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PubMedDate not supplied

Tamoxifen in the management of pseudoangiomatous stromal hyperplasia.

Pseudoangiomatous stromal hyperplasia (PASH) is a relatively uncommon histologic finding in breast specimens. The clinicopathologic spectrum of this disease entity can range from a focal nonsignificant microscopic finding to a dominant palpable breast mass. To confirm the diagnosis, a biopsy is required primarily to distinguish PASH from a low-grade angiosarcoma. The mammographic description of PASH is a round or ovoid, circumscribed or partially circumscribed mass. The sonographic feature is a hypoechoic mass. PASH is similar to a fibroadenoma in clinical and imaging features. Progressive breast enlargement associated with engorgement, cyclical breast pain, and burning sensation is of significant concern for some women. The management of the palpable mass and associated symptoms has included excisional biopsy, often leading to recurrent excisions and even mastectomy. This report documents an impressive response to tamoxifen in a patient with PASH presenting with breast enlargement, pain, and breast masses. To our knowledge, there are no reports on the use of tamoxifen or other selective estrogen receptor modulators in the management of this benign breast condition.

Adult↗
PubMed2002

Serum cholesterol efflux potential in postmenopausal monkeys treated with tibolone or conjugated estrogens.

Tibolone is a synthetic steroid used for the treatment of climacteric symptoms and the prevention of osteoporosis, but the effect on the cardiovascular system is unclear since tibolone lowers high-density lipoprotein (HDL) levels. We investigated if long-term treatment with tibolone or conventional hormone replacement therapy (HRT) in cynomolgus monkeys could affect their serum cholesterol efflux potential. Surgically postmenopausal cynomolgus monkeys were treated for 2 years with conjugated equine estrogens (CEE), CEE plus medroxyprogesterone acetate (MPA), low-dose tibolone, or high-dose tibolone. Plasma lipid, lipoprotein, and apolipoprotein levels were monitored during the study. The cholesterol efflux potential of the serum from each animal was determined in (3)H-cholesterol-labeled Fu5AH cells and skin fibroblasts in culture. Tibolone induced a dose-dependent 30% to 52% reduction in HDL levels. When HDL concentrations were reduced by 30%, as seen in women, there was no reduction in the serum cholesterol efflux potential in Fu5AH cells. With a 52% reduction in HDL, there was a 14% reduction in cholesterol efflux. Although CEE or CEE+MPA had no significant effect on HDL levels, CEE treatment increased serum cholesterol efflux potential by 7%. With the same sera, no changes in cholesterol efflux were seen with fibroblasts. Although our findings suggest that HDL concentration is correlated with cholesterol efflux potential of serum, this relationship is weak, explaining only 16% of the variability. This is emphasized by the fact that despite a 30% lowering of HDL with tibolone, there was no indication of an adverse effect on cellular cholesterol efflux. Other changes in the serum not measured in this study must contribute significantly to the cholesterol efflux potential of serum. Because changes in cholesterol efflux potential of serum were seen only in Fu5AH cells, a cell line rich in SR-B1 receptors, this implies that the changes seen in this study were mediated largely by the SR-B1 pathway.

Analysis of Variance↗
PubMed2002

Effects of tibolone and continuous combined hormone replacement therapy on mammographic breast density.

OBJECTIVE: Our purpose was to compare the effects of tibolone, continuous combined hormone replacement therapy, and placebo on mammographic breast density. STUDY DESIGN: A prospective, randomized, double-blind placebo-controlled study was performed. A total of 166 postmenopausal women were equally randomized to receive tibolone 2.5 mg, estradiol 2 mg/norethisterone acetate 1 mg (E(2)/NETA), or placebo. Mammograms were performed at baseline and after 6 months of treatment. Mammographic density was quantified according to the Wolfe classification and by the percentage area of the breast that had a dense pattern. RESULTS: An increase in mammographic density was much more common among women receiving continuous combined hormone replacement therapy (46%-50%) than among those receiving tibolone (2%-6%) and placebo (0%) treatment. The difference between E(2)/NETA and placebo was highly significant (P <.001). Treatment with tibolone did not differ from that with placebo. The relative risk of an increase in breast density for E(2)/NETA versus tibolone was found to be 8.3 (95% CI 2.7-25.0). CONCLUSION: An increase in mammographic density should be regarded as an unwanted side effect of hormone replacement therapy. In contrast to estrogen/progestogen treatment, tibolone seems to exert little stimulation of breast tissue.

Biopsy, Needle↗
PubMed2004

The Bik BH3-only protein is induced in estrogen-starved and antiestrogen-exposed breast cancer cells and provokes apoptosis.

Evidence has been accumulating that some estrogen-dependent human breast cancers require estrogen for not only proliferation but also survival. To obtain insights into the molecular mechanisms of apoptosis of breast cancer cells subjected to estrogen starvation or exposed to antiestrogens, we characterized changes in the gene expression profile of MCF-7/BUS human breast cancer cells and revealed a strong induction of Bik, a member of the BH3-only proapoptotic proteins. The Bik mRNA transcript and protein were strongly induced by estrogen starvation or exposure to fulvestrant, a pure antiestrogen that competes with the natural estrogens for binding to the estrogen receptors. This Bik induction preceded apoptotic cell death, which was blocked by zVAD-fmk, a pancaspase inhibitor. Amounts of the Bcl-2-related proteins, such as Bcl-2, Bcl-XL, or Bax, showed only marginal changes in the presence or absence of estrogens or antiestrogens. Suppression of Bik expression by using the small interfering RNA effectively blocked the fulvestrant-induced breast cancer cell apoptosis. These results indicate that Bik is induced in MCF-7/BUS cells in the absence of estrogen signaling and plays a critical role in the antiestrogen-provoked breast cancer cell apoptosis.

Apoptosis↗
PubMed2003

Helix-stabilized cyclic peptides as selective inhibitors of steroid receptor-coactivator interactions.

The interaction between nuclear receptors and coactivators provides an arena for testing whether protein-protein interactions may be inhibited by small molecule drug candidates. We provide evidence that a short cyclic peptide, containing a copy of the LXXLL nuclear receptor box pentapeptide, binds tightly and selectively to estrogen receptor alpha. Furthermore, as shown by x-ray analysis, the disulfide-bridged nonapeptide, nonhelical in aqueous solutions, is able to adopt a quasihelical conformer while binding to the groove created by ligand attachment to estrogen receptor alpha. An i, i+3 linked analog, H-Lys-cyclo(d-Cys-Ile-Leu-Cys)-Arg-Leu-Leu-Gln-NH2 (peptidomimetic estrogen receptor modulator 1), binds with a Ki of 25 nM, significantly better than an i, i+4 bridged cyclic amide, as predicted by molecular modeling design criteria. The induction of helical character, effective binding, and receptor selectivity exhibited by this peptide analog provide strong support for this strategy. The stabilization of minimalist surface motifs may prove useful for the control of other macromolecular assemblies, especially when an amphiphilic helix is crucial for the strong binding interaction between two proteins.

Amino Acid Sequence↗
PubMed2005

c-Myc suppresses p21WAF1/CIP1 expression during estrogen signaling and antiestrogen resistance in human breast cancer cells.

Estrogen rapidly induces expression of the proto-oncogene c-myc. c-Myc is required for estrogen-stimulated proliferation of breast cancer cells, and deregulated c-Myc expression has been implicated in antiestrogen resistance. In this report, we investigate the mechanism(s) by which c-Myc mediates estrogen-stimulated proliferation and contributes to cell cycle progression in the presence of antiestrogen. The MCF-7 cell line is a model of estrogen-dependent, antiestrogen-sensitive human breast cancer. Using stable MCF-7 derivatives with inducible c-Myc expression, we demonstrated that in antiestrogen-treated cells, the elevated mRNA and protein levels of p21(WAF1/CIP1), a cell cycle inhibitor, decreased upon either c-Myc induction or estrogen treatment. Expression of p21 blocked c-Myc-mediated cell cycle progression in the presence of antiestrogen, suggesting that the decrease in p21 is necessary for this process. Using RNA interference to suppress c-Myc expression, we further established that c-Myc is required for estrogen-mediated decreases in p21(WAF1/CIP1). Finally, we observed that neither c-Myc nor p21(WAF1/CIP1) is regulated by estrogen or antiestrogen in an antiestrogen-resistant MCF-7 derivative. The p21 levels in the antiestrogen-resistant cells increased when c-Myc expression was suppressed, suggesting that loss of p21 regulation was a consequence of constitutive c-Myc expression. Together, these studies implicate p21(WAF1/CIP1) as an important target of c-Myc in breast cancer cells and provide a link between estrogen, c-Myc, and the cell cycle machinery. They further suggest that aberrant c-Myc expression, which is frequently observed in human breast cancers, can contribute to antiestrogen resistance by altering p21(WAF1/CIP1) regulation.

Breast Neoplasms↗
PubMed2006

Solution structure and antiestrogenic activity of the unique C-terminal, NR-box motif-containing region of MTA1s.

Metastasis tumor-associated 1 short form (MTA1s) is a naturally occurring, alternatively spliced variant of MTA1 that functions as a repressor of estrogen receptor (ER) alpha transcriptional functions, at least in part by binding and sequestering ERalpha in the cytoplasm. A unique C-terminal 33-amino acid region containing a nuclear receptor (NR)-box motif (-LRILL-) mediates binding of MTA1s with ERalpha and is indispensable in this interaction. Here, we elucidated the solution structure of this 33-amino acid region by NMR spectroscopy. We found a predominance of the alpha-helical region toward the N-terminal region, which includes the NR-box motif. In silico docking and comparison studies showed similarities between the NR-box motif of MTA1s and a similar motif of coregulators, both in structure and mode of ERalpha binding. In MCF-7 breast cancer cells, the MTA1s peptide effectively repressed ERalpha transactivation function, as evidenced by the estrogen response element-luc assay and down-regulation of estrogen-induced genes. In mechanistic studies, we found that the antiestrogenic effects of the MTA1s peptide were due to its ability to compete with the coactivator recruitment to ERalpha. Furthermore, the peptide efficiently repressed estrogen-induced proliferation and anchorage-independent growth of MCF-7 cells. In addition, the MTA1s peptide blocked the progression of tumors formed by MCF-7 cells overexpressing an ERalpha coactivator in a xenograft-based assay. In brief, the characterization of structure and antiestrogenic activity of MTA1s peptide highlight its therapeutic potential.

Animals↗
PubMed2005

Adjuvant therapy of breast cancer.

The treatment of early-stage breast cancer includes the use of chemotherapeutic and hormonal agents. Both chemotherapy and hormonal therapy have been shown by large, randomized trials to offer a survival advantage. The most commonly used chemotherapeutic agents used in the United States are doxorubicin and cyclophosphamide (AC). However, 3 studies have suggested that there may be an advantage in the use of taxanes in the adjuvant treatment of breast cancer. Furthermore the use of dose dense chemotherapy, incorporating AC and paclitaxel, has shown very promising results. It is well established that tamoxifen, a selective estrogen receptor modulator (SERM), improves overall survival (OS) in women with hormone receptor (HR) positive breast cancer. However, the results from large multicenter, randomized trials, suggest the potential superiority of aromatase inhibitors, compared to tamoxifen or an advantage of sequencing tamoxifen followed by an aromatase inhibitor (AI). The role of ovarian suppression is still being investigated in patients who have received prior chemotherapy. Newer agents, such as the monoclonal antibody against the HER2/neu receptor, trastuzumab, are now being studied as adjuvant therapy in early-stage breast cancer. In the next few years, with the completion of several large randomized trials, we will be able to answer several questions, including the optimal way of incorporating AIs into adjuvant therapy, the long-term sequella of using trastuzumab in the adjuvant treatment of breast cancer and the role of ovarian suppression combined with an aromatse inhibitor in premenopausal women with breast cancer.

Antineoplastic Agents↗
PubMed2004

Management of anovulatory infertility associated with polycystic ovary syndrome: tamoxifen citrate an effective alternative compound to clomiphene citrate.

Clomiphene citrate (CC) is widely used as first-line treatment for ovulation induction in anovulatory women with polycystic ovary syndrome (PCOS). Tamoxifen citrate (TMX), another non-steroidal selective estrogen receptor modulator, may also be effective on the resumption of ovulation in these women. The aim of this controlled observational study was to compare the efficacy and safety of ovulation induction with TMX versus CC in anovulatory infertile women with PCOS. A total of 102 consecutive women (mean age+/-SD: 31+/-3.6 years; range: 26-38) with PCOS were studied. Following a spontaneous or progesterone-induced withdrawal bleed, women received either 50 mg daily of CC (days 2-6) or 20 mg daily of TMX (days 2-5). In case ovulation failed to occur, the dose was sequentially increased to 100 mg daily of CC and 40 mg daily of TMX, respectively. Serum progesterone levels were measured on cycle day 21 to monitor the ovulation pattern. The overall ovulation rate was significantly higher in women who received TMX compared with those who received CC (61/98, 62.2% vs. 60/127, 47.2%, p=0.03). Although not statistically significant, the pregnancy rate per ovulatory cycle was higher in the TMX group compared to the CC group (14/61, 22.9% vs. 11/60, 18.3%, respectively). All pregnancies were single and there were no side-effects in either group of treatment. Collectively, these data demonstrate that TMX is a safe and effective agent, and a suitable alternative to CC for anovulatory infertility in women with PCOS.

Adult↗
PubMed2005

Effect on sexual life--a comparison between tibolone and continuous combined conjugated equine estrogens and medroxyprogesterone acetate.

OBJECTIVES: To compare the effects of tibolone 2.5 mg with those of continuous combined conjugated equine estrogens 0.625 mg/day and medroxyprogesterone acetate 5 mg/day (CEE/MPA) on sexual life in postmenopausal women. METHODS: Eighty women were randomized to treatment with either tibolone or continuous combined CEE/MPA. Subjects were asked about sexual desire, sexual excitement, sexual arousal, orgasm capacity, vaginal lubrication during sexual activity and dyspareunia before and after the treatment. RESULTS: After 6 months of treatment, a total of 72 women completed the study. When tibolone was compared with continuous combined CEE/MPA, significantly higher scores were found for the items assessing sexual desire, sexual excitement, intercourse frequency and vaginal dryness (p < 0.05). CONCLUSION: This study indicates that both tibolone and continuous combined CEE/MPA treatment were associated with significant improvements in sexual function in postmenopausal women. However, tibolone treatment improved sexual function to a greater extent than continuous combined CEE/MPA.

Estrogen Receptor Modulators↗
PubMed2005

Is mammographic density, as currently measured, a robust surrogate marker for breast cancer?

In order to determine current beliefs concerning the relevance of breast mammographic percent density (MPD) as a surrogate marker for breast cancer, the panel and the delegates completed a questionnaire. There was general agreement between the panel and delegates on most aspects, although the delegates were unsure whether high breast MPD is a contraindication for hormone therapy and tended to err on the side of caution in suggesting that estrogen and estrogen/progestogen therapy should be stopped before screening mammography. The overall consensus of the panel and the delegates was that breast MPD should become an important clinical tool, and that carefully designed studies are needed to determine exactly how it can be best used to guide clinical decision-making.

Adult↗
PubMed2005

Cyclooxygenase-2 expression in endometrial polyps during menopause.

OBJECTIVE: To determine whether cyclooxygenase-2 (COX-2) is expressed in endometrial polyps during menopause and how previous hormone use may affect this expression. PATIENTS AND METHODS: Fifty-two postmenopausal patients with endometrial polyps were enrolled for this study. Eighteen patients had no history of previous hormone use, while the remaining patients had used vaginal conjugated estrogens for short periods of time (n = 25) or were long-term users of tibolone (n = 5) or tamoxifen (n = 4). The endometrial polyps were removed by hysteroscopy, and COX-2 and Ki-67 expression were measured in tissue samples by immunohistochemistry. RESULTS: Endometrial polyps expressed COX-2 in the glandular epithelium and this expression was not significantly greater in patients who had previously used tibolone, tamoxifen or vaginal estrogens. However, Ki-67 expression was greater in the group using vaginal estrogens compared with the group of non-users; while in the other two treatment groups Ki-67 expression was less than in hormone never-users. CONCLUSION: COX-2 expression is present in endometrial polyps during menopause and may play a role in their growth regulation.

Cyclooxygenase 2↗
PubMed2004

A comparative study of breast cell proliferation during hormone replacement therapy: effects of tibolon and continuous combined estrogen-progestogen treatment.

OBJECTIVE: To use the fine-needle aspiration (FNA) biopsy technique to compare the effects of tibolone, conventional hormone replacement therapy (HRT) and placebo on breast cell proliferation in postmenopausal women. METHODS: A total of 91 women were randomized to receive either estradiol 2 mg plus norethisterone acetate 1 mg (E2/NETA), tibolone 2.5 mg or placebo for 6 months in a prospective double-blind trial. Breast cell proliferation was assessed using the Ki-67/MIB-1 monoclonal antibody. RESULTS: From the 83 women who completed the study, a total of 166 FNA biopsies were obtained, and 118 of these aspirates (71%) were evaluable for MIB-1 content. Women with assessable biopsies were younger, had a lower body mass index, and had higher levels of sex hormone binding globulin and insulin-like growth factor-I than women in whom the cell yield was insufficient. During treatment with E2/NETA, there was an increase in proliferation (percentage of MIB-1) from a mean value of 2.2 to 6.4% after 6 months (p < 0.01). No significant changes were recorded during treatment with tibolone or placebo. There was a negative association between proliferation and serum levels of total (r(s) = -0.29, p < 0.05) and free (rs = -0.31, p < 0.03) testosterone. CONCLUSIONS: Tibolone seems to have little influence on breast cell proliferation.

Aged↗
PubMed2004

Clinical background of women prescribed tibolone or combined estrogen + progestogen therapies: a UK MediPlus study.

OBJECTIVES: To describe and compare the history and clinical characteristics of women who were prescribed tibolone or one of the following combined estrogen + progestogen therapies (CEPT): sequential conjugated equine estrogens (CEE)/norgestrel, sequential CEE/medroxyprogesterone acetate (MPA), continuous CEE/MPA or continuous estradiol/norethisterone acetate (NETA). METHODS: This was a descriptive study using MediPlus, a UK Primary Care database; 3762 women participated who, between July 1st, 1999 and June 30th, 2001, were prescribed either tibolone or one of the CEPT regimens mentioned above. Risk factors associated with endometrial cancer and breast cancer were assessed. RESULTS: The results of this study suggest that the clinical background of women who were prescribed tibolone differed from that of the women who were prescribed the combination products. More frequently than expected women who were most recently prescribed tibolone have a history of chronic breast disease, a personal history of breast cancer or a history of being prescribed (long-term) estrogen-only therapy. Furthermore, this group of women more frequently had hypertension and performed uterine procedures recorded in their medical records. This preferential prescribing of tibolone occurs at first-ever prescription of hormone therapy but is, in some instances, the underlying reason for switch behavior. CONCLUSION: In the UK, general practitioners seem to preferentially prescribe tibolone to women with an increased risk for breast and endometrial cancer, as compared to women being prescribed other CEPT products.

Breast Neoplasms↗
PubMed2005

Clinical effects of tibolone in postmenopausal women after 5 years of tamoxifen therapy for breast cancer.

OBJECTIVES: This observational, prospective, open, non-randomized study was designed to assess the safety and efficacy of tibolone for the treatment of climacteric symptoms in women with a history of breast cancer. METHODS: A total of 156 women who had been treated for breast cancer and had received tamoxifen for 5 years participated in the study. One month after stopping tamoxifen, 52 women started taking tibolone while the rest served as untreated controls (n = 104). They were followed up (mean duration 61 months) for climacteric symptoms, cancer recurrence rate, breast density, endometrial thickness and adverse events. RESULTS: There was no difference in cancer recurrence rate between the two groups. Breast density was not affected. Tibolone treatment alleviated climacteric symptoms and positively affected sexual problems. Endometrial thickness was not adversely affected by treatment and there was a low incidence of adverse events. CONCLUSIONS: Tibolone was effective in the treatment of climacteric symptoms and well tolerated in a group of 52 women with a history of breast cancer. The cancer recurrence rate in the tibolone group was comparable to that of untreated controls. It should be noted that the limitations of the study design and the small number of events preclude any definitive conclusions about the effects of tibolone on breast cancer recurrence in general clinical practice. There were no breast-related adverse effects, and overall safety and tolerance were similar to those of the general population of postmenopausal women treated with tibolone.

Adult↗
PubMed2006

Effects of tibolone on blood flow resistance and intima-media thickness of the carotid arteries: effect of time since menopause.

OBJECTIVE: The aim of this prospective study was to evaluate the effects of tibolone on carotid atherosclerosis in healthy postmenopausal women. METHODS: Twenty-five healthy postmenopausal women were included in the study. Patients received tibolone 2.5 mg daily for 6 months. Resistance indices of the common carotid artery (CCA), internal carotid artery (ICA), external carotid artery (ECA) and vertebral arteries, and intima-media thickness of the CCA were measured both at baseline and at the end of the study with ultrasonography. RESULTS: No significant differences were observed in the resistance indices of the CCA, ICA, ECA and vertebral arteries, as well as intima-media thickness of CCA at 6 months in comparison with baseline. Tibolone significantly improved the intima-media thickness of the CCA of women who were less than 18 months since menopause. CONCLUSION: Overall, these results demonstrate no significant effects of tibolone on either intima-media thickness or blood flow resistance in the carotid arteries in postmenopausal women. However, the results suggest that tibolone may have a positive effect on the vascular system if commenced within 18 months since menopause; this warrants further investigation.

Carotid Arteries↗
PubMed2006

Hormone replacement therapy in women with past history of endometriosis.

Endometriosis is a common clinical condition and its treatment will often lead to an estrogen deficiency status. As most of these patients are young, they will need to consider hormone replacement therapy. Endometriosis is a hormone-dependent disease and estrogen replacement can be associated with a risk of recurrence or malignant transformation. Only a few studies have addressed this problem. With the use of hormone replacement therapy (HRT), there is an increased, although undefined, risk of recurrence of endometriosis, especially in known severe cases and in obese patients. Unopposed estrogen appears to carry a higher risk than combined preparations. Delay in starting HRT after pelvic clearance is not of any benefit. After radical surgery for severe endometriosis, women often have much to gain from HRT, particularly in the early years. Benefits of HRT in terms of control of menopausal symptoms, prevention of urogenital atrophy and loss of libido and bone protection are of particular importance. HRT may still have a role in prevention of cardiovascular disease in early menopause, but this remains unproven. Although there is no firm evidence, continuous combined preparations or tibolone would appear to be the optimum choice.

Adult↗