Lessons to be learned from animal studies on hormones and the breast

The relation of hormone use by postmenopausal women to breast cancer risk has been controversial and unclear. A recent large randomized trial, the Women's Health Initiative (WHI) and a large observational study (Million Women Study) provided somewhat conflicting answers. The WHI found an increased incidence of breast cancer among women given hormone therapy (conjugated equine estrogen plus medroxyprogesterone acetate) but no increase in those given estrogen only therapy (conjugated equine estrogen alone). Whereas, the Million Women Study found an increased breast cancer risk among the estrogen plus progestin and the estrogen only users. This review brings comparative perspective to the issue of the effects of estrogen plus progestin versus estrogen only effects on breast cancer and is focused particularly on nonhuman primates. Although data from rodents is mixed, studies of monkeys suggest that estrogen only treatment has little or no effect on breast cell proliferation, and by inference, on breast cancer risk. On the other hand, data from both mouse and monkey studies strongly support the conclusion that the co-administration of a progestogen with an estrogen markedly increases breast cell proliferation and the potential for breast cancer promotion.     

Breast cancer risk in the WHI study: the problem of obesity

In the climacteric, about 40% of the women have occult breast tumors the growth of which may be stimulated by hormones. Many genetic, reproductive and lifestyle factors may influence the incidence of breast cancer. Epidemiological data suggest that the increase in the relative risk (RR) of breast cancer induced by hormone replacement therapy (HRT) is comparable with that associated with early menarche, late menopause, late first birth, alcohol consumption, etc. One of the most important risk factors is obesity which exceeds the effect of HRT by far, and in overweight postmenopausal women the elevated risk of breast cancer is not further increased by HRT. As in the WHI study the majority of women was overweight or obese, this trial was unsuitable for the investigation of breast cancer risk. In the women treated with an estrogen/progestin combination, the RR of breast cancer rose only in those women who have been treated with hormones prior to the study, suggesting a selection bias. In the women not pretreated with hormones, it was not elevated. In the estrogen-only arm of the WHI study, there was no increase but a steady decrease in the RR of breast cancer during 6.8 years of estrogen therapy. This result was unexpected, as estrogens are known to facilitate the development and growth of breast tumors, and the effect is enhanced by the addition of progestins. Obese women are at high risk to develop a metabolic syndrome including insulin resistance and hyperinsulinemia. In postmenopausal women, elevated insulin levels are not only associated with an increased risk for cardiovascular disease, but also for breast cancer. This might explain the effects observed in both arms of the WHI study: HRT with relative low doses of estrogens may improve insulin resistance and, hence, reduce the elevated breast cancer risk in obese patients, whereas this beneficial estrogen effect may be antagonized by progestins. The principal options for the reduction of breast cancer risk in postmenopausal women are the prevention of overweight and obesity to avoid the development of hyperinsulinemia, the medical treatment of insulin resistance, the use of low doses of estrogens and the reduction of exposure to progestins. The latter might include long-cycles with the sequential use of appropriate progestins every 3 months for 14 days. There are large inter-individual variations in the proliferative response to estrogens of the endometrium. Control by vaginalsonography and progestin challenge tests may help to identify those women who may be candidates for low-dose estrogen-only therapy.     

Rationale for use of lower estrogen doses for postmenopausal hormone therapy

In placebo-controlled clinical trials low dose estrogens have been shown to reduce hot flashes an average of 65%. Low dosage is effective in preventing bone loss in early menopause and both low and ultralow estrogen dosages can prevent bone loss among women many years beyond menopause. Epidemiological studies indicate less risk of cardiovascular disease and venous thromboembolism in women who use low dose estrogens compared to standard dose. Low dosages of estrogens are less likely to produce unacceptable side effects, such as vaginal bleeding or breast tenderness. When prescribing low dosage estrogen, one can safely use less progestogen, either less daily dosage or less frequent cycles. Older women on ultralow estrogen may not require regular progestogen because the endometrium is not stimulated. In conclusion, there is a strong rationale for use of lower estrogen dosage in HT. Low dosage estrogen can relieve vasomotor symptoms and can prevent postmenopausal bone loss. Women taking low dosages of estrogens are less likely to have unacceptable side effects, such as vaginal bleeding or breast tenderness. Moreover, the potential harm caused by standard dosages of estrogen with progestin, including coronary heart disease, venous thromboembolism, stroke, and breast cancer may be mitigated by use of lower estrogen doses that do not require daily or monthly progestin opposition.     

Cardioprotective effects of ovarian hormones and the HERS in perspective

The increased population of women in menopause living in the industrialized countries is associated with an increase of diseases which are dependent or facilitated by a state of estrogen deficiency such as cardiovascular and cerebrovascular diseases. Several studies have shown that estrogen replacement therapy reduces the occurrence of coronary and may be of cerebrovascular disease by nearly 50% in treated women compared to non-users. These findings are supported by the evidence that estrogens have a beneficial effect on cholesterol metabolism and deposition, contributing to the inhibition of atherosclerotic plaque formation in arterial walls as well as a direct effect on the vessel wall. Progestins may, in some cases, counteract the beneficial effect of estrogens upon cardiovascular functions. More androgenic progestins may have a detrimental effect upon vascular reactivity while less androgenic progestins seem not to reduce the beneficial effect of estrogens. Of interest, continuous combined administration of hormone replacement therapy seem to be preferable for women with coronary artery disease or for those with increased cardiovascular risk. Case-control and cohort studies have shown that estrogen progestin therapy is associated with a significant reduction of cardiovascular mortality and morbidity. The HERS study has added critical data regarding the cardioprotective effect of hormone replacement therapy in elderly women with proven coronary artery disease. Because of the several methodological and statistical flaws of the HERS study, further studies are warranted to evaluate the effect of hormone replacement therapy on cardiovascular prognosis. Large scale randomized studies will evaluate the effect of estrogen and estrogen-progestin replacement therapy upon cardiovascular events in menopausal women. Until completion of these studies hormone replacement therapy in women with increased cardiovascular risk should be seen with no enthusiasm but also with no fear.     

Postmenopausal testosterone therapy and breast cancer risk

Background: Testosterone therapy is being increasingly used in the management of postmenopausal women. However, as clinical trials have demonstrated a significantly increased risk of breast cancer with oral combined estrogen–progestin therapy, there is a need to ascertain the risk of including testosterone in such regimens. Objective: Evaluation of experimental and epidemiological studies pertaining to the role of testosterone in breast cancer. Design: Literature review. Setting: The Jean Hailes Foundation, Research Unit. Main Outcome Measures: Mammary epithelial proliferation, apoptosis and breast cancer. Results: In experimental studies, testosterone action is anti-proliferative and pro-apoptotic, and mediated via the AR, despite the potential for testosterone to be aromatized to estrogen. Animal studies suggest that testosterone may serve as a natural, endogenous protector of the breast and limit mitogenic and cancer promoting effects of estrogen on mammary epithelium. In premenopausal women, elevated testosterone is not associated with greater breast cancer risk. The risk of breast cancer is also not increased in women with polycystic ovary syndrome who have chronic estrogen exposure and androgen excess. However, in postmenopausal women, who are oestrogen deplete and have increased adipose aromatase activity, higher testosterone has been associated with greater breast cancer risk. Conclusion: Available data indicate the inclusion of testosterone in estrogen–progestin regimens has the potential to ameliorate the stimulating effects of hormones on the breast. However, testosterone therapy alone cannot be recommended for estrogen deplete women because of the potential risk of enhanced aromatisation to estrogen in this setting.     

Raloxifene lowers serum lipoprotein(A) in healthy postmenopausal women: a randomized, double-blind, placebo-controlled comparison with conjugated equine estrogens.

OBJECTIVE: Long-term postmenopausal estrogen replacement therapy lowers the risk of osteoporotic fractures and coronary artery disease but increases the risk of endometrial cancer and probably breast cancer. Raloxifene, a nonsteroidal estrogen receptor ligand, seems to have a tissue-specific antiestrogenic action on endometrium and breast and the desired estrogenic action on bone and lipid metabolism. The purpose of this study was to investigate the effects of 24-month treatment with orally administered raloxifene in two doses (60 mg and 150 mg daily) and conjugated equine estrogens in a standard oral dose (0.625 mg daily) on serum lipoprotein(a) [Lp(a)], an independent risk factor for coronary artery disease, in healthy postmenopausal women who had undergone hysterectomy. DESIGN: A randomized, double-blind, placebo-controlled study was performed with 56 women. RESULTS: In the placebo group serum Lp(a) levels did not change throughout the study. After 6 months, serum Lp(a) was significantly reduced versus baseline in the raloxifene 150 (-17%; p = 0.003) and conjugated equine estrogens (-26%; p = 0.003) groups, but this reduction was significantly different from placebo only in the conjugated equine estrogens group. At 12 and 24 months, serum Lp(a) levels were significantly lowered versus baseline in all active treatment groups. However, these reductions were significantly different from placebo only in the raloxifene 150 and conjugated equine estrogens groups. After 24 months, serum Lp(a) was reduced versus baseline with 30% (p = 0.001) in the raloxifene 150 group and 35% (p = 0.001) in the conjugated equine estrogens group. CONCLUSIONS: Long term raloxifene treatment significantly lowers serum Lp(a) levels in postmenopausal women and thus might reduce the risk of coronary artery disease.     

Breast cancer risk with postmenopausal hormonal treatment

This review was designed to determine from the best evidence whether there is an association between postmenopausal hormonal treatment and breast cancer risk. Also, if there is an association, does it vary according to duration and cessation of use, type of regimen, type of hormonal product or route of administration; whether there is a differential effect on risk of lobular and ductal cancer; and whether hormone treatment is associated with breast cancers that have better prognostic factors? Data sources for the review included Medline, the Cochrane Database of Systematic Reviews (Cochrane Library, 2005) and reference lists in the identified citations. Eligible citations addressed invasive breast cancer risk among postmenopausal women and involved use of the estrogen products with or without progestin that are used as treatment for menopausal symptoms. Abstracted data were demographic groupings, categories of hormone use, categories of breast cancer, two-by-two tables of exposure and outcome and adjusted odds ratios, relative risks (RRs) or hazard rates. Average estimates of risk were weighted by the inverse variance method, or if heterogeneous, using a random effects model. The average risk of invasive breast cancer with estrogen use was 0.79 [95% confidence interval (95% CI) = 0.61-1.02] in four randomized trials involving 12 643 women. The average breast cancer risk with estrogen-progestin use was 1.24 (95% CI = 1.03-1.50) in four randomized trials involving 19 756 women. The average risks reported in recent epidemiological studies were higher: 1.18 (95% CI = 1.01-1.38) with current use of estrogen alone and 1.70 (95% CI = 1.36-2.17) with current use of estrogen-progestin. The association of breast cancer with current use was stronger than the association with ever use, which includes past use. For past use, the increased breast cancer risk diminished soon after discontinuing hormones and normalized within 5 years. Reasonably adequate data do not show that breast cancer risk varies significantly with different types of estrogen or progestin preparations, lower dosages or different routes of administration, although there is a small difference between sequential and continuous progestin regimens. Epidemiological studies indicate that estrogen-progestin use increases risk of lobular more than ductal breast cancer, but the number of studies and cases of lobular cancer remains limited. Among important prognostic factors, the stage and grade in breast cancers associated with hormone use [corrected] do not differ significantly from those in non-users, but breast cancers in estrogen-progestin users are significantly more likely to be estrogen receptor (ER) positive. In conclusion, valid evidence from randomized controlled trials (RCTs) indicates that breast cancer risk is increased with estrogen-progestin use more than with estrogen alone. Epidemiological evidence involving more than 1.5 million women agrees broadly with the trial findings. Although new studies are unlikely to alter the key findings about overall breast cancer risk, research is needed, however, to determine the role of progestin, evaluate the risk of lobular cancer and delineate effects of hormone use on receptor presence, prognosis and mortality in breast cancer.     

HRT as secondary prevention of cardiovascular disease

Objective: To review the evidence of the efficacy of postmenopausal hormone replacement therapy (HRT) in secondary prevention of coronary artery disease or stroke. Results: Although a number of rather large and prolonged non-randomized observational studies have produced convincing and consistent evidence of the efficacy of HRT in the prevention of recurrence of cardiac events, the first randomized, placebo controlled trial (RCT) on heart disease and estrogen replacement study (HERS) reported no benefit of conjugated equine estrogen (CEE) and medroxyprogesterone acetate (MPA) in secondary prevention of cardiac events in women with established coronary artery disease. This was supported by RCT reporting no effect of CEE or CEE + MPA on the progress of coronary sclerosis. Similarly, some nonrandomized observational studies have evaluated the risk of recurrent stroke in regard to the use of HRT, and the data are conflicting reporting a reduced or increased risk of recurrence for HRT users. One RCT has shown that low-dose estrogen treatment can only slow down the progression of carotid arteriosclerosis in high-risk postmenopausal women, whereas two other RCTs have shown no benefit (or risk) of using HRT for secondary prevention of ischemic stroke or progression of carotid atherosclerosis. Conclusion: The evidence accumutaed so far shows that HRT has no place in secondary prevention of coronary or carotic artery disease. Its use in these patients must be based on solid nonvascular indications and expected benefits from these causes.     

Metabolic and vascular effect of progestins in post-menopausal women. Implications for cardioprotection

Estrogen therapy causes changes in a variety of cardiovascular risk factors, including insulin resistance, lipoprotein profile, haemostasis, coronary atherosclerosis and vascular reactive, that suggest a potential cardioprotective effect in postmenopausal women. With respect to the role of adjunctive progestins, currently available data suggest that the cardiovascular effects may differ depending on the type, dosage and route of administration of the progestin. Androgenic progestins antagonise the favourable cardiovascular effect of estrogens, whilst non-androgenic progestins do not impair, or may even enhance, the beneficial effect of estrogens. Therefore, less androgenic progestins would appear to be the agent of choice for combined hormone therapy in postmenopausal women with cardiovascular risk factors.     

Breast cancer incidence in postmenopausal women using testosterone in addition to usual hormone therapy

OBJECTIVE: There is now convincing evidence that usual hormone therapy for ovarian failure increases the risk for breast cancer. We have previously shown that ovarian androgens normally protect mammary epithelial cells from excessive estrogenic stimulation, and therefore we hypothesized that the addition of testosterone to usual hormone therapy might protect women from breast cancer. DESIGN: This was a retrospective, observational study that followed 508 postmenopausal women receiving testosterone in addition to usual hormone therapy in South Australia. Breast cancer status was ascertained by mammography at the initiation of testosterone treatment and biannually thereafter. The average age at the start of follow-up was 56.4 years, and the mean duration of follow-up was 5.8 years. Breast cancer incidence in this group was compared with that of untreated women and women using usual hormone therapy reported in the medical literature and to age-specific local population rates. RESULTS: There were seven cases of invasive breast cancer in this population of testosterone users, for an incidence of 238 per 100,000 woman-years. The rate for estrogen/progestin and testosterone users was 293 per 100,000 woman-years--substantially less than women receiving estrogen/pro-gestin in the Women's Health Initiative study (380 per 100,000 woman-years) or in the "Million Women" Study (521 per 100,000 woman-years). The breast cancer rate in our testosterone users was closest to that reported for hormone therapy never-users in the latter study (283 per 100,000 woman-years), and their age-standardized rate was the same as for the general population in South Australia. CONCLUSIONS: These observations suggest that the addition of testosterone to conventional hormone therapy for postmenopausal women does not increase and may indeed reduce the hormone therapy-associated breast cancer risk-thereby returning the incidence to the normal rates observed in the general, untreated population.     

New evidence regarding hormone replacement therapies is urgently required transdermal postmenopausal hormone therapy differs from oral hormone therapy in risks and benefits

Controversies about the safety of different postmenopausal hormone therapies (HTs) started 30 years ago and reached a peak in 2003 after the publication of the results from the Women Health Initiative (WHI) trial and the Million Women Study (MWS) [Writing group for the women's health initiative investigations. Risks and benefits of estrogen plus progestin in healthy postmenopausal women. JAMA 2002;288:321-33; Million women study collaborators. Breast cancer and hormone-replacement therapy in the million women study. Lancet 2003;362:419-27]. The single HT formulation used in the WHI trial for non hysterectomized women-an association of oral conjugated equine estrogens (CEE-0.625 mg/day) and a synthetic progestin, medroxyprogesterone acetate (MPA-2.5 mg/day)-increases the risks of venous thromboembolism, cardiovascular disease, stroke and breast cancer. The MWS, an observational study, showed an increased breast cancer risk in users of estrogens combined with either medroxyprogesterone acetate (MPA), norethisterone, or norgestrel. It is unclear and questionable to what extent these results might be extrapolated to other HRT regimens, that differ in their doses, compositions and administration routes, and that were not assessed in the WHI trial and the MWS. Significant results were achieved with the publication of the WHI estrogen-only arm study [Anderson GL, Limacher M, Assaf AR, et al. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women's Health Initiative randomized controlled trial. JAMA 2004;291:1701-1712] in which hormone therapy was reserved to women who had carried out hysterectomy. What emerged from this study will allow us to have some important argument to develop.     

Effects of estrogen and opioid blockade on blood pressure reactivity to stress in postmenopausal women

Estrogen may influence coronary heart disease risk in women through the effects of endogenous opioids on autonomic control of blood pressure. In a randomized, placebo-controlled trial, we examined the combined effects of estrogen and the opioid antagonist, naltrexone, on blood pressure responses to psychological stress in 42 postmenopausal women. After 3 months of estrogen or estrogen plus progestin (hormone replacement therapy; n = 27) or placebo replacement, participants completed a mental arithmetic task after administration of .7 mg/kg oral naltrexone or placebo. Systolic blood pressure (SBP), diastolic blood pressure, mean arterial pressure and heart rate (HR) were measured at rest and during the arithmetic stressor. Stress produced significant increases in circulatory measures regardless of estrogen condition or opioid blockade (p’s < .001). Interestingly, there was an estrogen by naltrexone interaction on SBP reactivity scores [F(1,38) = 4.36, p < .05], where women on estrogen with intact opioid receptors showed the largest SBP responses to stress, compared with all other conditions. This is consistent with some studies of premenopausal women, suggesting that estrogens may alter opioid function during stress. The interaction between estrogen and endogenous opioids may explain sex differences in opioid effects on stress reactivity in younger premenopausal women.     

Thyroid disease in relation to breast cancer

Summary A controversy exists in regard to thyroid function and breast cancer. Hypothyroidism has been suggested as being either protective from breast cancer or predisposing to the disease. It has been hypothesized that a deficiency in circulating thyroid hormones may hypersensitize the mammary glandular epithelium toward prolactin and estrogens, thus aiding in the development of breast neoplasia. On the other hand, thyroid hormone replacement therapy has been connected with an increased risk of breast cancer, but this has been contested. At this time the American Thyroid Association recommends that, if indicated, hypothyroid patients should take their thyroid hormone medication.Hyperthyroidism has been associated with a decreased risk of breast cancer. Also, in hyperthyroid patients with inoperable breast cancer, the malignant growth is thought to be slowed. However, this, too has been disputed. Moreover, hyperthyroidism has been connected with the development of breast cancer in premenopausal women.At present no role of thyroid hormone in the pathobiology of breast cancer can be defined. It seems that the thyroid-breast cancer controversy can only be resolved by a prospective study preferably on postmenopausal women correlating thyroid (T₃, T₄, PBI), pituitary (TSH, TRH, Prolactin), and adrenocortical (androgens) function tests with the clinical examination of thyroid, breast, and genital apparatus and determination of the estrogen status (vaginal smear, plasma estrogens) as well.     

Perspective on prescribing conjugated estrogens/bazedoxifene for estrogen-deficiency symptoms of menopause: A practical guide

Current guidelines recommend that hormone therapy (HT) in postmenopausal women with a uterus include a progestin to protect against endometrial hyperplasia. However, many concerns relating to HT use appear to be related to the progestin component, including cardiovascular risk, breast stimulation, and irregular vaginal bleeding. Conjugated estrogens (CE) combined with the selective estrogen receptor modulator bazedoxifene (BZA) is a new progestin-free HT option for alleviating estrogen deficiency symptoms in postmenopausal women with a uterus for whom treatment with progestin-containing therapy is not appropriate. Five double-blind, randomized, placebo-controlled, phase 3 studies, known as the Selective estrogens, Menopause, And Response to Therapy (SMART) trials have investigated the efficacy of CE/BZA for relieving vasomotor symptoms (VMS), and effect on bone mass, as well as endometrial and breast safety in postmenopausal women. In a 12-week study, CE 0.45 mg/BZA 20 mg significantly reduced the number and severity of hot flushes compared with placebo at weeks 4 and 12. Unlike estrogen-progestin therapy (EPT), CE 0.45 mg/BZA 20 mg did not increase breast density compared with placebo. In clinical trials up to 2 years, CE/BZA had a favorable tolerability profile, demonstrated by amenorrhea rates similar to placebo. Vascular disorders including venous thromboembolic events (pulmonary embolism, retinal vein thrombosis, deep vein thrombosis, and thrombophlebitis) were rare events, occurring in less than 1 per 1000 patients. CE/BZA was associated with significantly higher incidences of amenorrhea and lower incidences of bleeding compared with CE/medroxyprogesterone acetate in 2 comparative trials. Therefore, CE 0.45 mg/BZA 20 mg provides an effective, well-tolerated, progestin-free alternative to EPT for postmenopausal women with a uterus.     

HRT and breast cancer risk: a clue for interpreting the available data

Epidemiological and biological data on HRT and breast cancer risk are reviewed. Some aspects deserve consideration. (1) The majority of epidemiological data have been gathered from populations where high estrogen doses (≥1.25 mg daily of conjugated estrogens) were used as first line therapy. (2) HRT does not increase the risk in overweight women, even in the series in which a risk increase (in longterm users) is found. This could be as a result of the fact that oral estrogens, through their metabolic and hepatocellular effects, reverse some biological features of obesity (e.g. increased insulin-like growth factor I activity and decreased sex hormone binding globulin level) which potentially increase breast cancer risk, so balancing the estrogen stimulation. (3) The progestin addition seems to increase the risk when the 19 nor-testosterone derivatives are used. These androgenic compounds contrast the metabolic and hepatocellular effects of oral estrogens. To sum up, the possibility does exist that even the longterm use of oral estrogens at the right (‘low’) dose, with the addition of a non-androgenic progestin, will be shown to be associated with a very limited breast cancer risk increase.     

Interaction between menopausal status and obesity in affecting breast cancer risk

Obesity has a complex relationship to breast cancer risk that differs in premenopausal and postmenopausal women. Before the menopause, the level of adiposity is inversely related to risk, indicative of a protective effect, whereas in postmenopausal women, particularly the elderly, the association is a positive one, consistent with obesity being a risk factor. The importance of high estrogen production in adipose tissue, with consequent elevation of circulating biologically available estradiol, in the promotional effect of obesity on postmenopausal breast carcinogenesis is well established; the resulting tumors express both estrogen and progesterone receptors. The mechanism(s) for the protective effect in premenopausal women is less well understood, but the breast cancers that do develop in the presence of obesity are most often estrogen and progesterone receptor negative, consistent with the selection of non-estrogen-dependent tumor cells which are dependent on growth factors such as insulin, insulin-like growth factor-I and some adipokines. The influence of menopausal status on the relationships between adiposity and breast cancer appears to be modified within each category by age; the protective effect before the menopause may be limited to younger women (<35 years), and the adverse effect was found to apply specifically to older postmenopausal women. Although randomized trials of weight reduction for postmenopausal breast cancer prevention have not been performed, observational studies suggested that risk reduction does occur; in addition, other health benefits of weight control need to be considered regardless of menopausal status.     

Effects of progestins on estrogen-induced increase in C-reactive protein in postmenopausal women

Background: C-reactive protein (CRP) represents an independent risk factor for coronary disease and stroke. Because oral estrogens increase CRP levels, with inflammatory and thrombotic consequences, we determined whether the co-administration of a progestin might modify the estrogenic effect on CRP. Methods: In a non-randomized, non-blinded study, we measured C-reactive protein serum concentrations with high-sensitivity technique (hs-CRP) in 163 healthy postmenopausal women divided into groups as follow: 52 not taking hormones (referent group), and 111 taking hormone replacement therapy (HRT) (42 of whom treated with unopposed estrogen, and 69 with an estrogen/progestin combination). Results: Compared with non-users of hormones, median CRP levels were 66% (95% confidence interval: from 44 to 89%) higher and 112% (95% confidence interval: from 89 to 168%) higher among women using a combined estrogen/progestin regimen and, respectively, among women taking unopposed estrogen [1.54 mg/L in the referent group; 2.56 mg/L in the estrogen/progestin group (P=0.032), and 3.27 mg/L in the unopposed estrogen group (P=0.004)]. Furthermore, there was no difference in CRP distributions between women taking different types of progestins. Conclusion: concurrent progestin administration may attenuate estrogen’s pro-inflammatory effects, independently on the type of used progestin.     

Estrogen and cancers of the colorectum,breast, and lung in postmenopausal women

As estrogens play an important role in maintaining physiological function in various organs, the estrogen decrease after menopause is thought to cause various diseases frequently observed in postmenopausal or elderly women. With the aging of society and a decrease in infectious or vascular diseases, neoplasms have now become the most frequent cause of death in Japan. Cancers of the colorectum, breast, and lung have been rapidly increasing both in incidence and death, especially among postmenopausal women. Interestingly, all three of these cancers are associated with estrogens. In premenopausal women, ovarian estrogens plays major roles in the female reproductive organs through the classic estrogen receptor, ER‐α. In postmenopausal women, however, estrogens produced/activated by peripherally localized estrogen‐metabolizing enzymes such as aromatase, which converts androgen into estrogens, are thought to play physiologically and pathobiologically important roles in various organs through second ER, namely ER‐β, distributing systemically. In this article, the association of estrogens with these cancers in postmenopausal or elderly women are reviewed, especially focusing on the role of ER‐β and peripheral estrogen metabolism. The possibility of prevention or treatment of these diseases through estrogenic control is also discussed.     

Selective estrogen receptor modulators (SERMs) and retinoids in breast cancer chemoprevention

Tamoxifen has been shown to decrease the risk of invasive breast cancer by 49% and noninvasive breast cancer by 50%. Tamoxifen is also associated with a threefold increased risk of endometrial cancer. Raloxifene, a second-generation selective estrogen receptor modulator (SERM), has not been associated with endometrial cancer risk, and is currently under study in a large, multi-institutional, randomized Study of Tamoxifen and Raloxifene (STAR) for breast cancer prevention in postmenopausal women. A pilot trial of raloxifene in premenopausal women to assess the safety, tolerability, effects on bone mineral density, mammographic density, and other biological endpoints is ongoing. The retinoids have been shown to decrease mammary tumors in rodent carcinogenesis models. The Italian trial of fenretinide (4-HPR) in women with stage I breast cancer randomized women to fenretinide or no intervention. This study did not show an overall effect of decreasing the risk of contralateral breast cancer. However, a protective effect was suggested in premenopausal women. It has been suggested that this effect may be related to insulin-like growth factor 1 (IGF-1), which has been shown to be modulated by fenretinide in premenopausal but not postmenopausal women. Pilot studies of SERMs alone and in combination with retinoids or other agents provide a model for testing the safety and tolerability, pharmacokinetics and pharmacodynamics, and biomarker modulation in high-risk women. These studies can provide information as to both the pathophysiology of carcinogenesis and the mechanism of action of chemopreventive agents, and help select agents and doses for testing in large randomized studies.