Effects of tibolone and conventional HRT on the expression of estrogen and progesterone receptors in the breast

Objective

There is evidence that long-term hormone replacement therapy (HRT) is associated with an increased breast cancer risk. The aim of this study was to assess the effects of tibolone on estrogen and progesterone receptors in comparison to the effects of conventional HRT in the breast of surgically postmenopausal macaques.

Method

Sixty macaques were bilaterally ovariectomized 3 months before hormonal treatment was initiated. The animals were randomized into four treatment groups, including tibolone (TIB), conjugated equine estrogens (CEE), conjugated equine estrogens + medroxyprogesterone acetate (CEE + MPA) and control animals (C). After 2 years treatment, breast tissues were collected, fixed and paraffin embedded. Immunohistochemistry assays with monoclonal antibodies for estrogen receptors (ERα and ERβ) and progesterone receptors (PRA and PRB) were performed.

Results

The expression of ERα was markedly decreased in the CEE + MPA group as compared to C and TIB groups. The TIB group was not different from the C and CEE groups. No significant differences were found for ERβ immunostaining. The expression of PRA was strongly increased in the TIB group as compared to the C and CEE + MPA groups. Immunostaining of PRB was increased in the CEE and TIB treated animals as compared to both C and CEE + MPA groups.

Conclusions

Tibolone increased the expression of both PRA and PRB, without affecting ERα and ERβ expression in the macaque breast. These findings indicate that the effects of tibolone in breast tissue could be mediated via differential regulation of PRA and PRB isoforms and therefore distinct from those observed with conventional HRT.     

Effects of estrogen versus estrogen and progesterone on cortisol and interleukin-6

Objectives

The purpose of this study was to compare the effects of 3 months of estrogen replacement therapy, estrogen plus progesterone replacement therapy and a placebo, on the resting cortisol and interleukin-6 (IL-6) levels in post-menopausal women.

Methods

Forty-three women were randomised to one of three treatment arms: estradiol 2 mg/day (ERT), estradiol 2 mg/day plus medroxyprogesterone acetate 5 mg/day (HRT), or a placebo that was administered orally for 3 months.

Results

Cortisol levels showed a significant condition by intervention interaction. Post hoc tests showed that ERT significantly increased cortisol levels after treatment compared to baseline, while in the HRT group a trend toward increased cortisol was found. No changes were observed in IL-6 levels.

Conclusions

Estrogen administration elevated cortisol levels, but this effect may be moderated by progestins. IL-6 was not altered by ERT or HRT, future studies should consider the interaction of cortisol increases on change in IL-6 expression.     

Medroxyprogesterone acetate-driven increase in breast cancer risk might be mediated via cross-talk with growth factors in the presence of progesterone receptor membrane component-1

Background

The WHI trial suggests an increase of breast cancer in postmenopausal women probably according to the progestogenic compound, i.e. medroxyprogesterone acetate (MPA). However, the mechanism for a possible carcinogenic effect of MPA remains unclear so far. Progesterone receptor membrane component-1 (PGRMC1) may be important in tumorigenesis and thus may increase breast cancer risk. We investigated the influence of MPA alone and in combination with growth factors on breast cancer cells overexpressing PGRMC1.

Methods

MCF-7 cells were stably transfected with PGRMC1 expression plasmid (WT-12 cells). Cells transfected only with the vector were used as control cells (EVC-cells). Medroxyprogesterone acetate (MPA), norethisterone (NET) and progesterone (P) were tested alone and in combination with a mixture of growth factors. Cell proliferation was measured by MTT assay.

Results

The growth factor mixture (GF) was able to induce cell proliferation in both cell types, however, the effect was much higher in the WT-12 cells. In WT-12 cells both MPA and NET alone significantly increased cell proliferation with values of 40% and 97%, respectively. Progesterone, however, had no effect. In combination with GF MPA significantly further enhanced cell proliferation as compared to the effect of MPA alone and GF alone in both cell lines. NET showed no further increase as compared to NET alone and P had no effect.

Conclusions

We could demonstrate a significant proliferative effect of MPA when combined with high concentrations of growth factors. This effect was more pronounced in breast cancer cells overexpressing PGRMC1. These results may be of clinical relevance since in the combined WHI trial an increased breast cancer risk was found during treatment with conjugated equine estrogens plus MPA.     

Body fat distribution is associated with lumbar spine bone density independently of body weight in postmenopausal women

Objective

To assess the association between the body fat distribution and axial bone mineral density (BMD) in postmenopausal women with or without hormone replacement therapy (HRT).

Design

Cross-sectional population-based study.

Setting

University of Eastern Finland, Bone and Cartilage Research Unit, Kuopio, Finland.

Population

198 postmenopausal women, mean age 67.5 (1.9 SD), mean BMI 27.1 (3.9 SD).

Methods

Regional body composition and BMD assessed by dual X-ray absorptiometry (DXA, Prodigy).

Main outcome measures

Spinal and Femoral BMD.

Results

Out of the body composition parameters, FM was the main determinant of postmenopausal bone mass. Only the lumbar spine (L2–L4) BMD, not the femoral neck BMD, was positively associated with the trunk FM. Positive trends for association were revealed between the spinal BMD and the trunk FM regardless of the use of HRT. Adjustments did not change the results.

Conclusions

Higher trunk fat mass was associated with the spinal BMD, but not with the hip BMD in postmenopausal women, irrespective of the HRT use. In addition to biological factors, uncertainties related to DXA measurements in patients with varying body mass may contribute to this phenomenon.     

Population attributable risk of modifiable risk factors associated with invasive breast cancer in women aged 45–69 years in Queensland,Australia

Objectives

To quantify the population attributable risk of key modifiable risk factors associated with breast cancer incidence in Queensland, Australia.

Study design

Population attributable fractions (PAFs) for high body mass index (BMI), use of hormone replacement therapy (HRT), alcohol consumption and inadequate physical activity were calculated, using prevalence data from a representative survey of women attending mammographic screening at BreastScreen Queensland in 2008 and relative risk estimates sourced from published literature. Attributable cancers were calculated using ‘underlying’ breast cancer incidence data for 2008 based on Poisson regression models, adjusting for the inflation of incidence due to the effects of mammographic screening.

Main outcome measures

Attributable burden of breast cancer due to high body mass index (BMI), use of hormone replacement therapy (HRT), alcohol consumption and inadequate physical activity.

Results

In Queensland women aged 45–69 years, an estimated 12.1% (95% CI: 11.6–12.5%) of invasive breast cancers were attributable to high BMI in post-menopausal women who have never used HRT; 2.8% (95% CI: 2.7–2.9%) to alcohol consumption; 7.6% (95% CI: 7.4–7.9%) to inadequate physical activity in post-menopausal women and 6.2% (95% CI: 5.5–7.0%) to current use of HRT after stratification by BMI and type of HRT used. Combined, just over one quarter (26.0%; 95% CI: 25.4–26.6%) of all invasive breast cancers in Queensland women aged 45–69 years in 2008 were attributable to these modifiable risk factors.

Conclusions

There is benefit in targeting prevention strategies to modify lifestyle behaviours around BMI, physical activity, HRT use and alcohol consumption, as a reduction in these risk factors could decrease invasive breast cancer incidence in the Queensland population.     

Motives for initiation,temporary discontinuation,and permanent discontinuation of hormone replacement therapy use among Norwegian women

Objective

The use of hormone replacement therapy (HRT) declined strongly in many countries after publication of the WHI-study. The purpose of the present study was to investigate HRT usage patterns and motives for initiation, temporary discontinuation, and permanent discontinuation of HRT use among Norwegian women.

Methods

A questionnaire study about use and attitudes towards HRT was carried out in 2005. Women 45–64 years old were invited to the study (n = 2325, response rate 47%).

Results

Women initiated HRT use mainly due to climacteric complaints (74%), while prophylactic motives were less frequently reported (27%). The most often reported benefits of HRT use were reduced climacterical symptoms, especially hot flushes/sweating (83%), and improved quality of life (59%). The major proportion of ever-users (57%) had at some point temporarily discontinued HRT use. The motive for temporary discontinuation of HRT use most frequently reported was to see if climacterical symptoms had ceased (58%). Permanent discontinuation of HRT use was most often motivated by anxiety to side effects (55%). In multivariable analyses, women using HRT prophylactically were less likely to temporarily discontinue use. Women with a positive attitude towards HRT were the most unlikely ones to permanently discontinue HRT use.

Conclusions

Temporary discontinuation of HRT use was common among Norwegian women. The majority of HRT users reported a reduction in climacteric complaints after initiation of HRT use but many women were afraid of side effects.     

Lifestyle influences on the association between pre-diagnostic hormone replacement therapy and breast cancer prognosis—Results from The Danish ‘Diet,Cancer and Health’ prospective cohort

Objectives

The association between pre-diagnostic hormone replacement therapy (HRT) and breast cancer specific mortality as well as potential influences from other lifestyle factors on the association was investigated.

Study design

Female participants from the prospective cohort “Diet, Cancer, and Health” diagnosed with breast cancer (BC) were identified and their pre-diagnostic HRT use evaluated for association with tumour biology and breast cancer outcome in multivariate analysis.

Main outcome measure

Breast cancer specific mortality.

Results

Of the 1212 patients originally considered 1064 were included. Of these, 105 women died from breast cancer during a median follow-up of 6.3 years (range 0.2–14.3 years). In multivariate analyses women who used HRT at enrolment into the cohort study had 47% lower risk of dying from breast cancer as compared to women who had previously or never used HRT (adjusted HR: 0.53; 95% CI, 0.37–0.85). Pre-diagnostic HRT use was associated with smaller tumour size at the time of diagnosis and a higher frequency of receptor positive breast cancer. Paradoxically, a high pre-diagnostic intake of vitamin D supplements was associated with HRT use but also with a higher BC specific mortality (HR: 1.47; 95% CI, 1.07–2.00)

Conclusions

HRT use at enrolment was associated with breast tumours of smaller size at the time of diagnosis and positive receptor status, and with a lower BC mortality. The found association between vitamin D from supplements and higher BC mortality warrants further exploration.     

Update of the evolution of breast cancer incidence in relation to hormone replacement therapy use in Belgium

Background

Several studies reported a decrease in breast cancer (BC) incidence, subsequent to the decrease in hormone replacement therapy (HRT) use.

Aim

Although Belgium has one of the highest incidences of BC in Europe and one of the highest rates of HRT use, we were unable, in a previous study, to observe a significant association between BC incidence and HRT changes. In this updated report we added the BC data from incidence years 2007 and 2008.

Material and method

We used European standardized incidence rates for invasive BC in the age class 50–69 years for Flanders (1999–2008), Brussels and Wallonia (2004–2008), obtained from IMS Health HRT sales data (1997–2008) for Brussels, Flanders and Wallonia. The association between BC incidence and HRT use was analyzed using generalized estimating equations (GEE) in order to take into consideration the dependency between the subsequent data points.

Results

There was a significant association between the invasive BC incidence rate and estimated rate of HRT users in the previous year: p-value < 0.001.

Conclusion

Although this study is hampered by a number of limitations, these data support the idea that the drop in BC incidence can be partly attributed to the decrease in HRT use. Since HRT remains the most used medication for climacteric symptoms, we encourage the creation of a prospective registry in Europe, collecting detailed data in various European countries, in order to assess the adjusted increase in BC risk associated with HRT, which may be population and regimen dependent.     

Effects of progestins of human proliferative endometrium: an in vitro model of potential clinical relevance

Endometrium biopsy is a useful indicator of endometrium proliferation and is clinically relevant to diagnose cell proliferation and to evaluate response to progestin treatment and to monitor hormone replacement therapy. The aim of our study was to investigate the in vitro effects of progesterone and synthetic progestins on endometrium explants with a particular focus on estradiol receptor (ER) and progesterone receptor (PR) expression which reflects through cell secretion the hormone treatment efficiency. Most widely used progestagens belonging to three distinctive groups were investigated, i.e, medroxyprogesterone acetate (MPA), norethindrone acetate (NOR) and nomegestrol acetate (TX) which are respectively pregnane, 19-nortestosterone and norpregnane derivatives. We used organ culture from human proliferative endometrium, in which tissue integrity, particularly gland/stroma relationships are preserved. Progestins induce epithelial cell secretion and most effects were observed at the highest concentration tested (10(-7) M) and by TX and MPA on homogeneous and on heterogeneous (including also secretory glands) proliferative endometrium respectively. In these conditions, ER as well as PR expression were decreased on both glandular and stromal cells. In contrast, progesterone at 10(-7) M significantly decreased only PR, in glands and in stroma of homogeneous proliferative endometrium, and just in stroma of heterogeneous endometrium. NOR exhibited less effects. At lower concentrations (10(-8) M, 10(-9) M), significantly less effects were observed by synthetic progestins on proliferative endometrium. The experiments show that the different types of progestins do not exhibit in vitro similar effects. Since progestins variably act on proliferative endometrium, the exposure of endometrium explants to progestins may be a useful tool to predict clinical response to hormone therapy (individual "hormonogram") and to monitor endometrium proliferation.     

The multifaceted nature of access to compounded progesterone: A cross-sectional study from Australia

Objective

To explore the influences on accessibility of compounded progesterone therapy for Australian women.

Study design

A cross-sectional survey of a stratified sample of Australian women who use progesterone only products using the ‘Perspectives on Progesterone’ questionnaire.

Main outcome measures

Principle components analysis (PCA) to determine components of access to progesterone treatment and multi-way analysis of variance to compare groups.

Results

Women using compounded progesterone were likely to have made at least one lifestyle adaptation (73%), and to have tried and stopped using at least one complementary and alternative medicine therapy (63%) or conventional hormone therapy (41%). PCA revealed six components of access to progesterone treatment: affordable, values natural treatments and is concerned about other treatments, conventionally available, perceived knowledge, values information gathered from a variety of sources, and rural & disadvantaged.The multifaceted nature of progesterone use illustrates that there are multiple aspects to use of non-conventional medicines. Women looking for non-conventional treatment are neither stupid nor uninformed, their understandings, based on experience and research, need to be addressed by health professionals while assessing their condition prior to discussing the risks and benefits of non-conventional medicines.

Conclusion

Access to compounded progesterone is multifaceted, and many of the women who use it have tried other treatments first. Despite the clinical ambivalence towards progesterone as an alternative for women who may have tried and rejected other treatments, including conventional hormone therapy, the women described in this paper are using it.     

The Asian Menopause Survey: Knowledge,perceptions, hormone treatment and sexual function

Objective

To provide current insights into the opinions, attitudes, and knowledge of menopausal women in Asia regarding menopause and hormone replacement therapy (HRT).

Study design

Cross-sectional.

Main outcome measures

Between January 2006 and February 2006, 1000 postmenopausal women from China, Malaysia, Taiwan, Thailand and Hong Kong were interviewed to determine postmenopausal symptoms, HRT use and knowledge, breast discomfort and knowledge of breast cancer risks, and sexual function.

Results

Almost all women reported experiencing postmenopausal symptoms. Sleeplessness (42%) was reported as the main reason for seeking treatment. On average, 54% of women were aware of HRT, despite the fact that most (38%) were unable to mention any associated benefits. Most women had used natural or herbal treatments (37%) for the alleviation of menopausal symptoms. Only 19% had received HRT. 27% of respondents reported having breast discomfort, while 70% reported performing self-breast examinations. 53% of women had never received a mammogram, despite breast cancer concern (50%). 24% of women described HRT as being a risk factor for breast cancer. Most women and their partners reported no reductions in sexual function (66 and 51%, respectively), while 90% of respondents did not seek treatment for reduced sexual function. In the event of sexual dysfunction, 33% of women replied that they would be willing to seek treatment.

Conclusions

Many Asian women experience postmenopausal symptoms that are often left untreated (due to the acceptance of menopause as a natural process) or treated with herbal/natural remedies. There was a general lack of knowledge among these women regarding treatment options, HRT, and possible risks associated with HRT. A more concerted effort should be made to better disseminate information regarding the pathogenesis and risk factors associated with breast cancer, menopause, and menopausal symptoms to Asian women.     

Treatment of climacteric symptoms in breast cancer patients: A retrospective study from a medication databank

Introduction

Women affected by breast cancer (BC) will often go through menopause at an earlier age and display more frequent and severe symptoms than women who have a natural menopause. The safety of hormone replacement therapy (HRT) and vaginal estrogens for BC survivors has been debated over time and remains unclear. Non hormonal therapies such as antidepressants, gabapentine and clonidine may be useful for those patients but there are few data about their safety.

Aim

This retrospective study analyses the use by BC patients of treatments known to alleviate climacteric symptoms.

Material and method

Post-menopausal Estrogen Receptors positive (ER+) BC patients, aged 45–69, were identified as having bought, at least once, an aromatase inhibitor (AI) or tamoxifen between the years 2000 and 2012 through a pharmaceutical databank in Belgium. Among them, we defined users of a climacteric treatment those who bought, at least once, HRT, vaginal topical estrogens, antidepressants, clonidine and gabapentine.

Results

We identified 2530 BC patients. Among them, 45% were buying a treatment known to alleviate menopausal symptoms. The majority of these treatments were non-HRT therapies. HRT and vaginal estrogens were seldom bought (respectively 1.1% and 6%), but 3% bought vaginal estrogens while buying AI. About 9.2% of tamoxifen users patients bought antidepressants implicated in tamoxifen metabolism at the same time as tamoxifen.

Conclusions

Most BC patients follow current guidelines contra-indicating the use of HRT after BC, they use non hormonal therapies. In some cases they use unfortunately antidepressants that may alter the metabolism of tamoxifen.     

EMAS position statement: Managing menopausal women with a personal or family history of VTE

Introduction

Venous thromboembolism (VTE), including deep venous thrombosis (DVT) and pulmonary embolism (PE), is a serious cardiovascular event whose incidence rises with increasing age.

Aims

To formulate a position statement on the management of the menopause in women with a personal or family history of VTE.

Material and methods

Literature review and consensus of expert opinion.

Results and conclusions

Randomized controlled trials have shown an increased risk of VTE in oral hormone therapy (HT) users. There are no randomized trial data on the effect of transdermal estrogen on VTE. Recent observational studies and meta-analyses suggest that transdermal estrogen does not increase VTE risk. These clinical observations are supported by experimental data showing that transdermal estrogen has a minimal effect on hepatic metabolism of hemostatic proteins as the portal circulation is bypassed. A personal or family history of VTE, especially in individuals with a prothrombotic mutation, is a strong contraindication to oral HT but transdermal estrogen can be considered after careful individual evaluation of the benefits and risks. Transdermal estrogen should be also the first choice in overweight/obese women requiring HT. Observational studies suggest that micronized progesterone and dydrogesterone might have a better risk profile than other progestins with regard to VTE risk. Although these findings should be confirmed by randomized clinical trials, they strongly suggest that both the route of estrogen administration and the type of progestin may be important determinants of the overall benefit-risk profile of HT.     

Hormone replacement therapy use and the risk of stroke

Objectives

Randomised trials reported an increase risk of stroke with an estrogen plus progestogen formulation of hormone replacement therapy (HRT). A recent trial also reported an increased risk with tibolone, a selective tissue estrogenic activity regulator.

Methods

We used the General Practice Research Database to conduct a case–control study within a cohort of women aged 50–79 between January 1987 and October 2006, without history of stroke prior to cohort entry. We identified all cases of stroke occurring during the study period and selected up to four controls matched to each case on age, general practice and year of start in the practice. Information on HRT use during the year preceding the index date was obtained. Conditional logistic regression was used to estimate the rate ratios of stroke associated with current use of the different HRTs.

Results

The cohort included 870,286 women, of whom 15,710 experienced a stroke during follow-up and were matched to 59,958 controls. The adjusted rate ratio of stroke associated with current use of tibolone relative to non-use of HRT was 1.08 (95% CI: 0.82–1.44). The rate ratios with current use of estrogens alone and estrogen plus progestogen were 1.26 (95% CI: 1.10–1.45) and 1.19 (95% CI: 1.05–1.36) respectively.

Conclusions

We found no evidence of an elevated risk of stroke associated with the use of tibolone, although the low number of subjects using tibolone does not permit to rule out a small risk. The small elevated risk of stroke with estrogens or estrogens plus progestogen is consistent with that reported in randomised trials.     

EMAS position statement: Management of uterine fibroids

Introduction

Uterine fibroids (also termed leiomyomas or myomas) are the most common tumors of the female reproductive tract.

Aim

The aim of this position statement is to provide and critically appraise evidence on the management of women with uterine fibroids.

Methods

Literature review and consensus of expert opinion.

Results and conclusions

Many uterine fibroids are asymptomatic and require no intervention, although it is advisable to follow up patients to document stability in size and growth. Fibroid-associated symptoms include heavy menstrual bleeding and pain or pelvic discomfort. The association between infertility and fibroids increases with age. Fibroids do not increase the risk of malignant uterine disease and leiomyosarcomas are extremely rare (less than one in 1000). It is unknown at present whether leiomyosarcoma represents de novo growth or malignant transformation from benign uterine fibroids. Treatment options for symptomatic fibroids include pharmacologic, surgical and radiologically guided interventions. The range of medical treatments allows flexible management of fibroid-related symptoms; the options include tranexamic acid, non-steroidal anti-inflammatory drugs, contraceptive steroids, gonadotropin-releasing hormone analogs, antiprogesterone, and selective progesterone receptor modulators. However, these medical options do not remove the tumors and symptoms may return when treatment is stopped. Surgical and radiologically guided procedures may be tailored to age, general health, and individual patient wishes. Hysterectomy is the most effective treatment, although in some cases myomectomy may be sufficient to control symptoms. Alternatives to surgery include uterine artery embolization, myolysis and ablation by high-intensity focused ultrasound (guided with magnetic resonance imaging or ultrasound). The choice of treatment depends on fibroid size, the underlying symptoms and their severity and the woman's desire for subsequent fertility and pregnancy, as well as efficacy and need for repeated interventions.     

The menopause and oral health

Objectives

To review the literature about oral symptoms and signs at the menopause with an emphasis on hormone replacement therapy (HRT). To give practical guidelines for women and their physicians in menopause-related oral health problems.

Methods

The PubMed and Cochrane databases was searched until mid January 2009 with key words such as “menopause”, “menopausal complaints”, “postmenopausal complaints” and “oral diseases”, “oral discomfort”, “dental health”, “dental diseases”, “saliva”, “burning mouth syndrome”, “dry mouth”, “xerostomia”. Because of a scarcity of controlled studies no systematic review could be conducted.

Results

Oral discomfort is found in many menopausal women in addition to more general climacteric complaints. The principal peri- and postmenopausal symptoms are dry mouth and burning mouth (glossodynia) which, in turn, may increase the occurrence of oral mucosal and dental diseases, such as candidiasis. The mechanisms of hormone-related oral symptoms and signs are not known although oestrogen receptors, for example, have been detected in the oral mucosa and salivary glands. In principle, the histology of oral and vaginal mucosa is very similar and thus their symptoms might share a common cause. Yet, hormone replacement therapy use does not necessarily prevent or help women with oral symptoms.

Conclusion

Properly controlled long-term randomized studies are needed to assess the effect of HRT on oral discomfort. Future gene profiling could identify women who may or may not benefit from HRT with regard to oral symptoms.     

Effects of raloxifene and hormone replacement therapy on forearm skin elasticity in postmenopausal women

Objectives

Hormone replacement therapy (HRT) increases skin elasticity in postmenopausal women. However, the effects of raloxifene, a selective estrogen receptor modulator (SERM), on skin degenerative changes in postmenopausal women remain unknown. We investigated whether raloxifene increases skin elasticity, similar to HRT, in postmenopausal women.

Methods

In a 12-month trial, 17 postmenopausal women (mean age, 66.4 ± 7.8 years) received continuous raloxifene treatment (60 mg/day), 19 women (56.2 ± 6.4 years) received continuous 17-β estradiol treatment using a patch (0.72 mg/2 days) plus cyclic medroxyprogesterone acetate (2.5 mg/day, for 12 days/month), and 11 women (58.1 ± 7.3 years) did not receive either therapy. In each subject, the skin elasticity of the forearm was measured using a suction device at baseline and at 12 months after the start of the study.

Results

Raloxifene and HRT significantly increased skin elasticity from 52.4 ± 3.8% and 64.1 ± 7.2% at baseline to 55.1 ± 4.7% and 67.4 ± 7.4% after 12 months, respectively (P < 0.05, each), but the untreated subjects did not exhibit any significant change in skin elasticity during the study. The delta value for skin elasticity was significantly higher among the raloxifene and HRT subjects than among the untreated subjects (P < 0.05, each).

Conclusions

These findings suggest that raloxifene may have a beneficial effect on skin elasticity, which undergoes degenerative changes in postmenopausal women, in addition to its effects on bone metabolism.