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.     

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.     

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.     

Androgens and the breast

There is increasing interest in the role of androgens in the treatment of women but little is known about their long-term safety. There are also very few studies on testosterone therapy and breast cancer risk. However, some observations support the concept that androgens may counteract the stimulatory effects of estrogen and progestogen in the mammary gland. Mammographic breast density and breast cell proliferation could be regarded as surrogate markers for the risk of breast cancer. Recently the addition of testosterone to a common estrogen/progestogen regimen was found to inhibit the stimulatory effects of hormones on breast cell proliferation. The effects of testosterone alone on the postmenopausal breast remain to be investigated.     

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.     

Controversies about HRT--lessons from monkey models

Lessons from monkey models contribute significantly to a better understanding of the controversies in reconciling the differences in postmenopausal hormone treatment outcomes between observational and randomized trial data. Monkey studies brought attention to premenopausal estrogen deficiency with resulting premature coronary artery atherosclerosis. Recently, those monkey studies were confirmed for premenopausal women in the NHLBI-sponsored Women's Ischemia Syndrome Evaluation (WISE) Study. Monkey studies have provided convincing evidence for the primary prevention of coronary artery atherosclerosis when estrogens are administered soon after the development of estrogen deficiency. Equally convincing are the data from monkey studies indicating the total loss of these estrogens beneficial effects if treatment is delayed for a period equal to six postmenopausal years for women. An attempt has been made using the monkey model to identify the hormone treatment regimen most effective in preventing the progression of coronary artery atherosclerosis. By a substantial margin, the most effective approach is that of using estrogen containing oral contraceptive during the perimenopausal transition, followed directly by hormone replacement therapy postmenopausally. Because of similarities between human and nonhuman breast, monkeys have had a major role in clarifying controversies surrounding the breast cancer risk of estrogen only versus estrogen plus progestin therapies. The results of monkey studies suggest little or no effects of estrogen only treatment; whereas, estrogen+progestin clearly increases breast cancer risk.     

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.     

Aromatase inhibitors in breast cancer

Estrogens play important roles in breast cancer development and progression. In postmenopausal women, traditional endocrine therapies such as tamoxifen have sought to inhibit estrogen action by targeting the estrogen receptor itself. However, newer treatments are evolving that target estrogen production in postmenopausal tissues through inhibition of the aromatase enzyme. Clinical data demonstrate that these aromatase inhibitors are superior to tamoxifen as adjuvant therapy for breast cancer and have now replaced tamoxifen as first line therapy in a number of treatment regimens for postmenopausal breast cancer patients.     

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.     

Postmenopausal hormone therapy and the risk of breast cancer: the view of an epidemiologist

OBJECTIVES: Postmenopausal hormone therapy (PMH) has been widely used by menopausal women living in western countries for the past several decades. Numerous studies have evaluated the relationship between PMH and breast cancer risk because steroid hormones have been implicated in breast cancer etiology. METHODS: A review of selected studies was performed to evaluate the history of investigations of the association between PMH and breast cancer, with a focus on studies evaluating different PMH regimens and different histologic types of breast cancer. RESULTS: Though studies conducted before the early 1990s suggest that both combined estrogen and progestin (E + P) PMH and unopposed estrogen (E) PMH are associated with an increased risk of breast cancer, more recent observational studies suggest that E + P, particularly current use for 5 years or longer, is more strongly associated with breast cancer risk than is unopposed E. Results from the Women's Health Initiative (WHI) randomized trials have confirmed these findings as they indicate that E + P is causally related to breast cancer (relative risk (RR) = 1.24; 95% confidence interval (CI): 1.01-1.54), while E alone is not (RR = 0.77; 95% CI: 0.59-1.01). CONCLUSIONS: There is clear and consistent evidence that use of E + P increases a woman's risk of breast cancer. Alternatively, current evidence suggests that use of unopposed E is not as strongly associated with breast cancer risk. Further studies are needed though to examine how different PMH regimens, doses, and methods of delivery are related to breast cancer risk, and how PMH impacts the risks of different types of breast cancer.     

Adverse endometrial effects during long cycle hormone replacement therapy

Objectives: treatment with unopposed estrogen is known to increase the risk of endometrial hyperplasia, atypia, and carcinoma, and therefore the administration of a progestin during hormone replacement therapy (HRT) is recommended. The addition of a progestestin may cause unwanted side effects. Progestin administration of various durations are therefore used in HRT. Study design: data were obtained about endometrial histopathology, bleeding interval and compliance in 240 early postmenopausal women receiving HRT with a progestin administered for 10 days during 12 week or 4 week cycles of estrogen administration. These regimens were studied for as long as 4 years. The daily estrogen given was 17β-estradiol 2 mg per day which was reduced to 1 mg day during the last 6 days of each cycle. The progestin used was norethindrone acetate, given at a dose of 1 mg per day. Results: the incidence of endometrial hyperplastic changes, i.e. simple or complex hyperplasia, atypia or cancer, was significantly higher in the 12 weeks cycle than in the monthly cycle group (P=0.003), with an overall annual incidence of 5.6% in the 12 weeks cycle group and 1% in the monthly cycle group. One case of atypical hyperplasia and one case of endometrial adenocarcinoma was observed in the long cycle group. Long cycle treatment produced more irregular bleeding pattern. Accordingly, the rate of drop-out due to bleeding was significantly higher in the long cycle group (P<0.01). Conclusion: we conclude that the long cycle HRT modality investigated did not improve compliance and may increase the risk of endometrial hyperplasia and eventually cancer compared to conventional HRT with a monthly cycle. Caution using long cycle HRT regimens is advisable, and careful monitoring of the endometrium during treatment is recommended.     

Transdermal estrogen replacement therapy and plasma lipids in 693 French women

Objectives: The cardiovascular effects of transdermal estrogen are not so well established than those induced by oral estrogen. In a representative sample of French postmenopausal women, we assessed plasma lipid changes induced by transdermal 17β-estradiol. Methods: This cross-sectional study was carried out among the population sample of the third MONICA survey on cardiovascular risk factors. We selected 693 postmenopausal women according to the followed criteria; women with intact uterus and no menstruation for more than 12 months, women with bilateral oophorectomy, hysterectomized women older than 55 years and hysterectomized women who had followed hormone replacement therapy. We used multivariate linear regression models, taking into account confounding variables, to assess lipid changes induced by estrogen. Results: We compared 192 women currently taking transdermal 17β-estradiol (27 unopposed estrogen and 165 estrogen plus progestin) with 501 women without any hormonal treatment. After adjustment for living area, education level, income tax, smoking, alcohol consumption, physical activity, age and body mass index, transdermal estrogen replacement therapy (ERT) was significantly associated with lower levels of serum total cholesterol [6.10 (S.E., 0.11) vs 6.35 (0.09) mmol/l, P<0.01], triglycerides [1.06 (0.06) vs 1.23 (0.05) mmol/l, P<0.001], LDL-cholesterol [3.93 (0.11) vs 4.13 (0.09) mmol/l, P<0.05], VLDL-cholesterol [0.48 (0.03) vs 0.56 (0.02) mmol/l, P<0.001] and apolipoprotein B [1.20 (0.03) vs 1.26 (0.02) g/l, P<0.01]. Levels did not differ significantly for HDL-cholesterol [1.68 (0.05) vs 1.66 (0.04) mmol/l] and apolipoprotein A1 [1.79 (0.03) vs 1.81 (0.02) g/l]. Conclusion: Transdermal ERT may confer a cardiovascular protection by lowering atherogenic lipoproteins.     

The role of testosterone in the management of hypoactive sexual desire disorder in postmenopausal women

At least 16 million women over the age of 50 currently experience low sexual desire, with approximately 4 million women exhibiting hypoactive sexual desire disorder (HSDD). Although early research established that testosterone therapy improves sexual desire in postmenopausal women, safer and more efficacious administration routes were explored. Large randomized, double-blinded placebo-controlled studies demonstrate that transdermal testosterone improves sexual function and activity in postmenopausal women with HSDD. Large multi-center Phase III trials further confirm the positive effects of the testosterone patch in the treatment of HSDD. More recent studies are exploring the utility of testosterone gels. Based upon data from two recent clinical relevance studies, physicians can be reassured that postmenopausal women with HSDD report a meaningful benefit with testosterone therapy, and further, women will only continue therapy if they experience a meaningful benefit. Although most trials combined testosterone with estrogen/progesterone therapy, the recent APHRODITE trial examined testosterone alone, showing increased sexual desire with mild adverse events. Concerns regarding the long-term safety profile of transdermal testosterone must be addressed before the FDA will approve a testosterone product for women. Although some fear an increased risk of breast cancer with exogenous testosterone administration, recent studies support the idea that androgens can play a role in suppressing the proliferative effects of estrogen and progesterone. Long-term safety data is now being collected and analyzed and Phase III trials focusing on long-term risks are underway. In the meantime, transdermal testosterone appears to be a safe and effective therapy for postmenopausal women with HSDD [Swanson S, DeRogatis L, Snabes M, Simes S, Zborowski J. Treatment of HSDD in surgically menopausal women: a newly initiated Phase III, randomized, double-blind, placebo-controlled, multi-center study of the safety and efficacy of LibiGel. Presented at the Annual Meeting of the International Society for the Study of Women's Sexual Health, February 22–25, Orlando, FL; 2007].     

A simple method for determining the optimal dosage of progestin in postmenopausal women receiving estrogens

Progestin is often added to regimens of estrogen therapy in postmenopausal women to reduce the risk of endometrial hyperstimulation, but it may cause undesirable metabolic effects. Therefore, a low dosage is recommended. At present, the only way to determine whether the dosage of progestin is causing the desired secretory transformation of the endometrium is by endometrial sampling, which is invasive. We studied 102 postmenopausal women undergoing estrogen therapy who also took a progestin for 12 days each month, and we correlated the day of onset of bleeding with the endometrial histology over a three-month period. A bleeding pattern suitable for interpretation was observed in 96 women. Regardless of the preparation and dosage of the estrogen and progestin used, wholly or predominantly proliferative endometrium was always associated with bleeding on or before day 10 after the addition of progestin; wholly or predominantly secretory endometrium, or a lack of endometrial tissue, was associated with bleeding on day 11 or later. We conclude that the bleeding pattern reflected the histologic condition of the endometrium and that adjustment of the dosage of progestin so that regular bleeding is induced on or after day 11 may obviate the need for endometrial biopsy.     

Hormone replacement therapy improves arterial stiffness in normotensive postmenopausal women

Objectives: Aortic stiffness, determined by the pulse wave velocity (PWV), is an independent marker of cardiovascular risk. PWV is mainly influenced by age-associated alterations of arterial wall structure and blood pressure (BP). To determine the impact of hormone replacement therapy (HRT) on arterial compliance in normotensive, postmenopausal women, we examined the effects of HRT on PWV. Methods: Fifty-six postmenopausal women aged 50–70 years were recruited into the present retrospective study from the patients visiting our menopause clinic. Twenty-seven women who were prescribed HRT (14 on estrogen alone and 13 on estrogen plus progestogen) for several months to 6 years and an age-matched group of 29 women not on HRT were studied (Study 1). Nine postmenopausal women were also studied before and at 4 weeks of the treatment of estrogen replacement therapy (ERT) (Study 2). Brachial to ankle PWV (baPWV), which is correlated with aortic PWV, was determined using an automatic device, BP-203PRE. Results: In Study 1, PWV was significantly correlated with age in both groups (controls: r=0.392, P=0.035; HRT group: r=0.471, P=0.013), and HRT significantly lowered the PWV value at all ages examined (Mean±S.D. of baPWV in controls: 1382.2±114.1; HRT: 1245.3±124.8, P=0.0001). In Study 2, baPWV decreased significantly after ERT (P<0.05), without a significant change in systolic BP (P=0.851). Conclusions: Estrogen appears to improve arterial compliance independently of BP within 4 weeks.     

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.     

Curcumin inhibits MPA-induced secretion of VEGF from T47-D human breast cancer cells

OBJECTIVE: Recent clinical trials show that women who receive combined estrogen and progestin hormone therapy (HT) have a higher risk of breast cancer than women who receive estrogen alone or placebo. We have shown that progestins stimulate expression of vascular endothelial growth factor (VEGF), a potent angiogenic factor, in human breast cancer cells that express the progesterone receptors and mutant p53 protein. Because increased levels of VEGF promote tumor progression, compounds that prevent progestin-induced expression of VEGF could be clinically useful. The objective of this study was to examine whether the polyphenol compound curcumin has the capacity to block progestin-induced secretion of VEGF from T47-D human breast cancer cells. DESIGN: The estrogen and progesterone receptor containing T47-D human breast cancer cells was exposed to 10 nM progesterone or synthetic progestins and varying concentrations of curcumin to determine whether curcumin blocks progestin-dependent production of VEGF from tumor cells. RESULTS: Curcumin (0.001-10 microM for 18 h) reduced medroxyprogesterone acetate (MPA)-induced secretion of VEGF from T47-D cells in a dose-dependent manner. Secretion of VEGF from cells treated with progesterone or progestins other than MPA was unaffected by curcumin. CONCLUSIONS: MPA is the most widely used progestin in HT. Curcumin may therefore provide a clinically useful tool for the suppression of MPA-induced elaboration of VEGF by tumor cells. We propose therefore that clinical trials to assess the beneficial effects of curcumin in postmenopausal women are warranted.     

Post-menopausal women and osteoporosis: available choices for maintenance of skeletal health

Objective: To briefly summarize the therapeutic choices for osteoporosis prevention which are currently available to post-menopausal women. Methods: Results of randomized clinical trials and epidemiological studies in post-menopausal women, and pre-clinical studies in ovariectomized rats were summarized. Results: Estrogen combined with progestogen in hormone replacement therapy (HRT) is effective in relieving perimenopausal symptoms and maintaining bone mineral density. However, the increased breast cancer risk associated with long-term HRT use makes it a less desirable option for many women. Selective estrogen receptor modulators (SERMs), such as raloxifene, are also effective in maintaining bone density, without stimulating the breast or uterus. However, SERMs do not relieve perimenopausal hot flashes. Conclusion: HRT is effective for acute relief of perimenopausal symptoms, but for women who are unwilling or unable to take HRT long-term, SERMs such as raloxifene are a useful therapy for the prevention of osteoporosis.     

Testosterone inhibits estrogen/progestogen-induced breast cell proliferation in postmenopausal women

OBJECTIVE: During the past few years serious concern has been raised about the safety of combined estrogen/progestogen hormone therapy, in particular about its effects on the breast. Several observations suggest that androgens may counteract the proliferative effects of estrogen and progestogen in the mammary gland. Thus, we aimed to study the effects of testosterone addition on breast cell proliferation during postmenopausal estrogen/progestogen therapy. DESIGN: We conducted a 6-month prospective, randomized, double-blind, placebo-controlled study. A total of 99 postmenopausal women were given continuous combined estradiol 2 mg/norethisterone acetate 1 mg and were equally randomly assigned to receive additional treatment with either a testosterone patch releasing 300 microg/24 hours or a placebo patch. Breast cells were collected by fine needle aspiration biopsy at baseline and after 6 months, and the main outcome measure was the percentage of proliferating breast cells positively stained by the Ki-67/MIB-1 antibody. RESULTS: A total of 88 women, 47 receiving active treatment and 41 in the placebo group, completed the study. In the placebo group there was a more than fivefold increase (P<0.001) in total breast cell proliferation from baseline (median 1.1%) to 6 months (median 6.2%). During testosterone addition, no significant increase was recorded (1.6% vs 2.0%). The different effects of the two treatments were apparent in both epithelial and stromal cells. CONCLUSIONS: Addition of testosterone may counteract breast cell proliferation as induced by estrogen/progestogen therapy in postmenopausal women.     

Prevention of postmenopausal bone loss with long-cycle hormone replacement therapy

OBJECTIVE: Postmenopausal bone loss and osteoporotic fractures can be prevented by hormone replacement therapy (HRT). However, opposed HRT may increase the risk of breast cancer above that associated with estrogen alone and in non-hysterectomized women estrogen substitution alone increases the risk of uterine cancer, which triggered renewed interest in long-cycle HRT regimens (estrogen replacement therapy with progesterone-free intervals up to 6 months). The effects on bone of such long-cycle HRT regimens are unknown. The objective of the present study was to compare the effects on bone and the endometrium of long-cycle HRT and conventional HRT. METHODS: Seventy-three healthy non-hysterectomized postmenopausal women were randomized to either conventional HRT (estradiol (E2) 2 mg/d during 12 days, E2 2 mg/d plus 1 mg/d of norethisterone acetate (NETA) during 10 days, E2 1 mg/d for 6 days) or long-cycle HRT treatment (two cycles with E2 2 mg/d during 28 days, followed by one cycle of conventional HRT and repeated every 3 months). Primary endpoint was the change in bone mineral density (BMD) at the lumbar spine (LS) over 24 months. RESULTS: BMD at LS increased significantly versus baseline in both treatment groups (conventional HRT +3.8 +/- 0.6%, long-cycle HRT +3.3 +/- 0.5%, p < 0.0001 for both) with no significant difference between treatment groups over 24 months. Similar significant BMD increases versus baseline were observed at the femoral neck, while biochemical markers of bone turnover (osteocalcin and deoxypyridinoline) were significantly decreased over 24 months. There were no endometrial or breast related adverse events reported. CONCLUSION: Long-cycle HRT may be a valid alternative to conventional HRT with regard to protection against postmenopausal bone loss.