Estrogens and women's health: interrelation of coronary heart disease, breast cancer and osteoporosis

The determinants of blood levels of estrogen, estrogen metabolites, and relation to receptors and post-transitional effects are the likely primary cause of breast cancer. Very high risk women for breast cancer can now be identified by measuring bone mineral density and hormone levels. These high risk women have rates of breast cancer similar to risk of myocardial infarction. They are candidates for SERM therapies to reduce risk of breast cancer. The completion of the Women's Health Initiative and other such trials will likely provide a definite association of risk and benefit of both estrogen alone and estrogen-progesterone therapy, coronary heart disease, osteoporotic fracture, and breast cancer. The potential intervention of hormone replacement therapy, obesity, or weight gain and increased atherogenic lipoproteinemia may be of concern and confound the results of clinical trials. Estrogens, clearly, are important in the risk of bone loss and osteoporotic fracture. Obesity is the primary determinant of postmenopausal estrogen levels and reduced risk of fracture. Weight reduction may increase rates of bone loss and fracture. Clinical trials that evaluate weight loss should monitor effects on bone. The beneficial addition of increased physical activity, higher dose of calcium or vitamin D, or use of bone reabsorption drugs in coordination with weight loss should be evaluated. Any therapy that raises blood estrogen or metabolite activity and decreases bone loss may increase risk of breast cancer. Future clinical trials must evaluate multiple endpoints such as CHD, osteoporosis, and breast cancer within the study. The use of surrogate markers such as bone mineral density, coronary calcium, carotid intimal medial thickness and plaque, endothelial function, breast density, hormone levels and metabolites could enhance the evaluation of risk factors, genetic-environmental intervention, and new therapies.     

Effects of Combination of Estradiol with Selective Progesterone Receptor Modulators (SPRMs) on Human Breast Cancer Cells In Vitro and In Vivo

Use of estrogen or estrogen / progestin combination was an approved regimen for menopausal hormonal therapy (MHT). However, more recent patient-centered studies revealed an increase in the incidence of breast cancer in women receiving menopausal hormone therapy with estrogen plus progestin rather than estrogen alone. Tissue selective estrogen complex (TSEC) has been proposed to eliminate the progesterone component of MHT with supporting evidences. Based on our previous studies it is evident that SPRMs have a safer profile on endometrium in preventing unopposed estrogenicity. We hypothesized that a combination of estradiol (E2) with selective progesterone receptor modulator (SPRM) to exert a safer profile on endometrium will also reduce mammary gland proliferation and could be used to prevent breast cancer when used in MHT. In order to test our hypothesis, we compared the estradiol alone or in combination with our novel SPRMs, EC312 and EC313. The compounds were effectively controlled E2 mediated cell proliferation and induced apoptosis in T47D breast cancer cells. The observed effects were found comparable that of BZD in vitro. The effects of SPRMs were confirmed by receptor binding studies as well as gene and protein expression studies. Proliferation markers were found downregulated with EC312/313 treatment in vitro and reduced E2 induced mammary gland proliferation, evidenced as reduced ductal branching and terminal end bud growth in vivo. These data supporting our hypothesis that E2+EC312/EC313 blocked the estrogen action may provide basic rationale to further test the clinical efficacy of SPRMs to prevent breast cancer incidence in postmenopausal women undergoing MHT.     

Alternative hormone replacement regimens: is there a need for further clinical trials?

PURPOSE OF REVIEW: To review the randomized trials of hormone replacement therapy. RECENT FINDINGS: Studies have shown that conjugated equine estrogen 0.625 mg a day plus medroxyprogesterone acetate 2.5 mg a day increased the risk of cardiovascular events during the first year of treatment in women both with and without coronary heart disease. Conjugated equine estrogen plus medroxyprogesterone acetate also increased the overall risk of myocardial infarction and stroke in women without coronary heart disease, and myocardial infarction or death in women with coronary heart disease, and also increased the risk of breast cancer, cognitive decline and dementia. Unopposed, oral 17B-estradiol increased the risk of stroke during the first 6 months of treatment in women with a previous stroke. Oral 17B-estradiol with or without cyclic progestin had no effect on the progression of atherosclerosis or reinfarction. Transdermal 17B-estradiol plus cyclic progestin was associated with a non-significant increase in coronary heart disease events in women with coronary heart disease. Compared with placebo, cardiovascular events increased in the ongoing estrogen-only arm of the Women's Health Initiative, indicating that unopposed conjugated equine estrogen is unlikely to be cardioprotective. However, oral 17B-estradiol retarded the progression of subclinical atherosclerosis in younger women without coronary heart disease. SUMMARY: Hormone replacement therapy should not be initiated for the primary or secondary prevention of coronary heart disease in women. A trial of 17B-estradiol started at menopause in women without coronary heart disease should be considered.     

Should symptomatic menopausal women be offered hormone therapy?

Many physicians remain uncertain about prescribing hormone therapy for symptomatic women at the onset of menopause. The American Society for Reproductive Medicine (ASRM) convened a multidisciplinary group of healthcare providers to discuss the efficacy and risks of hormone therapy for symptomatic women, and to determine whether it would be appropriate to treat women at the onset of menopause who were complaining of menopausal symptoms. MAJOR FINDINGS: Numerous controlled clinical trials consistently demonstrate that hormone therapy, administered via oral, transdermal, or vaginal routes, is the most effective treatment for vasomotor symptoms. Topical vaginal formulations of hormone therapy should be preferred when prescribing solely for the treatment of symptoms of vulvar and vaginal atrophy. Data from the Women's Health Initiative indicate that the overall attributable risk of invasive breast cancer in women receiving estrogen plus progestin was 8 more cases per 10,000 women-years. No increased risk for invasive breast cancer was detected for women who never used hormone therapy in the past or for those receiving estrogen only. Hormone therapy is not effective for the treatment of cardiovascular disease and that the risk of cardiovascular disease with hormone therapy is principally in older women who are considerably postmenopause. CONCLUSIONS: Healthy symptomatic women should be offered the option of hormone therapy for menopausal symptoms. Symptom relief with hormone therapy for many younger women (at the onset of menopause) with menopausal symptoms outweighs the risks and may provide an overall improvement in quality of life. Hormone therapy should be individualized for symptomatic women. This involves tailoring the regimen and dose to individual needs.     

Should symptomatic menopausal women be offered hormone therapy?

Many physicians remain uncertain about prescribing hormone therapy for symptomatic women at the onset of menopause. The American Society for Reproductive Medicine (ASRM) convened a multidisciplinary group of healthcare providers to discuss the efficacy and risks of hormone therapy for symptomatic women, and to determine whether it would be appropriate to treat women at the onset of menopause who were complaining of menopausal symptoms. MAJOR FINDINGS: Numerous controlled clinical trials consistently demonstrate that hormone therapy, administered via oral, transdermal, or vaginal routes, is the most effective treatment for vasomotor symptoms. Topical vaginal formulations of hormone therapy should be preferred when prescribing solely for the treatment of symptoms of vulvar and vaginal atrophy. Data from the Women's Health Initiative indicate that the overall attributable risk of invasive breast cancer in women receiving estrogen plus progestin was 8 more cases per 10,000 women-years. No increased risk for invasive breast cancer was detected for women who never used hormone therapy in the past or for those receiving estrogen only. Hormone therapy is not effective for the treatment of cardiovascular disease and that the risk of cardiovascular disease with hormone therapy is principally in older women who are considerably postmenopause. CONCLUSIONS: Healthy symptomatic women should be offered the option of hormone therapy for menopausal symptoms. Symptom relief with hormone therapy for many younger women (at the onset of menopause) with menopausal symptoms outweighs the risks and may provide an overall improvement in quality of life. Hormone therapy should be individualized for symptomatic women. This involves tailoring the regimen and dose to individual needs.     

Suppression by 17beta-estradiol of monocyte adhesion to vascular endothelial cells is mediated by estrogen receptors

Several observational studies have shown that estrogen replacement therapy decreases cardiovascular mortality and morbidity in postmenopausal women. However, The Women's Health Initiative (WHI) study has found that women receiving estrogen plus progestin had a significantly higher risk of breast cancer, coronary heart disease, stroke, and pulmonary embolus. In the present study, we examined whether estrogen prevents mechanisms that relate to plaque formation by inhibiting monocyte adhesion to endothelial cells. ECV304 cells, an endothelial cell line that normally expresses minimal estrogen receptor (ER)alpha, were transfected with an ERalpha expression plasmid. Treatment with tumor necrosis factor (TNF)-alpha increased expression of vascular cell adhesion molecule (VCAM)-1 mRNA, activation of nuclear factor-kappaB (NF-kappaB), and U937 cell adhesion in ECV304 cells. These effects of TNF-alpha were not significantly inhibited by pretreatment of native ECV304 cells with 17beta-estradiol (E(2)). In ECV304 cells overexpressing ERalpha, E(2) significantly inhibited the effects of TNF-alpha on NF-kappaB activation, VCAM-1 expression, and U937 cell adhesion. These findings suggest E(2) suppresses inflammatory cell adhesion to vascular endothelial cells that possess functional estrogen receptors. The mechanism of suppression may involve inhibition of NF-kappaB-mediated up-regulation of VCAM-1 expression induced by atherogenic stimuli. E(2) may prevent plaque formation, as first stage of atheroscrelosis through inhibiting adhesion monocytes to endothelial cell. Actions of estrogen replacement therapy can be assessed in terms of densities of functional ERalpha.     

Progestins and menopause: epidemiological studies of risks of endometrial and breast cancer

Estrogen replacement therapy (ERT) increases a woman's risk of developing endometrial cancer approximately 120% for each 5 years of use. ERT increases a woman's risk of developing breast cancer approximately 10% for each 5 years of use. To reduce the greatly increased endometrial cancer risk, progestins have been added to ERT (estrogen-progestin replacement therapy; EPRT) for between 5 and 15 days (usually 7 or 10 days) per month in a sequential fashion (sequential EPRT; SEPRT) or with each dose of ERT (continuous-combined EPRT; CEPRT). We conducted two large case-control studies in postmenopausal women in Los Angeles to evaluate the effects of these changes on endometrial and breast cancer risks. As expected CEPRT was not associated with any increased risk of endometrial cancer. SEPRT with the progestin being given for 10 days per month also did not increase endometrial cancer risk. SEPRT with the progestin being given for 7 days per month did increase endometrial cancer risk with only a relatively slight reduction in risk compared to ERT effectively proportional to the reduction in the number of days of unopposed estrogen. The sharp contrast between the effects of 7 days and 10 days of progestin in SEPRT suggests that the extent of endometrial sloughing or of 'terminal' differentiation at the completion of the progestin phase may play a critical role in determining endometrial cancer risk. This may provide an explanation of why endometrial cancer risk increases so sharply with age in young women even in countries where obesity-associated anovulation is very uncommon; extended periods of unopposed estrogen is not an explanation but less than 10 days of an 'adequate' progesterone level may be. EPRT significantly increased the risk of breast cancer. EPRT was associated with an approximately 24% increase in risk for each 5 years of use; the effect was some 212-fold greater than the effect of ERT, which we had previously predicted on theoretical grounds. This effect could also be predicted from the results on mammographic densities seen in the PEPI randomized trial of different forms of hormone replacement therapy (HRT). In the PEPI trial EPRT increased mammographic densities to a much greater extent than ERT. Progestins need to be given to protect the endometrium. They need to be delivered to the endometrium in a manner that will have the least effect on the breast. This can be carried out by using a vaginal or direct endometrial route of administration. The vaginal route will provide adequate endometrial progestin levels with low blood levels so that the effects of the progestin on the breast should be small; with the direct endometrial route the blood progestin levels are even lower, and the effects of the progestin on the breast will be effectively zero. If this is unacceptable to a woman, then giving progestins by mouth (or transdermally) for 10 days every 3 to 4 months should provide satisfactory protection of the endometrium when used with standard-dose conjugated estrogen (CE). This regimen has much less effect on the breast than monthly SEPRT or CEPRT. Two clinical trials of 10 mg per day of MPA for 14 days every 3 months and 0.625 mg/day of CE have been published. Both studies suggest that this approach may be satisfactory in that the extent of hyperplasia was minimal. More studies of this approach are urgently needed.     

Bias in Observational Studies of the Association between Menopausal Hormone Therapy and Breast Cancer

BackgroundDuring the period 1985-2000 the breast cancer incidence rates increased 50% in the age group invited to mammography screening in Norway and Sweden. Simultaneously, use of hormone replacement treatment therapy (HT) increased 5 times. Several influential observational studies showed that HT was associated with 50% to 100% increased risk of breast cancer and most for those using combined (estrogen plus progestin) hormone replacement therapy (CHT). In contrast, the randomized WHI trial reported that CHT increased the risk by 10% for those not having previously used hormones and 24% when including previous users in the analyses. In another randomized trial, estrogen use only was not associated with any increased risk at all. After the WHI trial was published in 2003, use of HT dropped 70% within 5 years in Norway and Sweden while breast cancer rates were essentially unchanged. After 2008, HT use has dropped further and breast cancer incidence rates have started increasing again. The study objective is to calculate and to explain potential bias in the observational study design.ConclusionsWe suggest that the mechanism causing higher hazard ratio of breast cancer (compared to the observational studies) is the time-varying effect of CHT on the breast cancer risk and selective retrospective reporting of hormone use. Other risk factors for the increase in breast cancer risk in the age group 50-69 years should be considered, for example, overdiagnosis.     

Clinical practice guidelines for the care and treatment of breast cancer: 14. The role of hormone replacement therapy in women with a previous diagnosis of breast cancer

Objective

To provide information and recommendations to women with a previous diagnosis of breast cancer and their physicians regarding hormone replacement therapy (HRT).

Outcomes

Control of menopausal symptoms, quality of life, prevention of osteoporosis, prevention of cardiovascular disease, risk of recurrence of breast cancer, risk of death from breast cancer.

Evidence

Systematic review of English-language literature published from January 1990 to July 2001 retrieved from MEDLINE and CANCERLIT.

Recommendations

· Routine use of HRT (either estrogen alone or estrogen plus progesterone) is not recommended for women who have had breast cancer. Randomized controlled trials are required to guide recommendations for this group of women. Women who have had breast cancer are at risk of recurrence and contralateral breast cancer. The potential effect of HRT on these outcomes in women with breast cancer has not been determined in methodologically sound studies. However, in animal and in vitro studies, the development and growth of breast cancer is known to be estrogen dependent. Given the demonstrated increased risk of breast cancer associated with HRT in women without a diagnosis of breast cancer, it is possible that the risk of recurrence and contralateral breast cancer associated with HRT in women with breast cancer could be of a similar magnitude. · Postmenopausal women with a previous diagnosis of breast cancer who request HRT should be encouraged to consider alternatives to HRT. If menopausal symptoms are particularly troublesome and do not respond to alternative approaches, a well-informed woman may choose to use HRT to control these symptoms after discussing the risks with her physician. In these circumstances, both the dose and the duration of treatment should be minimized.

Validation

Internal validation within the Steering Committee on Clinical Practice Guidelines for the Care and Treatment of Breast Cancer; no external validation.

Sponsor

The steering committee was convened by Health Canada.

Completion date

October 2001.Hormone replacement therapy (HRT) connotes treatment with either estrogen alone or estrogen with progesterone in postmenopausal women. Menopausal symptoms, such as hot flashes and vaginal dryness, and the potential long-term effects of estrogen deprivation are a concern to women with breast cancer, particularly those in whom menopause develops early as a result of adjuvant chemotherapy.Traditionally, the use of HRT has been contraindicated in women with breast cancer because of the notion that the development and growth of breast cancer is estrogen dependent and that the introduction of HRT may increase the risk of breast cancer recurrence. The focus of this guideline is on whether it is safe to give HRT to women with breast cancer.     

Risk of breast cancer with progestins: critical assessment of current data

Whether progestins protect against the risk of breast cancer or enhance that risk has been a major area of controversy over the past several years. Observational studies have reported conflicting results and experimental studies examining whether progestins exert mitogenic or anti-mitogenic actions on breast tissue report divergent results. Based upon a wide range of animal, epidemiologic and clinical data, most investigators agree that estrogens contribute to the development of breast neoplasms. However, the additional effect of progestins on this risk has been the subject of substantial discussion and controversy. A variety of experiments have been carried out using human breast cancer cells grown in vitro and as xenografts in nude mice. These studies demonstrated both mitogenic and anti-mitogenic effects depending upon the precise experimental conditions. Two potential reasons for these differences include differential metabolism of progestins into inhibitory pregnenes or stimulatory 5-alpha-reduced pregnanes or the presence of a protein (GPR 30) which allows the anti-mitogenic effects of progestins to be manifest. Based upon the conflicting nature of the results in experimental studies, we believe that only data in patients provide substantial insight into the actions of progestins on the intact human breast. Studies have now demonstrated that cell proliferation and breast density is higher during the luteal than during the follicular phase of the menstrual cycle. In postmenopausal women, long-term exposure to estrogen plus a progestin results in a marked enhancement of proliferation of the terminal duct lobular units as well as in breast density. These data, taken together, provide substantial evidence that progestins are mitogenic on the human breast when given long term to postmenopausal women. To critically evaluate the observational studies regarding breast cancer risk from progestins, we developed a set of stringent criteria for acceptance of individual studies. Four of the five studies meeting these criteria reported a greater risk of breast cancer with combination estrogen/progestin regimens than with estrogen alone. More importantly, the first randomized, prospective, controlled trial of the risk of breast cancer with an estrogen/progestin combination (the Women's Health Initiative Study) has now been published. This study reported a 26% increased relative risk of breast cancer with the estrogen/progestin combination. Based upon these data, we believe that progestins do add to the risk of breast cancer over and above that imparted by estrogen alone. The attributable risk during use for 5 years or less is small but increases logarithmically during long-term use. The majority of data regarding progestins are derived from regimens using MPA. However, we conclude from our analysis that the burden of proof regarding progestins has now shifted. One must now prove that an estrogen/progestin combination is safe with respect to breast cancer rather than having to prove it harmful.     

Menopausal Hormone Therapy and Lung Cancer-Specific Mortality Following Diagnosis: The California Teachers Study

Previous results from research on menopausal hormone therapy (MHT) and lung cancer survival have been mixed and most have not studied women who used estrogen therapy (ET) exclusively. We examined the associations between MHT use reported at baseline and lung cancer-specific mortality in the prospective California Teachers Study cohort. Among 727 postmenopausal women diagnosed with lung cancer from 1995 through 2007, 441 women died before January 1, 2008. Hazard Ratios (HR) and 95% Confidence Intervals (CI) for lung-cancer-specific mortality were obtained by fitting multivariable Cox proportional hazards regression models using age in days as the timescale. Among women who used ET exclusively, decreases in lung cancer mortality were observed (HR, 0.69; 95% CI, 0.52–0.93). No association was observed for estrogen plus progestin therapy use. Among former users, shorter duration (<5 years) of exclusive ET use was associated with a decreased risk of lung cancer mortality (HR, 0.56; 95% CI, 0.35–0.89), whereas among recent users, longer duration (>15 years) was associated with a decreased risk (HR, 0.60; 95% CI, 0.38–0.95). Smoking status modified the associations with deceases in lung cancer mortality observed only among current smokers. Exclusive ET use was associated with decreased lung cancer mortality.     

The effects of postmenopausal hormone replacement therapy and oral contraceptives on the endogenous estradiol metabolism.

The estradiol metabolism may be of clinical relevance in the pathophysiology of various diseases; the increase in D-ring metabolites over A-ring metabolites in breast cancer patients is of special interest. Since estrogen therapy has been blamed for increasing the risk of breast cancer, the effects of hormonal replacement therapy (HRT) and oral contraception were investigated on the ratio of the main D-ring metabolite, 16alpha-hydroxyestrone (16-OHE1), to the main A-ring metabolite, 2-hydroxyestrone (2-OHE1). In our study, hormone replacement therapy (HRT) in postmenopausal women consisted of administration of estradiol valerate either with or without addition of the progestin dienogest. In the second part of the study, women of reproductive age received ethinylestradiol plus dienogest or ethinylestradiol plus norethisterone acetate as oral contraceptives (OC). 2-OHE1 and 16-OHE1 were measured by enzyme immunoassay in 8 h night-urine collected before and after 3 months of hormone administration. With HRT, that is, estradiol valerate or estradiol valerate plus dienogest, the ratios before treatment were 0.47 and 0.60; after 3 months, they were 0.54 and 0.52, respectively. There were no significant differences. With oral contraception, that is, ethinylestradiol plus dienogest or norethisterone acetate, the ratios before administration were 0.62 and 0.68, vs. 0.31 and 0.54 after 3 months, respectively. The ratio after ethinylestradiol and dienogest was significantly lower after treatment. HRT and OC in the estrogen-progestin combinations tested did not impose any negative effects on estradiol metabolism--they did not elicit a higher D-ring metabolism, which is considered to increase breast cancer risk.     

Antiestrogen use in breast cancer patients reduces the risk of subsequent lung cancer: A population-based study

BackgroundThere is accumulating epidemiological and preclinical evidence that estrogen might be a driver of lung cancer. Breast cancer survivors can offer a unique patient cohort to examine the effect of antiestrogen therapy on lung cancer carcinogenesis because many of these women would have received long-term selective estrogen receptor modulators (SERMs) and/or aromatase inhibitors (AIs) as adjuvant treatment. Our hypothesis is that estrogens play a role in lung cancer development, and that antiestrogen therapy would affect the incidence of subsequent lung cancer among breast cancer survivors.MethodsUsing the Taiwan National Health Insurance (NHI) database, the study included 40,900 survivors of non-metastatic breast cancer after primary surgery, and most antiestrogen users complied well with the medication regimen. We evaluate the effect of antiestrogen therapy on the incidence of subsequent lung cancers.ResultsThis population-based study revealed that antiestrogen use in breast cancer patients was associated with a reduced risk of subsequent lung cancer in older patients (≥50 years) (HR 0.73, 95%CI 0.54–0.99) when compared with breast cancer survivors who did not use antiestrogens.ConclusionThe study supports the hypothesis that antiestrogen therapy modifies lung cancer carcinogenesis in older women. Further well-designed clinical trials to explore the potential of antiestrogens in lung cancer prevention and treatment would be worthwhile.     

Serum metabolomic profiles associated with postmenopausal hormone use

Introduction

Postmenopausal hormone use is linked to several health outcomes and the risk associated with some may differ depending on whether estrogen is used alone or in combination with progestin.

Objective

Metabolomic analyses of postmenopausal hormone use and differences between hormone regimes was done to identify metabolites associated with each type of hormone treatment.

Methods

Untargeted metabolomics analysis was done on serum from 1336 women enrolled in the Cancer Prevention II Nutrition Cohort. Levels of 781 named metabolites were compared between 667 nonusers with 332 estrogen-only and with 337 estrogen plus progestin users using linear regression. Metabolite levels were also compared between estrogen-only and estrogen plus progestin users.

Results

Compared to nonusers, 276 metabolites were statistically significantly (P?<?6.40?×?10^??5) associated with estrogen-only use and 222 were associated with estrogen plus progestin use. The metabolites associated with both types of hormones included numerous lipids, acyl carnitines, and amino acids as well as the thyroid hormone thyroxine and the oncometabolite fumarate. The 65 metabolites that differed significantly between estrogen-only and estrogen plus progestin users included 19 steroids and 12 lipids that contained the bioactive fatty acid arachidonic acid.

Conclusions

These findings suggest that postmenopausal hormone use influences metabolic pathways linked to a variety of cellular processes, including the regulation of metabolism and stress responses, energy production, and inflammation. The differential association of numerous lipids which influence cellular signaling suggests that differences in signal transduction may contribute to the disparate risks for some diseases between estrogen-only and estrogen plus progestin users.

     

Influence of postmenopausal hormone replacement therapy on an estrogen metabolite biomarker of risk for breast cancer.

Whether postmenopausal hormone-replacement therapy (HRT) increases the risk of breast cancer remains controversial, despite numerous epidemiological studies. We approached the question from a biochemical rather than an epidemiological direction - we hypothesized that if estrogen administration increases the risk of breast cancer, it should also alter a known estrogen biomarker of risk towards what has been observed in patients who already have breast cancer. The specific biomarker we studied was the ratio of the urinary excretion of two principal estradiol metabolites, 2-hydroxyestrone and 16 alpha-hydroxyestrone, which is markedly decreased in women with breast cancer and women with familial risk for breast cancer. We studied 34 healthy postmenopausal women not on HRT and 19 women on HRT (Premarin 0.625 mg daily plus Provera, 2.5 mg daily, in women with a uterus and Premarin alone in women without a uterus); treatment duration ranged from 3 months to 15 years. We also studied four women with recently diagnosed, untreated breast cancer. The women with breast cancer showed a significantly lower 2-hydroxyestrone to 16 alpha-hydroxyestrone ratio than control women on HRT (1.35 +/- 0.13 vs. 2.71 +/- 0.84; p < 0.0001). There was no significant difference in the metabolite ratio between healthy women on HRT and women not on HRT (2.82 +/- 0.92 vs. 2.71 +/- 0.84). There was no significant difference between women receiving Premarin alone and women receiving Premarin plus Provera (2.46 +/- 0.84 vs. 3.13 +/- 0.90), and neither differed significantly from women not on HRT (2.71 +/- 0.84). The finding that the ratio of women on HRT was not decreased to or toward the ratio in women with breast cancer can be interpreted, we believe, as a suggestive item of biochemical evidence that HRT is not a risk for breast cancer.     

Progestin effects on growth in the human breast cancer cell line T-47D--possible therapeutic implications

In order to determine growth effects of the progestin R5020, (promegestone), we have utilized the progesterone-receptor rich human breast cancer cell line T-47D, growing the cells in the absence of the pH indicator phenol red, which has recently been found to be estrogenic. In contrast to reports on cells grown in the presence of phenol red, we find that promegestone alone, at physiological progestin concentration, significantly stimulates growth. Estradiol alone, at physiological concentration, stimulates growth much more. Promegestone in combination with estradiol is antiestrogenic for growth; that is, it significantly decreases the growth stimulatory effect of estradiol. These results raise the possibility that estrogen receptor and progesterone receptor-rich breast cancer patients might benefit more from a combination of anti-progestin and anti-estrogen therapy than from anti-estrogens alone.     

Role of sex hormones in lung cancer

Lung cancer represents the world’s leading cause of cancer deaths. Sex differences in the incidence and mortality rates for various types of lung cancers have been identified, but the biological and endocrine mechanisms implicated in these disparities have not yet been determined. While some cancers such as lung adenocarcinoma are more commonly found among women than men, others like squamous cell carcinoma display the opposite pattern or show no sex differences. Associations of tobacco product use rates, susceptibility to carcinogens, occupational exposures, and indoor and outdoor air pollution have also been linked to differential rates of lung cancer occurrence and mortality between sexes. While roles for sex hormones in other types of cancers affecting women or men have been identified and described, little is known about the influence of sex hormones in lung cancer. One potential mechanism identified to date is the synergism between estrogen and some tobacco compounds, and oncogene mutations, in inducing the expression of metabolic enzymes, leading to enhanced formation of reactive oxygen species and DNA adducts, and subsequent lung carcinogenesis. In this review, we present the literature available regarding sex differences in cancer rates, associations of male and female sex hormones with lung cancer, the influence of exogenous hormone therapy in women, and potential mechanisms mediated by male and female sex hormone receptors in lung carcinogenesis. The influence of biological sex on lung disease has recently been established, thus new research incorporating this variable will shed light on the mechanisms behind the observed disparities in lung cancer rates, and potentially lead to the development of new therapeutics to treat this devastating disease.     

Progestins and estrogens and Alzheimer's disease

Sex-specific incidence rates for Alzheimer's disease (AD) are higher in women than men. Many fundamental researches and some clinical investigations have reported therapeutic and preventive effects of estrogens on AD. But WHIMS [S.A. Shumaker, C. Legault, S.R. Rapp, L. Thal, R.B. Wallace, J.K. Ockene, S.L. Hendrix, B.N. Jones IIIrd, A.R. Assaf, R.D. Jackson, J.M. Kotchen, S. Wabertheil-Smoller, J. Wactawsk-Wende, WHIMS investigators, Estrogen plus progestin and the incidence of dementia and mild cognitive impairment in postmenopausal women. The women's health initiative memory study: a randomized controlled trial, JAMA 289 (2003) 2651–2662], which used daily continuous hormone replacement therapy (HRT), reported that the hazard ratio of the HRT for probable dementia was 2.05.

Effect of progestins, and continuous (not cyclically) HRT, even only with estrogen should be reconsidered.

In our clinical study, conjugated equine estrogen (CEE) alone showed good changes of psychiatric tests for AD on the 3rd week, but addition of medroxyprogesterone acetate (MPA) or norethindrone since 4th week suppressed these tests. Using human umbilical vein epithelial cell (HUVEC), levonorgestrel (LNG), norethindrone acetate (NETA), MPA increased intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion melocule-1 (VCAM-1) and E-secretin but dienogest (DNG) showed no effect. In vitro flow system, estradiol (E₂), suppressed adhesion of white cell, but LNG, NETA, MPA increased the adhesions. DNG showed less effect.

Non-feminizing estrogen J 861, which has Δ8,9 double bond and straight in its structure and has less effect on sexual organs. J 861 has shown ameliorative effects on central nervous system (CNS) (increasing of cholineacetyltransferase immunoreactive cells in substantia innominata (SI), etc.) like E₂.

More investigations about progestins and estrogens and AD should be done.