Ovarian hemangioma associated with tamoxifen therapy: a case report

Vascular tumors of the ovary are very rare. We report a case of ovarian hemangioma in a patient treated with tamoxifen for breast ductal carcinoma. CD31 and CD34 immunoreactivity confirmed the vascular origin of the tumor. It is interesting to note that estrogen and progesterone receptors were negative in endothelial cells of the hemangioma, but were positive in stromal ovarian cells. Tamoxifen is a synthetic, non-steroidal, anti-estrogenic drug widely used as adjuvant therapy for pre- and post-menopausal, early and metastatic, breast cancer patients with positive estrogen receptor proteins. The mechanism of action of tamoxifen in stimulating the development and/or growth of ovarian hemangioma is unknown. We may speculate that its prolonged, estrogenic effect on the ovary may be one of the stimulating factor.     

Adjuvant Therapy for Breast Cancer: A Summary of the Early Breast Cancer Trialists’ Collaborative Group (Oxford) Overview

Introduction: The Oxford Overview has clarified the role of adjuvant ovarian ablation, Tamoxifen and chemotherapy in women treated for breast cancer surgically with curative intent.Methodology: in 1995, information was collected on each patient in any randomized trial (beginning before 1990) of adjuvant ovarian ablation versus no adjuvant ovarian ablation or adjuvant Tamoxifen versus no adjuvant Tamoxifen and in any randomized trial involving treatment groups that differed only with respect to the adjuvant chemotherapy regimens that were being compared.Results: ovarian ablation performed alone significantly improved the 15-year survival rate (52 .4% versus 46.1%) and recurrence-free survival (45% versus 3%) in women under 50 in such studies. Tamoxifen in women with estrogen receptor-positive or estrogen receptor-unknown tumours significantly reduced recurrence (proportional recurrence reductions of 21%, 29% and 47% for trials of 1,2 and 5 years of tamoxifen, respectively) and mortality (proportional reductions of 12, 17 and 26%, respectively for trials of 1,2 and 5 years of Tamoxifen), regardless of age, nodal status or concurrent chemotherapy. Tamoxifen also prevented new primary breast cancers (47% reduction in trials of 5 years of Tamoxifen) but quadrupled (5 years of Tamoxifen) the incidence of endometrial cancer. There was no change in mortality from any other cause. Polychemotherapy produced reductions in recurrence of 35 percent and 20 percent in women under 50 and 50 to 69, respectively, and reductions in mortality of 27 percent and 11 percent in women under 50 and 50 to 69, respectively. Three to six months of chemotherapy seemed adequate. Anthracycline-containing regimens produced additional 12 percent proportional reductions in recurrence and mortality in comparison to CM F-type regimens alone.Summary: Adjuvant ovarian ablation reduces recurrence and mortality in women under 50. Adjuvant Tamoxifen reduces recurrence and mortality in estrogen receptor-positive women of any age or nodal status. Adjuvant polychemotherapy reduces recurrence and mortality, particularly in women under 50 but to a lesser degree in women aged 50 to 69.     

CYP2D6-Tamoxifen

Tamoxifen is a standard endocrine therapy for the prevention and treatment of steroid hormone receptor-positive breast cancer. Tamoxifen efficacy depends on the formation of clinically active metabolites. Endoxifen is the major metabolite and the cytochrome P450 (CYP) enzyme 2D6 plays a key role in its formation. CYP2D6 variants and drug interaction by CYP2D6 inhibitors influence plasma endoxifen concentrations and adjuvant tamoxifen outcome. As compared to patients with full CYP2D6 function (EM) patients with non-functional (poor metabolizer, PM) and impaired (intermediate metabolizer, IM) CYP2D6 variants have higher recurrence rates (e.g. PM vs EM: HR=1.9, 95% CI 1.10–3.28). A study with more than 1,300 patients confirmed for PM a significantly higher (11.5%) and for EM lower (2%) relapse rate after 9 years follow-up when compared to the total patient cohort not stratified by genotype. It follows that up-front CYP2D6 genotyping for the prediction of CYP2D6 metabolizer status may aid in the individualization of endocrine treatment choice and improve outcome. Strong CYP2D6 inhibitors (e.g. paroxetine) should be avoided as co-medication and all efforts should be made to ensure tamoxifen adherence.     

The effect of clomiphene citrate and tamoxifen on the cervical mucus

The anti-estrogenic effect of clomiphene citrate (CC) and tamoxifen (TMX) on cervical mucus was evaluated in a prospective crossover study. Ten women underwent randomized alternate cyclical treatment with either 100 mg CC, 40 mg TMX daily, or with placebo. The effect of CC, TMX and placebo on serum estradiol (E2), cervical mucus secretion and on the development of ovarian follicles was evaluated. Compared with placebo, treatment with CC and TMX significantly increased the number of mature ovarian follicles on the day of assumed ovulation (p less than 0.05), elevated E2 secretion (p less than 0.05) and decreased cervical score (p less than 0.05). It can be concluded that anti-estrogenic agents reduced the secretion of cervical mucus. However, in most cases, the excessive E2 production due to multiple follicular growth overcomes the anti-estrogenic effect.     

Tamoxifen increases plasma estrogen-binding equivalents and has an estradiol agonistic effect on histologically normal premenopausal and postmenopausal endometrium.

OBJECTIVE: To determine the effects of single dose tamoxifen on plasma estrogen (E)-binding equivalents and endometrial estradiol (E2) and progesterone (P) receptors. DESIGN: Controlled clinical study. SETTING: Normal human volunteers were studied in an academic research environment. PATIENTS: Premenopausal and postmenopausal women with histologically normal endometrium undergoing curettage or hysterectomy were selected. INTERVENTIONS: Tamoxifen was administered orally; blood and endometrial samples were collected 4 to 96 hours after tamoxifen administration. MAIN OUTCOME MEASURES: Plasma E-binding equivalents, endometrial cytosolic and nuclear E2 and P receptors. RESULTS: (1) Plasma E-binding equivalents increased eightfold at 4 to 24 hours of tamoxifen administration and declined exponentially thereafter, reaching control levels at 73 to 96 hours. Plasma E-binding equivalents were not affected by endogenous E2 levels. (2) Endometrial total E2 and P receptor levels increased in all women 2.9 to 19.2-fold after tamoxifen. (3) Tamoxifen resulted in an increase in the fraction of the E2 receptor measured in the nuclear extract 2.1 to 7.5-fold in midcycle, secretory, and menopausal endometria but not in proliferative endometrium. CONCLUSIONS: (1) Tamoxifen has an E2 agonistic effect on histologically normal human endometrium. (2) Irrespective of the total level of the endometrial E2 receptor, the nuclear capacity of that receptor in vivo is limited (approximately 75% to 80% of the total level).     

三苯氧胺对人卵巢癌细胞增殖和凋亡的影响

目的：探讨三苯氧胺的不同剂量（0.1、1、10μmol／L）对人卵巢癌细胞增殖和凋亡的影响,为卵巢癌的内分泌治疗提供实验依据。方法：以体外培养人卵巢癌细胞系HO－8910为研究对象,用免疫组化SABC法检测增殖细胞核抗原（PCNA）在细胞中表达情况,DNA缺口原位末端标记方法（TUNEL）检测细胞凋亡。结果：三苯氧胺通过诱导细胞凋亡抑制卵巢癌细胞生长,至剂量依赖性。低浓度（≤1μmol／L）的三苯氧胺对PCNA表达的影响无统计学意义,高剂量（10μmol／L）可明显降低PCNA表达。结论：三苯氧胺抗肿瘤作用与剂量有关,低剂量通过诱导细胞凋亡发挥作用,而高剂量与抑制细胞增殖和诱导凋亡有关。     

Effect of oxyprogesterone caproate, tamoxifen and their combination on the level of steroid hormone receptors in the tumor, and some parameters of the reproductive system in patients with endometrial cancer

The results of preoperative use of oxyprogesterone caproate (OPC), Tamoxifen and their combination in 165 patients suffering from primary endometrial carcinoma are presented. It was shown that Tamoxifen was able to increase concentrations cytoplasmatic receptors to progesterone in the tumor. The incidence of specific hormonal pathomorphosis in the tissue of the tumor in patients who received a combination of OPC and Tamoxifen was significantly higher (80% of cases) as compared to the separate use of OPC (60%) or Tamoxifen (57%).     

Effect of repeated administration of clomiphene citrate at two different times on the endometrium in patients undergoing intrauterine insemination

Background, Aims and Methods:  Clomiphene citrate (CC) has been widely used for induction of ovulation; however, despite the high rate of ovulation, the pregnancy rate is only 30%. The anti-estrogenic effect of CC on the endometrium is one explanation for this finding. It is well known that repeated administration of CC enhances its anti-estrogenic effect. To overcome this adverse affect, a number of techniques have been used. One technique is the early administration of CC, in an attempt to decrease the anti-estrogenic effects of CC on the endometrium. The aim of the present study was to retrospectively evaluate if repeated administration of CC at varying times may affect the endometrium during preovulatory period; pregnancy rates were compiled for patients with unexplained infertility undergoing intrauterine insemination (IUI). The patients were divided into four groups based on the number of repeat administrations and the time of CC administration.
Results:  The endometrial thickness at the day of human chorionic gonadotropin administration was greater in early administration within three consecutive CC cycles than the others.
Conclusion:  When the endometrium is thin during classical administration of CC, it is worth attempting the early administration of CC in the CC/IUI treatment for patients with unexplained infertility. However, this effect disappeared over the duration of the three consecutive CC cycles. (Reprod Med Biol 2004; 3 : 153–157)     

Histological analysis of endometrial polyps in breast cancer patients treated with tamoxifen (nolvadex)

Endometrial polyps are the most common endometrial pathology described in association with Tamoxifen exposure. The aim of this study was to evaluate the malignant potential of endometrial polyps in breast cancer patients receiving Tamoxifen. We analyzed 140 endometrial polyps divided into two groups: 1) 73 endometrial polyps from 57 breast cancer patients receiving Tamoxifen (Nolvadex): T+ endometrial polyps; 2) 67 control endometrial polyps received for analysis in the period January-December 2000. The analysis was performed on archival H&E sections. We found that the rates of endometrial carcinoma and atypical hyperplasia were high in patients treated with Tamoxifen (7.02% vs 2.99% and 17.54% vs 11.94%), but the results did not reach statistical significance (p > 0.05).     

Effects of tamoxifen on human breast cancer cells in vitro

Summary Long-term treatment of the estrogen sensitive human breast cancer cell line EFM-19 with the antiestrogenic compound Tamoxifen resulted in a variant line EFM-19 T, which was stimulated by Tamoxifen. Estrogen receptor analysis by radioligand assay (charcoal method), revealed a 2.5 fold higher receptor concentration in EF-19 T cells than in the parental EFM-19 cell-line. As demonstrated with the immunocytochemical assay (ER-ICA) only 60% of the parental EFM-19 cells were estrogen receptor positive, whereas 98% of the EFM-19 T cells expressed estrogen receptor protein. In addition, receptor content per cell was higher in the Tamoxifen treated subline than in the parental cell line. Analogous with the growth promoting effect of Tamoxifen on EFM-19 T cells, Tamoxifen acted like estrogen leading to a down regulation of cellular estrogen receptor concentration. The partial growth dependency of the EFM-19 T cells on the presence of Tamoxifen demonstrates estrogenic effects of Tamoxifen and explains the withdrawal response obtained in the treatment of breast cancer patients when remission occurs after termination of ineffective treatment with Tamoxifen.     

A study of endometrial adenocarcinoma treated with tamoxifen by scanning and transmission electron microscopy

By scanning and transmission electron microscopy the Authors studied four cases of endometrial adenocarcinoma (stage I, G1) after 15-days treatment with Tamoxifen (20 mg X 2) before surgery. The ultrastructural findings, similar to those observed in untreated adenocarcinomas but quite different from those obtained in MAP-responsive cases - as other Authors reported too - seem to indicate an almost complete absence of secretory or cytotoxic induction at least as far as 15-days treatment is concerned. According to the Authors this study raises many doubts about the usefulness of a first-instance therapeutical protocol based on Tamoxifen alone. However they believe that Tamoxifen can be utilized combined with a progestational agent in a simultaneous or sequence treatment.     

Tamoxifen and giant endometrial polyps

Tamoxifen is a synthetic non-steroid anti-estrogen that has been used effectively for several years in the adjuvant treatment of breast cancer. Although its therapeutic effect is due to its anti-estrogenic properties, the drug also shows modest type B estrogen-receptor agonist activity during the menopausal period in which estrogens are at a low level. Owing to the fall in estrogen levels in menopause, tamoxifen provokes an up-regulation of both estrogen and progesterone receptors at an endometrial tissue is a direct consequence of this. This proliferation, which is the result of an inappropriate response of the basal layer and the basis for the onset of hyperplasia and polyps in the tissue. At standard therapeutic dosages, tamoxifen in postmenopausal women is associated with the onset of alterations in the vaginal and endometrial epithelium. Cases of endometrial hyperplasia, endometrial polyps, adenomyosis, endometriosis and fibromyomas are described in the literature. Endometrial polyps represent the most common pathology associated with TAM in women with previous breast cancer in menopause. The estrogenic stimulus to polyps following TAM treatment may be considerable, resulting in their growth to sizeable proportions, causing metrorrhagia and suspected neoplastic pathology. Two cases of patients receiving adjuvant treatment with tamoxifen for previous breast cancer, who presented two giant endometrial polyps of uncommon dimension, are reported.     

Pathology of the endometrium in breast cancer patients treated with tamoxifen (nolvadex)

The objectives of this study were to: 1) characterize histologically endometrial biopsy findings for genital bleeding in breast cancer patients receiving Tamoxifen; 2) analyze histologically endometrial carcinoma in the same patients. We analyzed biopsy specimens divided into three groups: 1) 112 biopsies (curettages and hysterectomy specimens) from 88 breast cancer patients receiving Tamoxifen (Nolvadex): T+; 2) 27 biopsies (curettages and hysterectomy specimens) from 22 breast cancer patients not receiving Tamoxifen but biopsied for genital bleeding: T-; 3) 139 curettages control samples received for analysis in the period January-March 2000 from women with peri- and postmenopausal genital bleeding: K. The analysis was performed on archival H&E sections. The most frequent finding in breast cancer patients receiving Tamoxifen was endometrial polyp. Compared with the other two groups (T- and K) the frequency of this finding was statistically significant. No difference was found in the prevalence of endometrial cancer between the three groups. The analyzed endometrial carcinomas in Tamoxifen-treated breast cancer patients show signs, characteristic of Bochman type I: predominantly endometrioid, of low grade and FIGO stage, with good prognosis.     

Tamoxifen in gynaecology

Tamoxifen, a nonsteroidal synthetic anti-oestrogen is the most widely used selective estrogen receptor modulator (SERM). Designed as a contraceptive it is most frequently used in prevention and treatment of breast cancer. Its role in gynaecology is limited to ovulation induction. Although it has a favourable effect on lipid profiles and increases bone density in postmenopausal women its use for these indications is not warranted. The practising gynaecologist will most likely be faced with the risks associated with long-term tamoxifen use: endometrial polyps, endometrial hyperplasia and endometrial cancer; venous thromboembolism, ovarian cysts and endometrioid ovarian cancers. Further insight into the oestrogen receptor (ER) tamoxifen induced changes could potentially identify new therapeutic opportunities.     

Uterine abnormalities in non menopausal women who received tamoxifen for breast cancer adjuvant therapy

OBJECTIVE: To elaborate a strategy of endometrial follow-up for premenopausal women treated with Tamoxifen as adjuvant hormonal treatment of breast cancer. PATIENTS AND METHODS: Retrospective study of 152 premenopausal patients treated with Tamoxifen in Nantes Comprehensive Cancer Center for a breast cancer from January 2003 to December 2005. Vaginal sonography was used in the follow-up of 70 of them. RESULTS: Endometrial hypertrophy was found in 26 patients. Sonohysterography and hysteroscopy allowed to find 11 polyps and three hyperplasias in the 19 women who were investigated. In our study, endometrial pathology was found in 20% of premenopausal women treated with Tamoxifen (polyps or hyperplasia). Uterine bleeding was found in half patient of this group. DISCUSSION AND CONCLUSION: Vaginal sonography monitoring could be proposed to premenopausal women treated with Tamoxifen among whom endometrial pathology is usual.     

Ovarian overstimulation and cystic formation in premenopausal tamoxifen exposure: comparison between tamoxifen-treated and nontreated breast cancer patients

AIM: Tamoxifen is the antihormonal treatment of choice for premenopausal breast cancer patients with advanced breast disease. Its premenopausal administration has been shown to induce supraphysiological 17beta-estradiol serum levels and to be associated with the presence of persistent, bilateral functional ovarian cysts. However, these abnormalities have not yet been compared to controls. In this study we evaluated the possibility that the above hormonal and/or ovarian abnormalities are more frequent among premenopausal breast cancer patients treated with tamoxifen than among similar nontreated patients, and thus they may be attributed to tamoxifen effect. METHODS: We evaluated serum hormone levels of 17beta-estradiol, follicular-stimulating hormone, luteinizing hormone, and progesterone, the presence of ovarian cysts, and various demographic and clinical characteristics in 20 premenopausal breast cancer patients treated with tamoxifen (study group) and compared them to those observed in 12 similar nontreated patients (control group). RESULTS: Ovarian cysts were found in 80% of the study patients and only in 8.3% of the control patients (P = 0.001). The incidence of oligomenorrhea was nearly significantly higher in the study than in the control group (50 and 16.7%, respectively; P = 0.0651). Various serum hormone levels tested were not found to be significantly different between the two groups, except for 17beta-estradiol serum levels as detected on days 14 and 21 of the menstrual cycle, which were significantly higher among the study than in the control patients. (Day 14 serum estradiol: 757.7 +/- 372.0 pg/mL versus 206.5 +/- 275.0 pg/mL, P = 0.0012. Day 21 serum estradiol: 300.0 +/- 134.5 pg/mL versus 96.5 +/- 71.5 pg/mL, P = 0.0008.) CONCLUSIONS: Tamoxifen treatment increases the incidence of ovarian cysts and the significantly higher 17beta-estradiol serum levels in premenopausal breast cancer patients.     

Effects of tamoxifen administration in rat vaginas: an ultrastructural and light microscopy study

BACKGROUND: Tamoxifen (TAM) inhibits the initiation of carcinogen induced rat mammary tumours and is administrered for extended periods after the initiation of carcinogenesis. It is also a widely used treatment for breast and gynaecological cancer. OBJECTIVE: In this study, we aimed to investigate tamoxifen (TAM) administration on vagen development in rats. MATERIAL & METHODS: Twenty sexually mature and pregnant Wistar albino rats were chosen as the animal model. They were divided into two groups. Group I: Control group, Group II: Tamoxifen applied (between gestational day 16 and 21 days); 100 microg tamoxifen citrate (TAM) in 0.05 ml saline subcutaneously per day/animal. After birth, all female rats were sacrificed on the 60th day and were taken vaginal tissue. Transmission electron microscopy and light microscopy have been used to study changes to the vaginal epithelium. RESULTS: A statistically significant reduction of birth body weight was noted in the experimental group of rats when compared to the control group (P < 0.05). We saw increase in the thickness of the epithelium layer and irregularity and disappearance of microscopic papilla, cytoplasmic vacuolation in cells of the surface layer, thin and irregular basal membrane, lateral junction of cells were destroyed in the TAM treated groups. In conclusion, neonatal tamoxifen administration affects vagina epithelium and lead to decreasing birth body weight and vaginal adenosis.     

Serum CA 125 and survival of mice inoculated with ovarian carcinoma and treated with antiestrogen, estrogen, or progestin

The human ovarian carcinoma cell line NIH-OVCAR-3 grown in immunodeficient mice has been reported to be sensitive to estrogen medications and to express progestin receptor. To assess the effects of sex steroids on CA 125 production and survival times in these mice, we administered Tamoxifen, estrogen, and progestin. During the first 28 days after inoculation of mice with 2.3 million tumor cells ip, serum CA 125 rose exponentially, reaching 4308 +/- 776 and 3905 +/- 1013 units/ml (mean +/- SEM, P greater than 0.1) in placebo- and Tamoxifen-treated mice, respectively; median survival times were 41 and 39 days, respectively (P greater than 0.1). Uninoculated mice had nondetectable CA 125, and all outlived the inoculated mice. In tumor-inoculated mice, serum CA 125 levels and survival were similar when estrogen or progestin was injected alone and when both were given in combination. We detected no significant differences in production of CA 125 in vitro by tumor cells harvested from ascites fluid when the mice were treated with placebo, estrogen, or progestin. We conclude that, for our model, serial measurements of serum CA 125 provide excellent estimates of the relationship between tumor burden and survival, and that CA 125 production appears unaffected by estrogen, progestin, or Tamoxifen.     

Effect of tamoxifen on ultrastructure of endometrial carcinoma

Tamoxifen is a nonsteroidal antiestrogen whose mode of action is, as yet, unclear. The purpose of this report is to investigate the effects of Tamoxifen on endometrial adenocarcinoma ultrastructurally. Five patients with endometrial adenocarcinoma, 3 cases well differentiated and the others undifferentiated, were treated with 20mg Tamoxifen per os a day for 7 days, and the following changes were observed: The cells became roundish and slightly swollen. Development of cytoplasmic organelles was observed. In the cytoplasm, glycogen granules did not increase. These results suggest that an anti-cancer effect is brought about by the induction of the tissue toward functional differentiation as well as inhibition of glycogen metabolism in tumor cells.     

Comparative study of the endometrial pathology using flexible ambulatory hysteroscopy of patients treated with Tamoxifen

There were checked out 32 women in concern with genital bleeding receiving Tamoxifen 20 mg daily for a period of an year. The above mentioned were receiving this medicine because of breast cancer with the help of flexible office hysteroscopy. In the first case in group I--patients with Tamoxifen, was found endometrial pathology in 81.25%. In group II--patients without Tamoxifen was found endometrial pathology in 69%. As a result of this investigation the authors confirm that Tamoxifen increase the risk of endometrial pathology.