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Uterine leiomyomata and endometrial proliferation in postmenopausal women treated with the anti-oestrogen tamoxifen
European Journal of Obstetrics & Gynecology and IReproductive Biology 54 (I 994) I53- 156
Uterine leiomyomata and endometrial proliferation in postmenopausal women treated with the anti-oestrogen tamoxifen Austin H.N. Ugwumadu*a, Kate Hardingb “Department of Obsterics and Gynaecology, Queen Mary S University Hospital, Roehampton, London S WI5 SPN, UK bDeparrmenr of Obstetrics and Gynaecology, Chelsea and Westminster Hospital, Fulham Road, London SWIO 9NH, UK
(Accepted 1994)
Abstract
Two cases of fibroid growth and endometrial proliferqtion in postmenopausal women on tamoxifen (anti-oestrogen) breast cancer are described. Oestrogen in association with growth factors may control fibroid growth and differentiation.
therapy for The possi-
ble mechanisms and consequences of tamoxifen-induced fibroid growth are discussed. Oestrogen responsive tissues demonstrate a differential and contrasting response to tamoxifen and caution should be exercised in the expansion of its clinical application. Women on long-term tamoxifen therapy may benefit from ultrasound surveillance of their uterus and endometrium, with biopsy in suspicious cases, as there is a paucity of data on malignant transformation of these benign lesions induced by tamoxifen therapy. Key words:
Tamoxifen; Fibroid; Endometrial proliferation
1. Introduction Tamoxifen is a partial oestrogen agonist used mainly as adjuvant therapy for oestrogen receptor (ER) positive breast cancers. It binds irreversibly to the ER in the nuclei of responsive cells and is capable of activating receptor dimerisation and DNA binding with induction of transcription [I]. Messenger RNA and protein synthesis follow with resultant growth and proliferation. The prolonged nuclear binding is thought to deplete receptor sites and decrease tissue responsiveness to oestrogen, causing antagonist effects. This sequence of events is, however, not uniformly observed in all oestrogen responsive tissues, particularly the female genital tract where persistent stimulation by tamoxifen may result in endometrial proliferation, hyperplasia and polyposis [2-61, reactivation of dormant endometriosis [7,8], adenomyosis and giant adenomyomatous endometrial polyp [9], endometrial carcinoma [lo, 1 l] and oestrogenisation of the vaginal epithelium [ 121. All may occur in postmenopausal women treated with tamoxifen. * Corresponding author.
Oestrogenic effects of tamoxifen have also been reported in the liver, where sex hormone binding globulin (SHBG), corticotrophin and thyroid binding globulins synthesis were induced [ 13,141. Primary hepatocellular carcinoma has been associated with tamoxifen therapy in humans and in experimental animals [ 15,161. That the growth and differentiation of fibroids is dependent on oestrogen is undisputed. Fibroids occur almost entirely during the reproductive years, increase in growth during pregnancy and regress after the menopause. Recently, they have been shown to regress with gonadotrophin releasing hormone agonist (GnRH-A) treatment in premenopausal women [17-191. What is unclear, however, is whether oestrogen exerts this trophic effect by directly binding to the ER on the fibroids or through binding to the fibroids of secondary peptide hormone mediators - epidermal growth factor (EGF), insulin-like growth factors (IGF I & II) and transformation growth factor (TGF-ar) - or by both mechanisms. These growth factors, especially EGF, play an important role in the pathogenesis of uterine fibroids [20] and EGF receptors are present in fibroids and the surrounding myometrium [21]. Experimental evidence
0028-2243/94/$07.00 0 1994 Elsevier Science Ireland Ltd. All rights reserved. SSDI 0028-2243(94)01812-L
154
A.H.N. Ugwumadu, K. Harding / Eur. J. Obsret. Gynecol. Reprod. Biol. 54 (1994) 153-156
shows that oestrogen regulates the binding of EGF to the rat uterus [22] and increases the content of EGF and its receptors in the mouse uterus [23,24]. There is as yet no evidence in the published literature that tamoxifen regulates growth factor metabolism in fibroids but this remains a theoretical possibility given its proven oestrogenic actions. These agonist actions are exhibited predominantly in hypoestrogenic states such as menopause and treatment with GnRH-A [12,18]. Current evidence would suggest that oestrogen exerts its effects through the paracrine influence of growth factors as well as through gene transcription mediated through oestrogen receptors [ 1g-20,25]. The binding of EGF to fibroids has been shown to be significantly decreased in women rendered hypoestrogenic by GnRH-A [20], suggesting that oestrogen action may be mediated by EGF. Expression of steroid receptors may also be influenced by growth factors such that the effects of oestrogen and growth factors are intimately related and interdependent. ERs are present in fibroids in higher concentration than the surrounding myometrium [25,26] and if treated with GnRH-A the fibroids shrink in size but show a paradoxical increase in ER concentration [18,25,27]. In these GnRH-A-treated women the fibroids fail to shrink in size when tamoxifen is administered simultaneously [18,28]. This lack of response despite profound oestrogen suppression suggests that tamoxifen is exhibiting oestrogenic actions. 2. Case reports 2.1. Case 1 A 56-year-old nulligravid woman presented in June 1992 with postmenopausal bleeding. Her menopause was in 1985 at the age of 49. Two months before her periods ceased she had dilation and curettage for polymenorrhoea. The uterine size then was noted to be normal and histology of the curettings showed normal proliferative endometrium. In 1986, she had a left mastectomy and lymph node biopsy for a stage T2a invasive duct carcinoma of the breast. Post-operatively she received radiotherapy and was commenced on tamoxifen 20 mg daily. In 1988, her general practitioner took a smear, performed bimanual examination and noted that the uterus was irregular and about the size of a 6-g-weeks gestation. A routine recall smear test in 1991 was normal but bimanual examination was not performed on that occasion. On physical examination in 1992 she had a 20-week sized firm uterine mass. Pelvic ultrasound showed ‘a large completely heterogenous uterus measuring 18.2 x 8.5 x 7 cm with a 9.3 x 13.3 x 8 cm ? pedunculated fibroid in the right adnexum’. Neither ovary was identified. Diagnostic dilation and curettage was performed and histology showed ‘glandular proliferation and mitotic activity, focal cystic hyperplasia in an ac-
tively proliferating endometrium and an internal/external oestrogenic stimulation is suspected’. Laparotomy, total abdominal hysterectomy and bilateral salpingooophorectomy were performed. The specimen weighed 1200 g including two large fibroid masses, 13 x 10 x 8 cm and 11 x 9 x 8 cm. Histological examination again demonstrated markedly thickened endometrium, polyMultiple poid in places, and pseudostratification. myometrial benign leiomyomata were confirmed. The tubes and ovaries were unremarkable. Serum oestradiol level was undetectable and oestrone was 200 pmol/l. 2.2. Case 2 A 62-year-old parous woman presented in July 1992 with 3 episodes of postmenopausal bleeding. Her menopause had been at 55 years of age and she had received no hormone replacement. In 1990 she had a right breast lumpectomy and radiotherapy for a poorly differentiated invasive duct carcinoma of mammary origin staged as Tl NO MO. General and pelvic examinations, including abdominopelvic ultrasound scan, then showed normal organs including a small postmenopausal uterus. She was subsequently commenced on tamoxifen 20 mg daily. Pelvic examination on presentation 2.5 years later revealed a rather well oestrogenised vagina and an endocervical polyp. The uterus was firm, irregular and equivalent to a 1Cweek gestation. Ultrasound confirmed multiple fibroid masses. Histology of endometrial curettings showed normal proliferative endometrium and a compact but non-decidualised stroma. In view of these findings, considered to be inconsistent with her postmenopausal status, a total abdominal hysterectomy and bilateral salpingo-oophorectomy were recommended. She rejected the advice and was followed up with 6monthly transvaginal endometrial ultrasound scans with a view to biopsy if indicated. Her serum oestradiol was less than 50 pmol/l. 3. Discussion Since no other source of exogeneous or endogeneous oestrogen was demonstrable in these cases, the growth of the fibroids, the endometrial proliferation and polypopsis were attributed to the agonist actions of tamoxifen. The increased ER concentration in fibroids associated with GnRH-A therapy (and presumably with the menopause) will enhance the sensitivity and response of these fibroids to oestrogen. This will explain the fibroid growth in our postmenopausal women following the administration of the partial oestrogen agonist tamoxifen. The same concept may explain the rapid regrowth of fibroids once therapy with GnRH-A is discontinued in premenopausal women [28-301 since they resume endogenous oestrogen production after treatment. Perhaps it is for these same reasons that li-
A.H.N. Ugwumadu, K. Harding / Eur. J. Obsrel. Gynecol. Reprod. Biol. 54 (1994) 153-156
broids are clinically observed to increase in size during hormone replacement therapy even with very modest doses of oestrogen. Target organs may down-regulate or up-regulate their hormone receptor population and expression according to the circulating level of the substrate hormone. ER and EGF receptor counts and studies were not performed in the uterine and fibroid specimens obtained from these women. However, the evidence is strong that oestrogen action on fibroids may be mediated through growth factors as well as induction of dimerization, DNA binding and transcriptional activities [31]. That tamoxifen could elicit similar biologic effects may not be just theoretical or speculative. It prevents shrinkage of fibroids despite profound oestrogen suppression using GnRH-A [l&28]. Malignant transformation in fibroids is rare and widely believed to be less than 0.4%. This may be due to the presence of the inhibitory growth factor TGF-fl [32]. Whereas this substance is an important mediator of tamoxifen-induced inhibition of breast cancer growth by paracrine or autocrine mechanisms [32], its presence has not been demonstrated in normal human endometrial or myometrial tissue. In fibroid growth supported by tamoxifen the assumption of a malignancy rate of 0.4% may be untenable. Total abdominal hysterectomy was therefore performed in Case 1 and strongly recommended in Case 2. Indeed there is a strong case for surveillance with pelvic ultrasound and biopsies in postmenopausal women on tamoxifen therapy. For obvious ethical reasons we may never see studies addressing the true incidence of genital tract malignancies in women on tamoxifen chemotherapy for breast cancer. It has been speculated that the variable and contrasting actions of this substance on oestrogen responsive tissues may be pointers to some intrinsic differences in oestrogen receptors in target organs [33], a model comparable with the existence of cq, a2; Pi, P2 and dopamine receptors in the cardiovascular system. Animal experimental models have shown that while tamoxifen inhibited growth of breast cancer cells, it promoted endometrial cancer growth in the same animal [34] and until the mechanisms of action of tamoxifen are better understood the indications for its clinical application should be guarded and restrained.
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4. Acknowledgements We thank Professor P.J. Steer for his editorial comments and we acknowledge the tireless patience, of Mary Dumble whose secretarial assistance saw the manuscript through its may corrections and modifications.
19
20
5. References I
Parker MG. Fawell SE, Lees JA. White R, Emmas CE, Danielian P. Function of estrogen receptor as a transcription factor: a
21
155
target for antiestrogens. In: Brugge J. Curran E, McCormick F, eds. Origins of human cancer: a comprehensive review. New York: Cold Spring Harbour Laboratory Press, 1991; 667-674 Neven P, De Muylder X, Van Belle Y, Vanderick G, De Mulyder E. Tamoxifen and the uterus and the endometrium. Lancet 1989; i: 375. Neven P, De Mulyder X, Van Belle Y. Vanderick G, De Mulyder E. Hysteroscopic follow up during tamoxifen treatment, Eur J Obstet Gynecol Reprod Biol 1990; 35: 235-238. Nuovo MA, Nuovo GJ, McCaffrey RM, Levine RM, Baron B, Winkler B. Endometrial polyps in postmenopausal patients receiving tamoxifen. Int J Gynecol Pathol 1989; 8: 125-131. Corley D, Rowe J, Curtis MT, Hogan WM, Noumoff JS, Livolse VA. Postmenopausal bleeding from unusual endometrial polyps in women on chronic tamoxifen therapy. Obstet Gynecol 1992; 79(l): 111-116. De Muylder X, Neven P, De Somer M, Van Belle Y, Vanderick G. Muylder E. Endometrial lesions in patients undergoing tamoxifen therapy. Int J Gynaecol Obstet 1992; 36(2): 127-130. Cano A, Matallin P, Legua V, Tortajada M, Bonilla-Musoles F. Tamoxifen and the uterus and the endometrium. Lancet 1989; 376. Ford M, Turner M, Wood C, Soutter W. Endometriosis developing during tamoxifen therapy. Am J Obstet Gynecol 1988; 58: 1119. Ugwumadu AHN, Bower D, Ho PKH. Tamoxifen induced adenomyosis and adenomyomatous endometrial polyp. Br J Obstet Gynaecol 1993; 100: 386-388. Hardell L. Tamoxifen as risk factor for carcinoma of corpus uteri. Lancet 1988; ii: 563. Killackey MA, Hawdes TB, Pierce VK. Endometrial adenocarcinema in breast cancer patients receiving anti-oestrogens. Cancer Treat Rep 1985; 69: 237-238. Boccardo F, Guarneri D, Rubagotti A et al. Endocrine effects of tamoxifen in postmenopausal breast cancer patients. Tumori 1984; 70: 61-68. Fex B, Adielsson G. Mattson W. Oestrogen-like effects of tamoxifen on the concentration of protein of plasma. Acta Endocrinol 1981; 97: 109-113. Sakai F, Cheix F, Clavel M et al. Increases in steroid binding globulin induced by tamoxifen in patients with carcinoma of the breast. J Endocrinol 1978; 76: 219-226. Fornander T, Rutgvist LF, Cedermark B et al. Adjuvant tamoxifen in early breast cancer: occurrence of new primary cancers. Lancet 1989; i: 117-120. Gottardis MM, Robinson SP, Sataswaroop PG. Jordan VC. Contrasting actions of tamoxifen on endometrial and breast tumour growth in the athymic mouse. Cancer Res 1988; 48: 812-815. West CP, Lumsden MA, Lawson S, Williamson J, Baird DT. Shrinkage of uterine fibroids during therapy with goserelin (Zoladex): a luteinizing hormone-releasing hormone agonist administered as a monthly subcutaneous depot. Fertil Steril 1987; 48: 45-51. Lumsden MA, West CP, Hillier H, Baird DT. Estrogenic actions of tamoxifen in women treated with luteinizing hormonereleasing agents (goserelin) lack of shrinkage of uterine fibroids. Fertil Steril 1989; 52(6): 924-929. Healy D, Lawson S, Fraser H. Shrinkage of a uterine fibroid alter subcutaneous infusion of an LHRH agonist. Br Med J 1984; 289: 1267-1268. Lumsden MA, West CP, Bramley T, Rumgay L, Baird DT. The binding of epidermal growth factor to the human uterus and leiomyomata in women rendered hypo-oestrogenic by continous administration of an LHRH agonist. Br J Obstet Gynaecol 1988; 95: 1299- 1304. Hoffmann GE. Rao VCH, Borrows GH, Schultz GS, Santilippo
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FS. Binding sites for epidermal growth factors in human uterine tissues and leiomyomas. J Clin Endocrinol Metab 1984; 58: 880-884. Mikku VR, Stance] GM. Regulation of epidermal growth factor receptor by oestrogen. J Bol Chem 1985; 260: 9820-9824. Gonzalez F, Lakshmanan J, Hoath S, Fisher DA. Effect of oestradiol-17 on uterine epidermal growth factor concentration in immature mice. Acta Endocrinol 1984, 105: 425-428. Smith SK. Physiology of normal menstruation. In: Shaw RH, ed. Dysfunctional uterine bleeding. Advances in reproductive endocrinology, vol. 2. Lancashire: Parthenon, 1990; l-l 1. Lumsden MA, West CP, Hawkins RA, Bramley TA, Rumgay L, Baird DT. The binding of steroids to myometrium and leiomyomata (fibroids) in women treated with the gaonadotrophinreleasing hormone agonist Zoladex (ICI 118630). J Endoccrinol 1989; 121: 389-396. Wilson EA, Yang F, Rees ED. Estradiol and progesterone binding in uterine leiomyomata and in nomal uterine tissues. Obstet Gynecol 1980; 55: 20. Rein MS, Friedman AJ, Stuart JM, MacLaughlin DT. Fibroids and myometrial steroid receptors in women treated with a gonadotrophin-releasing hormone agonist leuprolide acetate. Fertil Steril 1990; 53(6): 1018-1023.
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West CP, Lumsden MA, Baird DT. LHRH Analogues and fibroids - Potential for Longer-Term Use. Horm Res 1989; 32 Suppl I: 146-149. Friedman AJ, Barbieri RL, Banacerraf BR, Schiff I. Treatment of leiomyomata with intranasal or subcutaneous leuprolide, a gondotrophin releasing hormone agonist. Fertil Stetil 1987; 48: 560. Friedman AJ, Harrison-Atlas D, Barvieri RL, Benacerraf B, Gleason R, Schiff I. A randomized, placebo controlled, doubleblind study evaluating the efficacy of leuprolide acetate depot in the treatment of uterine leiomyomata. Fertil Steril 1989; 51: 251. Green S, Chambon P. The oestrogen receptor: from perception to mechanism. In: Parker MG, ed. Nuclear hormone receptors. London: Academic Press, 1991; 15-38. Wang JL, Hsu YM. Negative regulators of cell growth. TIBS 1986: 2; 24-26. Ugwumadu A. Endometrial changes and lesions in postmenopausal women treated with tamoxifen. Br J Obstet Gynaecol 1993; 100: 704-705. Gottardis MM, Robinson SP, Satyaswaroop PG, Jordan VC. Contrasting actions of tamoxifen on endometrial and breast tumour growth in the athymic mouse. Cancer Res 1988; 48: 812-815.
Uterine leiomyomata and endometrial proliferation in postmenopausal women treated with the anti-oestrogen tamoxifen Austin H.N. Ugwumadu*a, Kate Hardingb “Department of Obsterics and Gynaecology, Queen Mary S University Hospital, Roehampton, London S WI5 SPN, UK bDeparrmenr of Obstetrics and Gynaecology, Chelsea and Westminster Hospital, Fulham Road, London SWIO 9NH, UK
(Accepted 1994)
Abstract
Two cases of fibroid growth and endometrial proliferqtion in postmenopausal women on tamoxifen (anti-oestrogen) breast cancer are described. Oestrogen in association with growth factors may control fibroid growth and differentiation.
therapy for The possi-
ble mechanisms and consequences of tamoxifen-induced fibroid growth are discussed. Oestrogen responsive tissues demonstrate a differential and contrasting response to tamoxifen and caution should be exercised in the expansion of its clinical application. Women on long-term tamoxifen therapy may benefit from ultrasound surveillance of their uterus and endometrium, with biopsy in suspicious cases, as there is a paucity of data on malignant transformation of these benign lesions induced by tamoxifen therapy. Key words:
Tamoxifen; Fibroid; Endometrial proliferation
1. Introduction Tamoxifen is a partial oestrogen agonist used mainly as adjuvant therapy for oestrogen receptor (ER) positive breast cancers. It binds irreversibly to the ER in the nuclei of responsive cells and is capable of activating receptor dimerisation and DNA binding with induction of transcription [I]. Messenger RNA and protein synthesis follow with resultant growth and proliferation. The prolonged nuclear binding is thought to deplete receptor sites and decrease tissue responsiveness to oestrogen, causing antagonist effects. This sequence of events is, however, not uniformly observed in all oestrogen responsive tissues, particularly the female genital tract where persistent stimulation by tamoxifen may result in endometrial proliferation, hyperplasia and polyposis [2-61, reactivation of dormant endometriosis [7,8], adenomyosis and giant adenomyomatous endometrial polyp [9], endometrial carcinoma [lo, 1 l] and oestrogenisation of the vaginal epithelium [ 121. All may occur in postmenopausal women treated with tamoxifen. * Corresponding author.
Oestrogenic effects of tamoxifen have also been reported in the liver, where sex hormone binding globulin (SHBG), corticotrophin and thyroid binding globulins synthesis were induced [ 13,141. Primary hepatocellular carcinoma has been associated with tamoxifen therapy in humans and in experimental animals [ 15,161. That the growth and differentiation of fibroids is dependent on oestrogen is undisputed. Fibroids occur almost entirely during the reproductive years, increase in growth during pregnancy and regress after the menopause. Recently, they have been shown to regress with gonadotrophin releasing hormone agonist (GnRH-A) treatment in premenopausal women [17-191. What is unclear, however, is whether oestrogen exerts this trophic effect by directly binding to the ER on the fibroids or through binding to the fibroids of secondary peptide hormone mediators - epidermal growth factor (EGF), insulin-like growth factors (IGF I & II) and transformation growth factor (TGF-ar) - or by both mechanisms. These growth factors, especially EGF, play an important role in the pathogenesis of uterine fibroids [20] and EGF receptors are present in fibroids and the surrounding myometrium [21]. Experimental evidence
0028-2243/94/$07.00 0 1994 Elsevier Science Ireland Ltd. All rights reserved. SSDI 0028-2243(94)01812-L
154
A.H.N. Ugwumadu, K. Harding / Eur. J. Obsret. Gynecol. Reprod. Biol. 54 (1994) 153-156
shows that oestrogen regulates the binding of EGF to the rat uterus [22] and increases the content of EGF and its receptors in the mouse uterus [23,24]. There is as yet no evidence in the published literature that tamoxifen regulates growth factor metabolism in fibroids but this remains a theoretical possibility given its proven oestrogenic actions. These agonist actions are exhibited predominantly in hypoestrogenic states such as menopause and treatment with GnRH-A [12,18]. Current evidence would suggest that oestrogen exerts its effects through the paracrine influence of growth factors as well as through gene transcription mediated through oestrogen receptors [ 1g-20,25]. The binding of EGF to fibroids has been shown to be significantly decreased in women rendered hypoestrogenic by GnRH-A [20], suggesting that oestrogen action may be mediated by EGF. Expression of steroid receptors may also be influenced by growth factors such that the effects of oestrogen and growth factors are intimately related and interdependent. ERs are present in fibroids in higher concentration than the surrounding myometrium [25,26] and if treated with GnRH-A the fibroids shrink in size but show a paradoxical increase in ER concentration [18,25,27]. In these GnRH-A-treated women the fibroids fail to shrink in size when tamoxifen is administered simultaneously [18,28]. This lack of response despite profound oestrogen suppression suggests that tamoxifen is exhibiting oestrogenic actions. 2. Case reports 2.1. Case 1 A 56-year-old nulligravid woman presented in June 1992 with postmenopausal bleeding. Her menopause was in 1985 at the age of 49. Two months before her periods ceased she had dilation and curettage for polymenorrhoea. The uterine size then was noted to be normal and histology of the curettings showed normal proliferative endometrium. In 1986, she had a left mastectomy and lymph node biopsy for a stage T2a invasive duct carcinoma of the breast. Post-operatively she received radiotherapy and was commenced on tamoxifen 20 mg daily. In 1988, her general practitioner took a smear, performed bimanual examination and noted that the uterus was irregular and about the size of a 6-g-weeks gestation. A routine recall smear test in 1991 was normal but bimanual examination was not performed on that occasion. On physical examination in 1992 she had a 20-week sized firm uterine mass. Pelvic ultrasound showed ‘a large completely heterogenous uterus measuring 18.2 x 8.5 x 7 cm with a 9.3 x 13.3 x 8 cm ? pedunculated fibroid in the right adnexum’. Neither ovary was identified. Diagnostic dilation and curettage was performed and histology showed ‘glandular proliferation and mitotic activity, focal cystic hyperplasia in an ac-
tively proliferating endometrium and an internal/external oestrogenic stimulation is suspected’. Laparotomy, total abdominal hysterectomy and bilateral salpingooophorectomy were performed. The specimen weighed 1200 g including two large fibroid masses, 13 x 10 x 8 cm and 11 x 9 x 8 cm. Histological examination again demonstrated markedly thickened endometrium, polyMultiple poid in places, and pseudostratification. myometrial benign leiomyomata were confirmed. The tubes and ovaries were unremarkable. Serum oestradiol level was undetectable and oestrone was 200 pmol/l. 2.2. Case 2 A 62-year-old parous woman presented in July 1992 with 3 episodes of postmenopausal bleeding. Her menopause had been at 55 years of age and she had received no hormone replacement. In 1990 she had a right breast lumpectomy and radiotherapy for a poorly differentiated invasive duct carcinoma of mammary origin staged as Tl NO MO. General and pelvic examinations, including abdominopelvic ultrasound scan, then showed normal organs including a small postmenopausal uterus. She was subsequently commenced on tamoxifen 20 mg daily. Pelvic examination on presentation 2.5 years later revealed a rather well oestrogenised vagina and an endocervical polyp. The uterus was firm, irregular and equivalent to a 1Cweek gestation. Ultrasound confirmed multiple fibroid masses. Histology of endometrial curettings showed normal proliferative endometrium and a compact but non-decidualised stroma. In view of these findings, considered to be inconsistent with her postmenopausal status, a total abdominal hysterectomy and bilateral salpingo-oophorectomy were recommended. She rejected the advice and was followed up with 6monthly transvaginal endometrial ultrasound scans with a view to biopsy if indicated. Her serum oestradiol was less than 50 pmol/l. 3. Discussion Since no other source of exogeneous or endogeneous oestrogen was demonstrable in these cases, the growth of the fibroids, the endometrial proliferation and polypopsis were attributed to the agonist actions of tamoxifen. The increased ER concentration in fibroids associated with GnRH-A therapy (and presumably with the menopause) will enhance the sensitivity and response of these fibroids to oestrogen. This will explain the fibroid growth in our postmenopausal women following the administration of the partial oestrogen agonist tamoxifen. The same concept may explain the rapid regrowth of fibroids once therapy with GnRH-A is discontinued in premenopausal women [28-301 since they resume endogenous oestrogen production after treatment. Perhaps it is for these same reasons that li-
A.H.N. Ugwumadu, K. Harding / Eur. J. Obsrel. Gynecol. Reprod. Biol. 54 (1994) 153-156
broids are clinically observed to increase in size during hormone replacement therapy even with very modest doses of oestrogen. Target organs may down-regulate or up-regulate their hormone receptor population and expression according to the circulating level of the substrate hormone. ER and EGF receptor counts and studies were not performed in the uterine and fibroid specimens obtained from these women. However, the evidence is strong that oestrogen action on fibroids may be mediated through growth factors as well as induction of dimerization, DNA binding and transcriptional activities [31]. That tamoxifen could elicit similar biologic effects may not be just theoretical or speculative. It prevents shrinkage of fibroids despite profound oestrogen suppression using GnRH-A [l&28]. Malignant transformation in fibroids is rare and widely believed to be less than 0.4%. This may be due to the presence of the inhibitory growth factor TGF-fl [32]. Whereas this substance is an important mediator of tamoxifen-induced inhibition of breast cancer growth by paracrine or autocrine mechanisms [32], its presence has not been demonstrated in normal human endometrial or myometrial tissue. In fibroid growth supported by tamoxifen the assumption of a malignancy rate of 0.4% may be untenable. Total abdominal hysterectomy was therefore performed in Case 1 and strongly recommended in Case 2. Indeed there is a strong case for surveillance with pelvic ultrasound and biopsies in postmenopausal women on tamoxifen therapy. For obvious ethical reasons we may never see studies addressing the true incidence of genital tract malignancies in women on tamoxifen chemotherapy for breast cancer. It has been speculated that the variable and contrasting actions of this substance on oestrogen responsive tissues may be pointers to some intrinsic differences in oestrogen receptors in target organs [33], a model comparable with the existence of cq, a2; Pi, P2 and dopamine receptors in the cardiovascular system. Animal experimental models have shown that while tamoxifen inhibited growth of breast cancer cells, it promoted endometrial cancer growth in the same animal [34] and until the mechanisms of action of tamoxifen are better understood the indications for its clinical application should be guarded and restrained.
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3
4
5
6
I
8
9
10 I1
12
13
14
15
16
17
18
4. Acknowledgements We thank Professor P.J. Steer for his editorial comments and we acknowledge the tireless patience, of Mary Dumble whose secretarial assistance saw the manuscript through its may corrections and modifications.
19
20
5. References I
Parker MG. Fawell SE, Lees JA. White R, Emmas CE, Danielian P. Function of estrogen receptor as a transcription factor: a
21
155
target for antiestrogens. In: Brugge J. Curran E, McCormick F, eds. Origins of human cancer: a comprehensive review. New York: Cold Spring Harbour Laboratory Press, 1991; 667-674 Neven P, De Muylder X, Van Belle Y, Vanderick G, De Mulyder E. Tamoxifen and the uterus and the endometrium. Lancet 1989; i: 375. Neven P, De Mulyder X, Van Belle Y. Vanderick G, De Mulyder E. Hysteroscopic follow up during tamoxifen treatment, Eur J Obstet Gynecol Reprod Biol 1990; 35: 235-238. Nuovo MA, Nuovo GJ, McCaffrey RM, Levine RM, Baron B, Winkler B. Endometrial polyps in postmenopausal patients receiving tamoxifen. Int J Gynecol Pathol 1989; 8: 125-131. Corley D, Rowe J, Curtis MT, Hogan WM, Noumoff JS, Livolse VA. Postmenopausal bleeding from unusual endometrial polyps in women on chronic tamoxifen therapy. Obstet Gynecol 1992; 79(l): 111-116. De Muylder X, Neven P, De Somer M, Van Belle Y, Vanderick G. Muylder E. Endometrial lesions in patients undergoing tamoxifen therapy. Int J Gynaecol Obstet 1992; 36(2): 127-130. Cano A, Matallin P, Legua V, Tortajada M, Bonilla-Musoles F. Tamoxifen and the uterus and the endometrium. Lancet 1989; 376. Ford M, Turner M, Wood C, Soutter W. Endometriosis developing during tamoxifen therapy. Am J Obstet Gynecol 1988; 58: 1119. Ugwumadu AHN, Bower D, Ho PKH. Tamoxifen induced adenomyosis and adenomyomatous endometrial polyp. Br J Obstet Gynaecol 1993; 100: 386-388. Hardell L. Tamoxifen as risk factor for carcinoma of corpus uteri. Lancet 1988; ii: 563. Killackey MA, Hawdes TB, Pierce VK. Endometrial adenocarcinema in breast cancer patients receiving anti-oestrogens. Cancer Treat Rep 1985; 69: 237-238. Boccardo F, Guarneri D, Rubagotti A et al. Endocrine effects of tamoxifen in postmenopausal breast cancer patients. Tumori 1984; 70: 61-68. Fex B, Adielsson G. Mattson W. Oestrogen-like effects of tamoxifen on the concentration of protein of plasma. Acta Endocrinol 1981; 97: 109-113. Sakai F, Cheix F, Clavel M et al. Increases in steroid binding globulin induced by tamoxifen in patients with carcinoma of the breast. J Endocrinol 1978; 76: 219-226. Fornander T, Rutgvist LF, Cedermark B et al. Adjuvant tamoxifen in early breast cancer: occurrence of new primary cancers. Lancet 1989; i: 117-120. Gottardis MM, Robinson SP, Sataswaroop PG. Jordan VC. Contrasting actions of tamoxifen on endometrial and breast tumour growth in the athymic mouse. Cancer Res 1988; 48: 812-815. West CP, Lumsden MA, Lawson S, Williamson J, Baird DT. Shrinkage of uterine fibroids during therapy with goserelin (Zoladex): a luteinizing hormone-releasing hormone agonist administered as a monthly subcutaneous depot. Fertil Steril 1987; 48: 45-51. Lumsden MA, West CP, Hillier H, Baird DT. Estrogenic actions of tamoxifen in women treated with luteinizing hormonereleasing agents (goserelin) lack of shrinkage of uterine fibroids. Fertil Steril 1989; 52(6): 924-929. Healy D, Lawson S, Fraser H. Shrinkage of a uterine fibroid alter subcutaneous infusion of an LHRH agonist. Br Med J 1984; 289: 1267-1268. Lumsden MA, West CP, Bramley T, Rumgay L, Baird DT. The binding of epidermal growth factor to the human uterus and leiomyomata in women rendered hypo-oestrogenic by continous administration of an LHRH agonist. Br J Obstet Gynaecol 1988; 95: 1299- 1304. Hoffmann GE. Rao VCH, Borrows GH, Schultz GS, Santilippo
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27
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Ugwumadu, K. Harding/Eur.
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