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BMC Women's Health
Published in: BMC Women's Health 1/2006

Open Access 01-12-2006 | Research article

Effects of tamoxifen on vaginal blood flow and epithelial morphology in the rat

Authors: Noel N Kim, Miljan Stankovic, Abdullah Armagan, Tulay T Cushman, Irwin Goldstein, Abdulmaged M Traish

Published in: BMC Women's Health | Issue 1/2006

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Abstract

Background

Tamoxifen, a selective estrogen receptor modulator with both estrogenic and anti-estrogenic activity, is widely used as adjuvant therapy in breast cancer patients. Treatment with tamoxifen is associated with sexual side effects, such as increased vaginal dryness and pain/discomfort during sexual activity. There have been limited investigations of the effect of tamoxifen on estrogen-dependent peripheral genital arousal responses. The objective of this study was to investigate the effects of tamoxifen on vaginal physiology in the rat.

Methods

Female Sprague-Dawley rats were subjected to sham surgery or bilateral ovariectomy. After 2 weeks, sham-operated rats were implanted with subcutaneous osmotic infusion pumps containing vehicle (control) or tamoxifen (150 μg/day). Ovariectomized rats were similarly infused with vehicle. After an additional 2 weeks, vaginal blood flow responses to pelvic nerve stimulation were measured by laser Doppler flowmetry and vaginal tissue was collected for histological and biochemical assay.

Results

Tamoxifen treatment did not change plasma estradiol concentrations relative to control animals, while ovariectomized rats exhibited a 60% decrease in plasma estradiol. Tamoxifen treatment caused a significant decrease in mean uterine weight, but did not alter mean vaginal weight. Vaginal blood flow was significantly decreased in tamoxifen-infused rats compared to controls. Similar to ovariectomized animals, estrogen receptor binding was increased and arginase enzyme activity was decreased in tamoxifen-infused rats. However, different from control and ovariectomized animals, the vaginal epithelium in tamoxifen-infused rats appeared highly mucified. Periodic acid-Schiff staining confirmed a greater production of carbohydrate-rich compounds (e.g. mucin, glycogen) by the vaginal epithelium of tamoxifen-infused rats.

Conclusion

The observations suggest that tamoxifen exerts both anti-estrogenic and pro-estrogenic effects in the vagina. These physiological alterations may eventually lead to vaginal atrophy and compromise sexual function.
Appendix
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Literature
1.
Jordan VC: Tamoxifen: a most unlikely pioneering medicine. Nat Rev Drug Discov. 2003, 2: 205-213. 10.1038/nrd1031.CrossRefPubMed
2.
Jordan VC, Collins MM, Rowsby L, Prestwich G: A monohydroxylated metabolite of tamoxifen with potent antioestrogenic activity. J Endocrinol. 1977, 75: 305-316.CrossRefPubMed
3.
Allen KE, Clark ER, Jordan VC: Evidence for the metabolic activation of non-steroidal antioestrogens: a study of structure-activity relationships. Br J Pharmacol. 1980, 71: 83-91.CrossRefPubMedPubMedCentral
4.
Katzenellenbogen BS, Norman MJ, Eckert RL, Peltz SW, Mangel WF: Bioactivities, estrogen receptor interactions, and plasminogen activator-inducing activities of tamoxifen and hydroxy-tamoxifen isomers in MCF-7 human breast cancer cells. Cancer Res. 1984, 44: 112-119.PubMed
5.
Benshushan A, Brzezinski A: Tamoxifen effects on menopause-associated risk factors and symptoms. Obstet Gynecol Surv. 1999, 54: 272-278. 10.1097/00006254-199904000-00024.CrossRefPubMed
6.
Mourits MJ, De Vries EG, Willemse PH, Ten Hoor KA, Hollema H, Van der Zee AG: Tamoxifen treatment and gynecologic side effects: a review. Obstet Gynecol. 2001, 97: 855-866. 10.1016/S0029-7844(00)01196-0.PubMed
7.
Mortimer JE, Boucher L, Baty J, Knapp DL, Ryan E, Rowland JH: Effect of tamoxifen on sexual functioning in patients with breast cancer. J Clin Oncol. 1999, 17: 1488-1492.PubMed
8.
Marttunen MB, Cacciatore B, Hietanen P, Pyrhönen S, Tiitinen A, Wahlström T, Ylikorkala O: Prospective study on gynaecological effects of two antioestrogens tamoxifen and toremifene in postmenopausal women. Br J Cancer. 2001, 84: 897-902. 10.1054/bjoc.2001.1703.CrossRefPubMedPubMedCentral
9.
10.
Fornander T, Rutqvist LE, Cedermark B, Glas U, Mattsson A, Silfverswärd C, Skoog L, Somell A, Theve T, Wilking N, Askergren J, Hjalmar ML: Adjuvant tamoxifen in early breast cancer: occurrence of new primary cancers. Lancet. 1989, 1: 117-120. 10.1016/S0140-6736(89)91141-0.CrossRefPubMed
11.
Fisher B, Costantino JP, Redmond CK, Fisher ER, Wickerham DL, Cronin WM: Endometrial cancer in tamoxifen-treated breast cancer patients: findings from the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-14. J Natl Cancer Inst. 1994, 86: 527-537.CrossRefPubMed
12.
Sasco AJ, Chaplain G, Amoros E, Saez S: Endometrial cancer following breast cancer: Effect of tamoxifen and castration by radiotherapy. Epidemiology. 1996, 7: 9-13.CrossRefPubMed
13.
Morales L, Neven P, Timmerman D, Christiaens MR, Vergote I, Van Limbergen E, Carbonez A, Van Huffel S, Ameye L, Paridaens R: Acute effects of tamoxifen and third-generation aromatase inhibitors on menopausal symptoms of breast cancer patients. Anticancer Drugs. 2004, 15: 753-760. 10.1097/00001813-200409000-00003.CrossRefPubMed
14.
Mourits MJ, Bockermann I, de Vries EG, van der Zee AG, ten Hoor KA, van der Graaf WT, Sluiter WJ, Willemse PH: Tamoxifen effects on subjective and psychosexual well-being, in a randomised breast cancer study comparing high-dose and standard-dose chemotherapy. Br J Cancer. 2002, 86: 1546-1550. 10.1038/sj.bjc.6600294.CrossRefPubMedPubMedCentral
15.
Ganz PA, Desmond KA, Leedham B, Rowland JH, Meyerowitz BE, Belin TR: Quality of life in long-term, disease-free survivors of breast cancer: a follow-up study. J Natl Cancer Inst. 2002, 94: 39-49.CrossRefPubMed
16.
Park K, Ahn K, Lee S, Ryu S, Park Y, Azadzoi KM: Decreased circulating levels of estrogen alter vaginal and clitoral blood flow and structure in the rabbit. Int J Impot Res. 2001, 13: 116-24. 10.1038/sj.ijir.3900655.CrossRefPubMed
17.
Min K, Munarriz R, Kim NN, Goldstein I, Traish A: Effects of ovariectomy and estrogen and androgen treatment on sildenafil-mediated changes in female genital blood flow and vaginal lubrication in the animal model. Am J Obstet Gynecol. 2002, 187: 1370-1376. 10.1067/mob.2002.126641.CrossRefPubMed
18.
Min K, Munarriz R, Kim NN, Choi S, O'Connell L, Goldstein I, Traish AM: Effects of ovariectomy and estrogen replacement on basal and pelvic nerve stimulated vaginal lubrication in an animal model. J Sex Marital Ther. 2003, 29: 77-84.CrossRefPubMed
19.
Kim SW, Kim NN, Jeong SJ, Munarriz R, Goldstein I, Traish AM: Modulation of rat vaginal blood flow and estrogen receptor by estradiol. J Urol. 2004, 172: 1538-1543. 10.1097/01.ju.0000137744.12814.2e.CrossRefPubMed
20.
Kim SW, Jeong SJ, Munarriz R, Kim NN, Goldstein I, Traish AM: An in vivo rat model to investigate female vaginal arousal response. J Urol. 2004, 171: 1357-1361. 10.1097/01.ju.0000109868.19569.d7.CrossRefPubMed
21.
Traish AM, Muller RE, Wotiz HH: A new procedure for the quantitation of nuclear and cytoplasmic androgen receptors. J Biol Chem. 1981, 256: 12028-12033.PubMed
22.
Katzenellenbogen JA, Johnson HJ, Carlson KE: Studies on the uterine, cytoplasmic estrogen binding protein. Thermal stability and ligand dissociation rate. An assay of empty and filled sites by exchange. Biochemistry. 1973, 12: 4092-4099. 10.1021/bi00745a011.CrossRefPubMed
23.
Kim NN, Cox JD, Baggio RF, Emig FA, Mistry SK, Harper SL, Speicher DW, Morris SM, Ash DE, Traish A, Christianson DW: Probing erectile function: S-(2-boronoethyl)-L-cysteine binds to arginase as a transition state analogue and enhances smooth muscle relaxation in human penile corpus cavernosum. Biochemistry. 2001, 40: 2678-2688. 10.1021/bi002317h.CrossRefPubMed
24.
Pessina MA, Hoyt RF, Goldstein I, Traish AM: Differential effects of estradiol, progesterone, and testosterone on vaginal structural integrity. Endocrinol. 2006, 147: 61-69. 10.1210/en.2005-0870.CrossRef
25.
Sjoberg NO: Increase in transmitter content of adrenergic nerves in the reproductive tract of female rabbits after oestrogen treatment. Acta Endocrinol (Copenh). 1968, 57: 405-413.
26.
Owman C: Pregnancy induces degenerative and regenerative changes in the autonomic innervation of the female reproductive tract. Ciba Found Symp. 1981, 83: 252-279.PubMed
27.
Kaleczyc J: Effect of estradiol and progesterone on noradrenaline content in nerves of the oviduct, uterus and vagina in ovariectomized pigs. Folia Histochem Cytobiol. 1994, 32: 119-126.PubMed
28.
Forsberg JG: A morphologist's approach to the vagina – age-related changes and estrogen sensitivity. Maturitas. 1995, S7-S15. 10.1016/0378-5122(95)00957-4. 22 Suppl
29.
Ting AY, Blacklock AD, Smith PG: Estrogen regulates vaginal sensory and autonomic nerve density in the rat. Biol Reprod. 2004, 71: 1397-1404. 10.1095/biolreprod.104.030023.CrossRefPubMed
30.
Kim NN, Min K, Pessina MA, Munarriz R, Goldstein I, Traish AM: Effects of ovariectomy and steroid hormones on vaginal smooth muscle contractility. Int J Impot Res. 2004, 16: 43-50. 10.1038/sj.ijir.3901138.CrossRefPubMed
31.
Al-Hijji J, Larsson B, Batra S: Nitric oxide synthase in the rabbit uterus and vagina: hormonal regulation and functional significance. Biol Reprod. 2000, 62: 1387-1392. 10.1095/biolreprod62.5.1387.CrossRefPubMed
32.
Berman JR, McCarthy MM, Kyprianou N: Effect of estrogen withdrawal on nitric oxide synthase expression and apoptosis in the rat vagina. Urology. 1998, 51: 650-656. 10.1016/S0090-4295(97)00683-3.CrossRefPubMed
33.
Traish AM, Kim NN, Huang YH, Min K, Munarriz R, Goldstein I: Sex steroid hormones differentially regulate nitric oxide synthase and arginase activities in the proximal and distal rabbit vagina. Int J Impot Res. 2003, 15: 397-404. 10.1038/sj.ijir.3901097.CrossRefPubMed
34.
Kim NN, Christianson DW, Traish AM: Role of arginase in the male and female sexual arousal response. J Nutr. 2004, 134 (10 Suppl): 2873S-2879S.PubMed
35.
Li H, Meininger CJ, Kelly KA, Hawker JR, Morris SM, Wu G: Activities of arginase I and II are limiting for endothelial cell proliferation. Am J Physiol Regul Integr Comp Physiol. 2002, 282: R64-9.PubMed
36.
37.
Vijayalakshmi V, Gupta PD: Estradiol-regulated transamidation of keratins by vaginal epithelial cell transglutaminase. Exp Cell Res. 1994, 214: 358-366. 10.1006/excr.1994.1268.CrossRefPubMed
38.
Gupta PD, Swarup G, Reddy AG: Modulation of phosphorylation and dephosphorylation of keratin and other polypeptides by estradiol-17β in rat vaginal epithelium. FEBS Lett. 1990, 273: 135-138. 10.1016/0014-5793(90)81068-Y.CrossRefPubMed
39.
Iguchi T, Todoroki R, Yamaguchi S, Takasugi N: Changes in the uterus and vagina of mice treated neonatally with antiestrogens. Acta Anat (Basel). 1989, 136: 146-154.CrossRef
40.
Carthew P, Edwards RE, Noloan BM, Martin EA, Heydon RT, White IN, Tucker MJ: Tamoxifen induces endometrial and vaginal cancer in rats in the absence of endometrial hyperplasia. Carcinogenesis. 2000, 21: 793-797. 10.1093/carcin/21.4.793.CrossRefPubMed
41.
Ketani MA, Ketani S, Kaloglu C, Guney B: Effects of tamoxifen administration in rat vaginas: an ultrastructural and light microscopy study. Eur J Gynaecol Oncol. 2002, 23: 557-560.PubMed
42.
Lahti E, Vuopala S, Kauppila A, Blanco G, Ruokonen A, Laatikainen T: Maturation of vaginal and endometrial epithelium in postmenopausal breast cancer patients receiving long-term tamoxifen. Gynecol Oncol. 1994, 55: 410-414. 10.1006/gyno.1994.1314.CrossRefPubMed
43.
Yokosuka K, Teshima H, Katase K, Fujimoto I, Yamauchi K, Hasumi K, Tatsuki Y: Effects of long-term administration of tamoxifen on vaginal epithelium and complications of endometrial lesions in breast cancer patients. Nippon Sanka Fujinka Gakkai Zasshi. 1995, 47: 125-132.PubMed
44.
Bertolissi A, Cartei G, Turrin D, Cioschi B, Rizzi V: Behaviour of vaginal epithelial maturation and sex hormone binding globulin in post-menopausal breast cancer patients during the first year of tamoxifen therapy. Cytopathology. 1998, 9: 263-270. 10.1046/j.1365-2303.1998.00077.x.CrossRefPubMed
45.
Friedrich M, Mink D, Villena-Heinsen C, Woll-Hermann A, Schmidt W: Tamoxifen and proliferation of vaginal and cervical epithelium in postmenopausal women with breast cancer. Eur J Obstet Gynecol Reprod Biol. 1998, 80: 221-225. 10.1016/S0301-2115(98)00117-1.CrossRefPubMed
46.
Love RR, Kurtycz DF, Dumesic DA, Laube DW, Yang Y: The effects of tamoxifen on the vaginal epithelium in postmenopausal women. J Womens Health Gend Based Med. 2000, 9: 559-563. 10.1089/15246090050073648.CrossRefPubMed
47.
Ellmen J, Hakulinen P, Partanen A, Hayes DF: Estrogenic effects of toremifene and tamoxifen in postmenopausal breast cancer patients. Breast Cancer Res Treat. 2003, 82: 103-111. 10.1023/B:BREA.0000003957.54851.11.CrossRefPubMed
48.
O'Brian CA, Liskamp RM, Solomon DH, Weinstein IB: Inhibition of protein kinase C by tamoxifen. Cancer Res. 1985, 45: 2462-2465.PubMed
49.
Lam H-YP: Tamoxifen is a calmodulin antagonist in the activation of cAMP phosphodiesterase. Biochem Biophys Res Commun. 1984, 118: 27-32. 10.1016/0006-291X(84)91062-3.CrossRefPubMed
50.
Riggs BL, Hartmann LC: Selective estrogen-receptor modulators – mechanisms of action and application to clinical practice. New Engl J Med. 2003, 348: 618-629. 10.1056/NEJMra022219.CrossRefPubMed
51.
Jordan VC: Selective estrogen receptor modulation: Concept and consequences in cancer. Cancer Cell. 2004, 5: 207-213. 10.1016/S1535-6108(04)00059-5.CrossRefPubMed
52.
Katzenellenbogen BS, Frasor J: Therapeutic targeting in the estrogen receptor hormonal pathway. Semin Oncol. 2004, 31 (Suppl 3): 28-38. 10.1053/j.seminoncol.2004.01.004.CrossRefPubMed
53.
Singh S, Gupta PD: Induction of phosphoinositide-mediated signal transduction pathway by 17β-oestradiol in rat vaginal epithelial cells. J Mol Endocrinol. 1997, 19: 249-257. 10.1677/jme.0.0190249.CrossRefPubMed
54.
Singh S, Shaul PW, Gupta PD: Conventional estrogen receptors are found in the plasma membrane of vaginal epithelial cells of the rat. Steroids. 2002, 67: 757-764. 10.1016/S0039-128X(02)00028-4.CrossRefPubMed
55.
Balasinor N, Parte P, Gill-Sharma MK, Kini J, Juneja HS: Mechanism delineating differential effect of an antiestrogen, tamoxifen, on the serum LH and FSH in adult male rats. J Endocrinol Invest. 2006, 29: 485-496.CrossRefPubMed
56.
Ickenstein LM, Holsmer SL, Bandiera SM: Tamoxifen alters hepatic cytochrome P450 enzyme expression and circulating growth hormone levels in intact male rats. Pharm Res. 2004, 21: 1631-1636. 10.1023/B:PHAM.0000041458.81836.c4.CrossRefPubMed
57.
Lofgren L, Wallberg B, Wilking N, Fornander T, Rutqvist LE, Carlstrom K, von Schoultz B, von Schoultz E: Tamoxifen and megestrol acetate for postmenopausal breast cancer: diverging effects on liver proteins, androgen, and glucocorticoids. Med Oncol. 2004, 21: 309-318. 10.1385/MO:21:4:309.CrossRefPubMed
58.
Leo G, Cappiello G, Poltronieri P, Giardina C, Manca C, Storelli C, Marsigliante S: Tamoxifen binding sites heterogeneity in breast cancer: a comparative study with steroid hormone receptors. Eur J Cancer. 1991, 27: 452-456.CrossRefPubMed
59.
Kawashima H, Tanaka T, Cheng JS, Sugita S, Ezaki K, Kurisu T, Nakatani T: Effect of anti-estrogens on the androgen receptor activity and cell proliferation in prostate cancer cells. Urol Res. 2004, 32: 406-410. 10.1007/s00240-004-0424-8.CrossRefPubMed
60.
Lim CK, Yuan ZX, Lamb JH, White IN, De Matteis F, Smith LL: A comparative study of tamoxifen metabolism in female rat, mouse and human liver microsomes. Carcinogenesis. 1994, 15: 589-593.CrossRefPubMed
61.
Glatt H, Davis W, Meinl W, Hermersdorfer H, Venitt S, Phillips DH: Rat, but not human, sulfotransferase activates a tamoxifen metabolite to produce DNA adducts and gene mutations in bacteria and mammalian cells in culture. Carcinogenesis. 1998, 19: 1709-1713. 10.1093/carcin/19.10.1709.CrossRefPubMed
Metadata
Title
Effects of tamoxifen on vaginal blood flow and epithelial morphology in the rat
Authors
Noel N Kim
Miljan Stankovic
Abdullah Armagan
Tulay T Cushman
Irwin Goldstein
Abdulmaged M Traish
Publication date
01-12-2006
Publisher
BioMed Central
Published in
BMC Women's Health / Issue 1/2006
Electronic ISSN: 1472-6874
DOI
https://doi.org/10.1186/1472-6874-6-14

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