberg M, Evans WE. Pharmacogenomics and individualized drug therapy. Annu Rev Med, 2006, 57:119-137.
14.	Ingelman-Sundberg M, Sim SC, Gomez A, et al. Influence of cytochrome P450 polymorphisms on drug therapies:pharmacogenetic, pharmacoepigenetic and clinical aspects. Pharmacol Ther, 2007, 116(3):496-526.
15.	Schroth W, Antoniadou L, Fritz P, et al. Breast cancer treatment outcome with adjuvant tamoxifen relative to patient CYP2D6 and CYP2C19 genotypes. J Clin Oncol, 2007, 25(33):5187-5193.
16.	Xu Y, Sun Y, Yao L, et al. Association between CYP2D6*10 genotype and survival of breast cancer patients receiving tamoxifen treatment. Ann Oncol, 2008, 19(8):1423-1429.
17.	Binkhorst L, Mathijssen RH, Jager A, et al. Individualization of tamoxifen therapy:much more than just CYP2D6 genotyping. Cancer Treat Rev, 2015, 41(3):289-299.
18.	Jin Y, Desta Z, Stearns V, et al. CYP2D6 genotype, antidepressant use, and tamoxifen metabolism during adjuvant breast cancer treatment. J Natl Cancer Inst, 2005, 97(1):30-39.
19.	Borges S, Desta Z, Li L, et al. Quantitative effect of CYP2D6 genotype and inhibitors on tamoxifen metabolism:implication for optimization of breast cancer treatment. Clin Pharmacol Ther, 2006, 80(1):61-74.
20.	Bradford LD. CYP2D6 allele frequency in European Caucasians, Asians, Africans and their descendants. Pharmacogenomics, 2002, 3(2):229-243.
21.	Griese EU, Asante-Poku S, Ofori-Adjei D, et al. Analysis of the CYP2D6 gene mutations and their consequences for enzyme function in a West African population. Pharmacogenetics, 1999, 9(6):715-723.
22.	Abraham JE, Maranian MJ, Driver KE, et al. CYP2D6 gene variants:association with breast cancer specific survival in a cohort of breast cancer patients from the United Kingdom treated with adjuvant tamoxifen. Breast Cancer Res, 2010, 12(4):R64.
23.	Ji L, Pan S, Wu J, et al. Genetic polymorphisms of CYP2D6 in Chinese mainland. Chin Med J, 2002, 115(12):1780-1784.
24.	Kubota T, Yamaura Y, Ohkawa N, et al. Frequencies of CYP2D6 mutant alleles in a normal Japanese population and metabolic activity of dextromethorphan O-demethylation in different CYP2D6 genotypes. Br J Clin Pharmacol, 2000, 50(1):31-34.
25.	Brauch H, Schroth W, Eichelbaum M, et al. Clinical relevance of CYP2D6 genetics for tamoxifen response in breast cancer. Breast Care (Basel), 2008, 3(1):43-50.
26.	Zeng Z, Liu Y, Liu Z, et al. CYP2D6 polymorphisms influence tamoxifen treatment outcomes in breast cancer patients:a metaanalysis. Cancer Chemother Pharmacol, 2013, 72(2):287-303.
27.	向华, 寥清江.选择性雌激素受体调节剂有关药物的研究进展.中国药房, 2001, 12(9):561-563.
28.	Cirillo F, Nassa G, Tarallo R, et al. Molecular mechanisms of selective estrogen receptor modulator activity in human breast cancer cells:identification of novel nuclear cofactors of antiestrogen-ERαcomplexes by interaction proteomics. J Proteome Res, 2013, 12(1):421-431.
29.	Kato S, Endoh H, Masuhiro Y, et al. Activation of the estrogen receptor through phosphorylation by mitogen-activated protein kinase. Science, 1995, 270(5241):1491-1494.
30.	Kumar V, Green S, Stack G, et al. Functional domains of the human estrogen receptor. Cell, 1987, 51(6):941-951.
31.	Murphy LC, Watson PH. Is oestrogen receptor-beta a predictor of endocrine therapy responsiveness in human breast cancer? Endocr Relat Cancer, 2006, 13(2):327-334.
32.	Thomas P, Pang Y, Filardo EJ, et al. Identity of an estrogen membrane receptor coupled to a G protein in human breast cancer cells. Endocrinology, 2005, 146(2):624-632.
33.	Filardo EJ, Graeber CT, Quinn JA, et al. Distribution of GPR30, a seven membrane-spanning estrogen receptor, in primary breast cancer and its association with clinicopathologic determinants of tumor progression. Clin Cancer Res, 2006, 12(21):6359-6366.
34.	Wang C, Prossnitz ER, Roy SK. G protein-coupled receptor 30 expression is required for estrogen stimulation of primordial follicle formation in the hamster ovary. Endocrinology, 2008, 149(9):4452-4461.
35.	赵承军, 邓其跃, 张东梅, 等.非基因型雌激素膜性受体GPR30在生后雌性大鼠海马内的发育学表达与亚细胞水平定位研究.生物化学与生物物理进展, 2009, 36(1):103-107.
36.	Otto C, Rohde-Schulz B, Schwarz G, et al. G protein-coupled receptor 30 localizes to the endoplasmic reticulum and is not activated by estradiol. Endocrinology, 2008, 149(10):4846-4856.
37.	Matsuda KI, Sakamoto H, Mori H, et al. Expression and intracellular distribution of the G protein-coupled receptor 30 in rat hippocampal formation. Neurosci Lett, 2008, 441(1):94-99.
38.	Carmeci C, Thompson DA, Ring HZ, et al. Identification of a gene (GPR30) with homology to the G-protein-coupled receptor superfamily associated with estrogen receptor expression in breast cancer. Genomics, 1997, 45(3):607-617.
39.	Filardo EJ, Quinn JA, Bland KI, et al. Estrogen-induced activation of Erk-1 and Erk-2 requires the G protein-coupled receptor homolog, GPR30, and occurs via trans-activation of the epidermal growth factor receptor through release of HB-EGF. Mol Endocrinol, 2000, 14(10):1649-1660.
40.	Filardo EJ. Epidermal growth factor receptor (EGFR) transactivation by estrogen via the G-protein-coupled receptor, GPR30:a novel signaling pathway with potential significance for breast cancer. J Steroid Biochem Mol Biol, 2002, 80(2):231-238.
41.	Revankar CM, Cimino DF, Sklar LA, et al. A transmembrane intracellular estrogen receptor mediates rapid cell signaling. Science, 2005, 307(5715):1625-1630.
42.	Lee JW, Lee YC, Na SY, et al. Transcriptional coregulators of the nuclear receptor superfamily:coactivators and corepressors. Cell Mol Life Sci, 2001, 58(2):289-297.
43.	Martini PG, Katzenellenbogen BS. Modulation of estrogen receptor activity by selective coregulators. J Steroid Biochem Mol Biol, 2003, 85(2-5):117-122.
44.	Riggs BL, Hartmann LC. Selective estrogen-receptor modulatorsmechanisms of action and application to clinical practice. N Engl J Med, 2003, 348(7):618-629.
45.	Savkur RS, Burris TP. The coactivator LXXLL nuclear receptor recognition motif. J Pept Res, 2004, 63(3):207-212.
46.	White JH, Fernandes I, Mader S, et al. Corepressor recruitment by agonist-bound nuclear receptors. Vitam Horm, 2004, 68(2):123-143.
47.	Klopper A, Hall M. New synthetic agent for the induction of ovulation:preliminary trials in women. Br Med J, 1971, 1(5741):152-154.
48.	Macourt DC. A new synthetic agent for the induction of ovulation. Med J Aust, 1974, 1(16):631-632.
49.	Shoda T, Aono T, Miyake A, et al. Study on the mechanism of ovulation induction during Clomid, Clomid-HCG and Clomid-HMG-HCG therapy in anovulatory patients. Acta Obstetrica et Gynaecologica Japonica, 1976, 23(2):161-162.
50.	Tajima C, Maeyama M. The clinical application of tamoxifen (author, s transl). Nihon Funin Gakkai Zasshi, 1979, 24(2):141-149.
51.	Tsuiki A, Uehara S, Kyono K, et al. Induction of ovulation with an estrogen antagonist, tamoxifen. Tohoku J Exp Med, 1984, 144(1):21-31.
52.	Messinis IE, Nillius SJ. Comparison between tamoxifen and clomiphene for induction of ovulation. Acta Obstet Gynecol Scand, 1982, 61(4):377-379.
53.	Boostanfar R, Jain JK, Mishell DR, et al. A prospective randomized trial comparing clomiphene citrate with tamoxifen citrate for ovulation induction. Fertil Steril, 2001, 75(5):1024-1026.
54.	Steiner AZ, Terplan M, Paulson RJ. Comparison of tamoxifen and clomiphene citrate for ovulation induction:a meta-analysis. Hum Reprod, 2005, 20(6):1511-1515.
55.	Williamson JG, Ellis JD. The induction of ovulation by tamoxifen. J Obstet Gynaecol Br Commonw, 1973, 80(9):844-847.
56.	Fukushima T, Tajima C, Fukuma K, et al. Tamoxifen in the treatment of infertility associated with luteal phase deficiency. Fertil Steril, 1982, 37(6):755-761.
57.	Groom GV, Griffiths K. Effect of the anti-oestrogen tamoxifen on plasma levels of luteinizing hormone, follicle-stimulating hormone, prolactin, oestradiol and progesterone in normal pre-menopausal women. J Endocrinol, 1976, 70(3):421-428.
58.	Powles TJ, Jones AL, Ashley SE, et al. The royal marsden hospital pilot tamoxifen chemoprevention trial. Breast Cancer Res Treat, 1994, 31(1):73-82.
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1. von Ahsen N, Binder C, Brockmöller J, et al. CYP2D6 und tamoxifen:pharmakogenetische neuentdeckung eines etablierten medikaments?/CYP2D6 and tamoxifen:pharmacogenetic reinvention of an established drug? Lab Med, 2009, 33(5):293-302.
2. Berliere M, Duhoux FP, Dalenc F, et al. Tamoxifen and ovarian function. PLoS One, 2013, 8(6):e66616.
3. Harper MJ, Walpole AL. Contrasting endocrine activities of cis and trans isomers in a series of substituted triphenylethylenes. Nature, 1966, 212(5057):87.
4. Skidmore J, Walpole AL, Woodburn J. Effect of some triphenylethylenes on oestradiol binding in vitro to macromolecules from uterus and anterior pituitary. J Endocrinol, 1972, 52(2):289-298.
5. Jordan VC. Tamoxifen (ICI46, 474) as a targeted therapy to treat and prevent breast cancer. Br J Pharmacol, 2006, 147 Suppl 1:S269-S276.
6. Meirow D, Raanani H, Maman E, et al. Tamoxifen co-administration during controlled ovarian hyperstimulation for in vitro fertilization in breast cancer patients increases the safety of fertility-preservation treatment strategies. Fertil Steril, 2014, 102(2):488-495.e3.
7. 龙馄.临床药物手册.北京:金盾出版社, 1992:193.
8. Irvin WJ, Walko CM, Weck KE, et al. Genotype-guided tamoxifen dosing increases active metabolite exposure in women with reduced CYP2D6 metabolism:a multicenter study. J Clin Oncol, 2011, 29(24):3232-3239.
9. Reid JM, Goetz MP, Buhrow SA, et al. Pharmacokinetics of endoxifen and tamoxifen in female mice:implications for comparative in vivo activity studies. Cancer Chemother Pharmacol, 2014, 74(6):1271-1278.
10. Gjerde J, Kisanga ER, Hauglid M, et al. Identification and quantification of tamoxifen and four metabolites in serum by liquid chromatography-tandem mass spectrometry. J Chromatogr A, 2005, 1082(1):6-14.
11. Borges S, Desta Z, Li L, et al. Quantitative effect of CYP2D6 genotype and inhibitors on tamoxifen metabolism:implication for optimization of breast cancer treatment. Clin Pharmacol Ther, 2006, 80(1):61-74.
12. Newman WG, Hadfield KD, Latif A, et al. Impaired tamoxifen metabolism reduces survival in familial breast cancer patients. Clin Cancer Res, 2008, 14(18):5913-5918.
13. Eichelbaum M, Ingelman-Sundberg M, Evans WE. Pharmacogenomics and individualized drug therapy. Annu Rev Med, 2006, 57:119-137.
14. Ingelman-Sundberg M, Sim SC, Gomez A, et al. Influence of cytochrome P450 polymorphisms on drug therapies:pharmacogenetic, pharmacoepigenetic and clinical aspects. Pharmacol Ther, 2007, 116(3):496-526.
15. Schroth W, Antoniadou L, Fritz P, et al. Breast cancer treatment outcome with adjuvant tamoxifen relative to patient CYP2D6 and CYP2C19 genotypes. J Clin Oncol, 2007, 25(33):5187-5193.
16. Xu Y, Sun Y, Yao L, et al. Association between CYP2D6*10 genotype and survival of breast cancer patients receiving tamoxifen treatment. Ann Oncol, 2008, 19(8):1423-1429.
17. Binkhorst L, Mathijssen RH, Jager A, et al. Individualization of tamoxifen therapy:much more than just CYP2D6 genotyping. Cancer Treat Rev, 2015, 41(3):289-299.
18. Jin Y, Desta Z, Stearns V, et al. CYP2D6 genotype, antidepressant use, and tamoxifen metabolism during adjuvant breast cancer treatment. J Natl Cancer Inst, 2005, 97(1):30-39.
19. Borges S, Desta Z, Li L, et al. Quantitative effect of CYP2D6 genotype and inhibitors on tamoxifen metabolism:implication for optimization of breast cancer treatment. Clin Pharmacol Ther, 2006, 80(1):61-74.
20. Bradford LD. CYP2D6 allele frequency in European Caucasians, Asians, Africans and their descendants. Pharmacogenomics, 2002, 3(2):229-243.
21. Griese EU, Asante-Poku S, Ofori-Adjei D, et al. Analysis of the CYP2D6 gene mutations and their consequences for enzyme function in a West African population. Pharmacogenetics, 1999, 9(6):715-723.
22. Abraham JE, Maranian MJ, Driver KE, et al. CYP2D6 gene variants:association with breast cancer specific survival in a cohort of breast cancer patients from the United Kingdom treated with adjuvant tamoxifen. Breast Cancer Res, 2010, 12(4):R64.
23. Ji L, Pan S, Wu J, et al. Genetic polymorphisms of CYP2D6 in Chinese mainland. Chin Med J, 2002, 115(12):1780-1784.
24. Kubota T, Yamaura Y, Ohkawa N, et al. Frequencies of CYP2D6 mutant alleles in a normal Japanese population and metabolic activity of dextromethorphan O-demethylation in different CYP2D6 genotypes. Br J Clin Pharmacol, 2000, 50(1):31-34.
25. Brauch H, Schroth W, Eichelbaum M, et al. Clinical relevance of CYP2D6 genetics for tamoxifen response in breast cancer. Breast Care (Basel), 2008, 3(1):43-50.
26. Zeng Z, Liu Y, Liu Z, et al. CYP2D6 polymorphisms influence tamoxifen treatment outcomes in breast cancer patients:a metaanalysis. Cancer Chemother Pharmacol, 2013, 72(2):287-303.
27. 向华, 寥清江.选择性雌激素受体调节剂有关药物的研究进展.中国药房, 2001, 12(9):561-563.
28. Cirillo F, Nassa G, Tarallo R, et al. Molecular mechanisms of selective estrogen receptor modulator activity in human breast cancer cells:identification of novel nuclear cofactors of antiestrogen-ERαcomplexes by interaction proteomics. J Proteome Res, 2013, 12(1):421-431.
29. Kato S, Endoh H, Masuhiro Y, et al. Activation of the estrogen receptor through phosphorylation by mitogen-activated protein kinase. Science, 1995, 270(5241):1491-1494.
30. Kumar V, Green S, Stack G, et al. Functional domains of the human estrogen receptor. Cell, 1987, 51(6):941-951.
31. Murphy LC, Watson PH. Is oestrogen receptor-beta a predictor of endocrine therapy responsiveness in human breast cancer? Endocr Relat Cancer, 2006, 13(2):327-334.
32. Thomas P, Pang Y, Filardo EJ, et al. Identity of an estrogen membrane receptor coupled to a G protein in human breast cancer cells. Endocrinology, 2005, 146(2):624-632.
33. Filardo EJ, Graeber CT, Quinn JA, et al. Distribution of GPR30, a seven membrane-spanning estrogen receptor, in primary breast cancer and its association with clinicopathologic determinants of tumor progression. Clin Cancer Res, 2006, 12(21):6359-6366.
34. Wang C, Prossnitz ER, Roy SK. G protein-coupled receptor 30 expression is required for estrogen stimulation of primordial follicle formation in the hamster ovary. Endocrinology, 2008, 149(9):4452-4461.
35. 赵承军, 邓其跃, 张东梅, 等.非基因型雌激素膜性受体GPR30在生后雌性大鼠海马内的发育学表达与亚细胞水平定位研究.生物化学与生物物理进展, 2009, 36(1):103-107.
36. Otto C, Rohde-Schulz B, Schwarz G, et al. G protein-coupled receptor 30 localizes to the endoplasmic reticulum and is not activated by estradiol. Endocrinology, 2008, 149(10):4846-4856.
37. Matsuda KI, Sakamoto H, Mori H, et al. Expression and intracellular distribution of the G protein-coupled receptor 30 in rat hippocampal formation. Neurosci Lett, 2008, 441(1):94-99.
38. Carmeci C, Thompson DA, Ring HZ, et al. Identification of a gene (GPR30) with homology to the G-protein-coupled receptor superfamily associated with estrogen receptor expression in breast cancer. Genomics, 1997, 45(3):607-617.
39. Filardo EJ, Quinn JA, Bland KI, et al. Estrogen-induced activation of Erk-1 and Erk-2 requires the G protein-coupled receptor homolog, GPR30, and occurs via trans-activation of the epidermal growth factor receptor through release of HB-EGF. Mol Endocrinol, 2000, 14(10):1649-1660.
40. Filardo EJ. Epidermal growth factor receptor (EGFR) transactivation by estrogen via the G-protein-coupled receptor, GPR30:a novel signaling pathway with potential significance for breast cancer. J Steroid Biochem Mol Biol, 2002, 80(2):231-238.
41. Revankar CM, Cimino DF, Sklar LA, et al. A transmembrane intracellular estrogen receptor mediates rapid cell signaling. Science, 2005, 307(5715):1625-1630.
42. Lee JW, Lee YC, Na SY, et al. Transcriptional coregulators of the nuclear receptor superfamily:coactivators and corepressors. Cell Mol Life Sci, 2001, 58(2):289-297.
43. Martini PG, Katzenellenbogen BS. Modulation of estrogen receptor activity by selective coregulators. J Steroid Biochem Mol Biol, 2003, 85(2-5):117-122.
44. Riggs BL, Hartmann LC. Selective estrogen-receptor modulatorsmechanisms of action and application to clinical practice. N Engl J Med, 2003, 348(7):618-629.
45. Savkur RS, Burris TP. The coactivator LXXLL nuclear receptor recognition motif. J Pept Res, 2004, 63(3):207-212.
46. White JH, Fernandes I, Mader S, et al. Corepressor recruitment by agonist-bound nuclear receptors. Vitam Horm, 2004, 68(2):123-143.
47. Klopper A, Hall M. New synthetic agent for the induction of ovulation:preliminary trials in women. Br Med J, 1971, 1(5741):152-154.
48. Macourt DC. A new synthetic agent for the induction of ovulation. Med J Aust, 1974, 1(16):631-632.
49. Shoda T, Aono T, Miyake A, et al. Study on the mechanism of ovulation induction during Clomid, Clomid-HCG and Clomid-HMG-HCG therapy in anovulatory patients. Acta Obstetrica et Gynaecologica Japonica, 1976, 23(2):161-162.
50. Tajima C, Maeyama M. The clinical application of tamoxifen (author, s transl). Nihon Funin Gakkai Zasshi, 1979, 24(2):141-149.
51. Tsuiki A, Uehara S, Kyono K, et al. Induction of ovulation with an estrogen antagonist, tamoxifen. Tohoku J Exp Med, 1984, 144(1):21-31.
52. Messinis IE, Nillius SJ. Comparison between tamoxifen and clomiphene for induction of ovulation. Acta Obstet Gynecol Scand, 1982, 61(4):377-379.
53. Boostanfar R, Jain JK, Mishell DR, et al. A prospective randomized trial comparing clomiphene citrate with tamoxifen citrate for ovulation induction. Fertil Steril, 2001, 75(5):1024-1026.
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CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Pharmacological Mechanism of Tamoxifen and Its Influence on Ovary Function

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