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.     

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.     

Testosterone aromatization and cognition in women: a randomized, placebo-controlled trial

OBJECTIVE: To explore whether inhibition of the conversion of testosterone to estradiol modifies the effects of testosterone on cognition in 61 healthy, estrogen-treated postmenopausal women. DESIGN: Seventy-six postmenopausal women using transdermal estrogen for at least 8 weeks, with a serum total testosterone less than 1.2 nmol/L participated in a single-center, double-blind, randomized, placebo-controlled study. All participants received transdermal testosterone, 400 muL of a 0.5% testosterone gel, daily and were randomized to receive either letrozole 2.5 mg/day or an identical placebo tablet. The main outcome measure was cognition, evaluated using a comprehensive battery of standardized neuropsychological tests, at baseline and week 16. RESULTS: Thirty women in each group completed the study. Free testosterone increased from baseline in both groups, with no difference between groups. Free testosterone levels achieved were below the 90th centile for young women in 80% of the participants at week 16. Serum estradiol and sex hormone-binding globulin levels did not differ from baseline or between groups during the study. No clinically significant effects of testosterone treatment were seen for attention and working memory, psychomotor speed, or executive function. Significant improvements were seen for immediate and delayed visual and verbal memory and for simple concentration with testosterone therapy, all of which were unaffected by the aromatase inhibitor. CONCLUSIONS: We did not observe any effects of aromatase inhibition on cognition in healthy, estrogen-treated postmenopausal women treated with testosterone. This may be due to insufficient study power or a true lack of effect. However, our findings highlight that the detection of subtle changes in cognition in well women require the development of sensitive instruments and large randomized, controlled trials.     

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.     

Efficacy and safety of a testosterone patch for the treatment of hypoactive sexual desire disorder in surgically menopausal women: a randomized, placebo-controlled trial

OBJECTIVE: Evaluation of the use of testosterone therapy for hypoactive sexual desire disorder (HSDD) after oophorectomy has mostly involved women treated with oral estrogen preparations. We investigated the efficacy and safety of a testosterone patch in surgically menopausal women receiving concurrent transdermal estrogen. DESIGN: Women with HSDD after oophorectomy, for whom this was a concern, who were using transdermal estrogen, were recruited to a 24-week, randomized, double-blind, placebo-controlled trial in Europe and Australia. Patients were randomly allocated to placebo (n = 40) or testosterone 300 microg/day (n = 37) treatment. Primary endpoints were changes in sexual desire measured by the sexual desire domain of the Profile of Female Sexual Function and the frequency of satisfying sexual activity at 24 weeks. RESULTS: Sixty-one women (79%) completed the trial. All subjects who received at least one application of study medication were included in analysis. The testosterone-treated group experienced a significantly greater change from baseline in the domain sexual desire score compared with placebo (change from baseline, 16.43 versus 5.98; P = 0.02). The domain scores for arousal, orgasm, decreased sexual concerns, responsiveness, and self-image as well as decreased distress were also significantly greater with testosterone therapy than placebo. The frequency of satisfactory sexual events increased but was not statistically different between treatment groups (P = 0.06) Adverse events occurred with similar frequency in both groups, and no serious risks of therapy were observed CONCLUSIONS: In this study, transdermal testosterone therapy via a skin patch improved sexual desire and other sexual function domains. It was well tolerated in these oophorectomized women with HSDD receiving concomitant transdermal estrogen.     

Efficacy and tolerability of a new estradiol delivering matrix patch (Estraderm MX) in postmenopausal women

OBJECTIVE: To examine the efficacy and tolerability of a new matrix patch delivering estradiol (E2 Matrix) at doses of 0.05 and 0.10 mg per day (Estraderm MX 50, 100) in the treatment of moderate to severe postmenopausal symptoms. METHODS: A total of 254 postmenopausal women were randomized to receive treatment with E2 Matrix 0.10 mg (N = 86), E2 Matrix 0.05 mg (N = 82), or placebo (N = 86) in a double-blind, double-dummy fashion for a period of 12 weeks continuously. Patches were applied twice weekly to the buttocks with each patient wearing two patches at all times. The primary efficacy criterion was the difference from baseline of the mean number of moderate to severe hot flushes per 24 h during the last 2 weeks of treatment. Other efficacy variables included reduction in hot flushes at 4 and 8 weeks, reduction in daytime flushing and night sweats, and Kupperman Index at 4, 8, and 12 weeks. RESULTS: E2 Matrix 0.10 and 0.05 mg were both significantly superior to placebo in reducing hot flushes per 24 h after 4, 8, and 12 weeks of treatment (P < 0.001). Also, for all other efficacy parameters studied, both dosage strengths of E2 Matrix were statistically significantly superior to placebo at all time points (P < 0.001). Local tolerability was good in both groups. A slight increase in estrogen related adverse effects (breast tenderness, leukorrhoea) was seen with the 0.10 mg patch. Adhesion of patches and compliance were good. Overall systemic tolerability was good in both treated groups. However, a 4.8% overall incidence of endometrial hyperplasia was observed in patients with an intact uterus. CONCLUSIONS: This new matrix patch offers an effective and well tolerated dosage form for delivery of 0.05 and 0.1 mg estradiol per day. It may be particularly suitable for those women who experience local sensitivity to alcohol-containing systems. In light of the observed hyperplasia after treatment in five patients, estrogen therapy should as yet be supplemented monthly with a progestogen in women with an intact uterus.     

An isopropanolic extract of black cohosh does not increase mammographic breast density or breast cell proliferation in postmenopausal women

OBJECTIVE: The aim of this study was to determine the effects of the isopropanolic extract of black cohosh (Remifemin) on mammographic breast density and breast epithelial proliferation in healthy, naturally postmenopausal women with climacteric symptoms. DESIGN: This was a prospective, open, uncontrolled drug safety study in which baseline status was compared with status after 6 months of treatment by blinded observers. A total of 74 women were treated with 40 mg black cohosh daily, and 65 women completed the study. Mammograms were performed, and breast cells were collected by percutaneous fine needle aspiration biopsies at baseline and after 6 months. Mammographic density was quantified according to the Wolfe classification or a percentage scale. Breast cell proliferation was assessed using the Ki-67/MIB-1 monoclonal antibody. Safety was monitored by adverse event reporting, laboratory assessments, and measurement of the endometrium by vaginal ultrasound. RESULTS: None of the women showed any increase in mammographic breast density. Furthermore, there was no increase in breast cell proliferation. The mean change +/- SD in proportion of Ki-67-positive cells was -0.5% +/- 2.4% (median, 0.0; 95% CI = -1.32 to 0.34) for paired samples. The mean change in endometrial thickness +/- SD was 0.0 +/- 0.9 mm (median, 0.0). A modest number of adverse events were possibly related to treatment, but none of these were serious. Laboratory findings and vital signs were normal. CONCLUSIONS: The findings suggest that the isopropanolic extract of black cohosh does not cause adverse effects on breast tissue. Furthermore, our data do not indicate to any endometrial or general safety concerns during 6 months of treatment.     

Testosterone patch for the treatment of hypoactive sexual desire disorder in naturally menopausal women: results from the INTIMATE NM1 Study

OBJECTIVE: To evaluate the efficacy and safety of a testosterone patch for the treatment of women with hypoactive sexual desire disorder after natural menopause. DESIGN: A multicenter, randomized, double-blind, placebo-controlled, parallel-group trial was conducted in naturally menopausal women with hypoactive sexual desire disorder receiving a stable dose of oral estrogen with or without progestin (N = 549). Women were randomized to receive testosterone 300 microg/day or placebo patches twice weekly for 24 weeks. The primary efficacy measure was change from baseline in frequency of total satisfying sexual activity over a 4-week period (weeks 21-24). RESULTS: A total of 483 women (88%) were included in the primary analysis population (those with baseline sex hormone binding globulin levels < or = 160 nmol/L). The change from baseline in number of total satisfying sexual episodes was significantly greater for testosterone compared with placebo (participants with baseline sex hormone binding globulin levels < or = 160 nmol/L, mean change of 2.1 +/- 0.28 versus 0.5 +/- 0.23 episodes/4 weeks; P < 0.0001; intent-to-treat population, mean change from baseline of 1.9 +/- 0.26 versus 0.5 +/- 0.21 episodes/4 weeks, P < 0.0001). Testosterone also produced statistically significant improvements compared with placebo in all secondary efficacy measures, including sexual desire and personal distress. The testosterone patch was well tolerated. CONCLUSIONS: Testosterone patch treatment increased the frequency of satisfying sexual activity and sexual desire, decreased personal distress, and was well tolerated in naturally menopausal women with hypoactive sexual desire disorder.     

Comparison of physical and emotional side effects of progesterone or medroxyprogesterone in early postmenopausal women

OBJECTIVE: To compare the mood and somatic effects during the initial 2 months of medroxyprogesterone acetate (MPA) or progesterone combined with conjugated equine estrogen (CEE) in early postmenopausal women. DESIGN: Twenty-three nondepressed, early postmenopausal women (average age, 52.5 years) completed a 91-day, single-blind pilot study with the following sequence of treatments: 1 week of no substance; 2 weeks of placebo; 2 weeks of progestogen only; 1 week of placebo; and 2 months of "standard hormone replacement therapy cycles," which consisted of (in order) 2 weeks of 0.625 mg CEE, 2 weeks of CEE plus progestogen, 2 weeks of CEE, and 2 weeks of CEE plus progestogen. Ten women who completed the study received MPA (5 mg/day) as their progestogen, and 13 who completed the study received micronized, oil-suspended progesterone (200 mg/day) as their progestogen. All participants made daily assessments of mood using the Profile of Mood States and daily recordings of somatic symptoms. All subjects had plasma follicle-stimulating hormone of greater than 35 IU/L and had not had spontaneous vaginal bleeding for more than 1 year. RESULTS: None of the hormone treatments had a detectable effect on mood. MPA users reported more vaginal bleeding and breast tenderness than progesterone users. CONCLUSIONS: In contrast with the widely held belief among psychiatrists that progesterone depresses mood, neither of the progestogens we used in normal, nondepressed and nonanxious women showed this effect. Absence of an effect on mood was also found when the results of the two progestogens were combined. The lesser side effects of the micronized progesterone-containing regimen suggest that some women may prefer it to an MPA-containing regimen.     

Effects of ultralow-dose transdermal estradiol on postmenopausal symptoms in women aged 60 to 80 years

OBJECTIVE: To investigate the effect of ultralow-dose transdermal estradiol on postmenopausal symptoms and side effects in a cohort of largely asymptomatic postmenopausal women aged 60 to 80 years. DESIGN: This secondary analysis used data from the UltraLow-dose Transdermal estRogen Assessment trial, a randomized, placebo-controlled, double-blind trial in postmenopausal women to determine the skeletal effects and safety of ultralow-dose transdermal estradiol. Four hundred seventeen postmenopausal women, aged 60 to 80 years, were randomly assigned to receive either unopposed transdermal estradiol at 0.014 mg/d (n = 208) or placebo (n = 209). Participants were queried at each clinic visit about postmenopausal symptoms and side effects purported to be associated with estrogen therapy using a standardized questionnaire. RESULTS: At baseline, 16% of women reported hot flashes, 32% reported vaginal dryness, and 35% reported trouble sleeping. Women who received ultralow-dose estradiol were no more likely to report improvement of hot flashes, vaginal dryness, or sleep difficulties than those who received placebo. Treatment with ultralow-dose estradiol did not cause breast tenderness, uterine bleeding, or other symptoms often attributed to estrogen, but vaginal discharge was more common in women who received estradiol compared with those who received placebo. CONCLUSION: In this population of older, largely asymptomatic women, ultralow-dose transdermal estradiol did not improve postmenopausal symptoms and did not cause side effects other than vaginal discharge. Further study is needed to determine whether this dose of transdermal estradiol is effective in treating symptoms of postmenopause in younger, more symptomatic women.     

Continuous versus cyclical transdermal estrogen replacement therapy in postmenopausal women: influence on climacteric symptoms,body weight and bleeding pattern

Objectives: To compare continuous and cyclical transdermal estrogen replacement therapy (ERT) with or without an oral progestogen regarding climacteric symptoms, body weight and bleeding pattern. Methods: A total of 2459 postmenopausal women were treated for three cycles of 28 days in an open, randomized, parallel group multicenter study. Patients received an estrogen matrix patch (50 μg 17/β-estradiol/day) twice weekly, either continuously (eight patches/cycle) or cyclically (six patches/cycle, i.e. 3 weeks on, 1 week off). A total of 1232 patients were treated continuously and 1227 cyclically. In the study group 1150 patients had an intact uterus (543 in the continuous and 607 in the cyclical treatment arm) and received, in addition to the estrogen patch, an oral progestogen in a transformation dose for 12 days of each cycle. Hysterectomized patients totaling 1309 (689 in the continuous versus 620 in the cyclical group) did not receive progestogen. Of the 2459 patients, 771 (31.4%) participated in a follow-up study with two further treatment cycles, which was offered to the patients at the end of the main study. The main outcome measures were climacteric symptoms, measured at the end of cycles 1–3 by a Visual Analogue Scale at baseline, and body weight measured at baseline at the end of cycles 3 and 5. In addition, the bleeding time per cycle (days) was evaluated in all patients with an intact uterus. Results: Continuous and cyclical transdermal ERT reduced, over three treatment cycles, the average climacteric symptom score by 1.77 and 1.70, respectively. The percentage remission and improvement rates for the ten climacteric symptoms ranged between 69.3 and 88.0% and did not differ between the two groups. In patients with a higher symptom score at baseline, the continuous treatment was slightly more effective. However, this effect was statistically not significant. After three treatment cycles body weight increased in both treatment groups by between 500 and 700 g. Further treatment during the follow-up study induced an additional average weight gain of 200–400 g. These results were not influenced by the addition of an oral progestogen. In patients with an intact uterus, the average bleeding time at the end of the first cycle (5.4 days in the continuous versus 5.3 days in the cyclical group) increased slightly during cycle 2 and returned to baseline values at the end of cycle 3. Conclusions: Continuous and cyclical transdermal ERT were equally effective in reducing climacteric symptoms. The short term use of five cycles transdermal ERT induced a slight increase in body weight which was independent of the treatment regimen. These results were not influenced by the type and mode of administration of a progestogen. Both ERT regimens were very well tolerated and are suitable alternatives for estrogen replacement therapy of postmenopausal women.     

Tibolone: clinical recommendations and practical guidelines. A report of the International Tibolone Consensus Group

An international multidisciplinary panel of experts in the management of the menopause met at the 4th Amsterdam Menopause Symposium in October 2004 to determine the specific place of tibolone, a synthetic steroid with a unique clinical profile, within the wide range of currently available postmenopausal therapy options. The consensus was that tibolone is a valuable treatment option for women with climacteric complaints. As well as relieving vasomotor symptoms, tibolone has positive effects on sexual well-being and mood, and improves vaginal atrophy and urogenital symptoms. Prevention of bone loss with tibolone is comparable to that seen with estrogen therapy (ET) and estrogen/progestogen therapy (EPT). As tibolone rarely causes endometrial proliferation, no additional progestogen is required. It also has good tolerability, being associated with a low incidence of vaginal bleeding and of breast pain. Tibolone does not increase mammographic density. Absolute numbers of women at increased risk for breast cancer are estimated to be low or absent with both tibolone and ET, and the risk with tibolone should be significantly lower than that with EPT. Tibolone might therefore be preferable to EPT in certain women who have not been hysterectomised. Based on the evidence available, the panel proposed a number of subgroups of postmenopausal women with vasomotor symptoms in whom tibolone might have added value; these included women with sexual dysfunction, mood disorders, fibroids and urogenital complaints, as well as those with breast tenderness or high mammographic breast density with EPT use.     

Esterified estrogen therapy in postmenopausal women. Relationships of bone marker changes and plasma estradiol to BMD changes: a two-year study

OBJECTIVE: To determine the relationships among bone mineral density changes, bone marker changes, and plasma estrogens in postmenopausal women receiving estrogen replacement therapy. DESIGN: A total of 406 postmenopausal women received 1,000 mg calcium and continuous esterified estrogens (0.3 mg, 0.625 mg, or 1.25 mg) or placebo daily for up to 24 months. Bone mineral density and bone marker measurements were determined at 6-month intervals; plasma estrogens were measured in a subset after 12, 18, and 24 months. RESULTS: Esterified estrogens produced significant increases in bone mineral density (lumbar spine, hip) compared with baseline and placebo at 6, 12, 18, and 24 months. Bone markers decreased from baseline with all esterified estrogen doses relative to placebo. Bone marker changes at 6 months correlated negatively with bone mineral density changes at 24 months (correlation coefficient range = -0.122 to -0.439). The strongest correlation was noted for spine bone mineral density changes and serum osteocalcin. Mean plasma estrogen levels increased with esterified estrogen dose, and bone mineral density changes correlated positively with plasma estrogen levels. Positive bone mineral density changes were noted in treatment groups with plasma estradiol levels at and above 25 pg/mL. CONCLUSIONS: Esterified estrogens, at doses from 0.3 mg to 1.25 mg/day, unopposed by progestin, increase bone mineral density of the spine and hip in postmenopausal women. These bone mineral density changes correlated significantly with bone marker changes at 6 months and with plasma estrogens at 12, 18, or 24 months. Data variability minimizes the predictive value of the bone marker changes in monitoring individual therapy.     

Trimegestone in a low-dose, continuous-combined hormone therapy regimen prevents bone loss in osteopenic postmenopausal women

OBJECTIVE: To determine the efficacy of estrogen + progestogen therapy with 1 mg 17beta-estradiol and 0.125 mg trimegestone in the prevention of postmenopausal osteoporosis. DESIGN: For this study, 360 healthy, postmenopausal women with osteopenia [lumbar spine bone mineral density (BMD) between -1.0 and -2.5 SD of the premenopausal mean value] were enrolled in a 2-year prospective, randomized study, and 70% completed. Treatments were 1 mg 17beta-estradiol + 0.125 mg trimegestone (n = 179) or placebo (n = 181), given as daily oral therapy. All received a daily supplement of 500 mg calcium and 400 IU vitamin D. BMD measurements at the lumbar spine, total hip, and femoral neck as well as blood and urinary biochemical markers of bone turnover (serum osteocalcin), serum bone-specific alkaline phosphatase, serum CrossLaps, and urinary CrossLaps took place regularly. RESULTS: BMD increases relative to placebo were 6.3%, 3.9%, and 3.8% at the lumbar spine, total hip, and femoral neck, respectively (all P < 0.001). The biochemical markers of bone turnover were suppressed accordingly. Serum CrossLaps and urinary CrossLaps decreased rapidly, by 52% and 54%, respectively, whereas serum osteocalcin and serum bone-specific alkaline phosphatase revealed a more retarded decrease of 40% and 33%, respectively. Of the women receiving hormone therapy, 75% had amenorrhea from the first cycle, and 5% withdrew prematurely due to metrorrhagia or mastalgia. CONCLUSION: This new estrogen + progestogen therapy is efficient in increasing BMD in an osteopenic postmenopausal population. Furthermore, it is well tolerated, with few adverse events and an early bleeding control, which is likely to improve compliance to the treatment over the long term.     

Characterization of hot flashes reported by healthy postmenopausal women receiving raloxifene or placebo during osteoporosis prevention trials

OBJECTIVE: Raloxifene, a selective estrogen receptor modulator, is estrogen-like in the skeleton and cardiovascular system and antiestrogenic in reproductive tissues. In contrast to estrogens, raloxifene is not indicated for the treatment of hot flashes. This study was designed to examine the characteristics of hot flashes among healthy postmenopausal women participating in osteoporosis prevention trials who were receiving raloxifene or placebo. METHODS: Adverse event data from three randomized, double-blind trials (N = 876) comparing raloxifene 60 mg/day with placebo for 30 months were integrated and analyzed. Two of the three trials (one European, two North American) were identically designed and were open to healthy postmenopausal women ages 45 through 60 without regard to prior hysterectomy. The third trial was multinational, was open to women ages 40 through 60, and all enrollees had prior hysterectomy at baseline. Women were questioned in general terms about the occurrence of adverse events at 3-6-month intervals. Treatment-emergent adverse events pertaining to hot flashes were included in the current study. RESULTS: At baseline, 12% of women randomly assigned to placebo and 13% assigned to raloxifene reported prevalent hot flashes. After 30 months, the cumulative incidence of hot flashes was 21% for placebo and 28% for raloxifene (P = 0.022), with the difference in incidence rate confined to the first 6 months of therapy. There was no difference between placebo and raloxifene in reported maximum severity of or early discontinuations as a result of hot flashes (< or = 3% per group for both outcomes). Among women whose hot flashes had stopped completely during the 30-month study period, the median total duration of the event prior to becoming symptom-free was 246 days for placebo and 205 days for raloxifene. Among all women reporting a hot flash, the extrapolated total duration of hot flashes was the same for women treated with either raloxifene or placebo. No subgroup-by-therapy interactions were detected. Multivariable regression analysis revealed several factors that were independently weakly predictive of hot flashes. CONCLUSIONS: Raloxifene slightly affects the incidence but not the natural history of hot flashes in healthy postmenopausal women seeking prevention therapy.     

Cytokine changes in postmenopausal women treated with estrogens: a placebo-controlled study

PROBLEM: Hormone replacement therapy (HRT) is being increasingly used in postmenopausal women. Sex steroids are known to affect the immune system in several ways, although this is mainly based on clinical observations and experimental studies. METHOD OF STUDY: We studied the in vivo effects of transdermal estrogens (50 microg 17 beta-Estradiol/24 hr) on cytokine production in postmenopausal women. A total of 17 women were randomized to either placebo (n = 7) or active estrogen therapy (n = 10) for 14 weeks, with addition of oral medoxyprogesterone acetate 10 mg daily during the last 2 weeks in both groups. Secretion of the cytokines IFN-gamma, IL-4, IL-10 and IL-6 in blood mononuclear cells was determined, spontaneously and after stimulation with common vaccination antigens and mitogen, using the cell ELISA technique. RESULTS: IL-6 production after stimulation with purified protein derivate (PPD) decreased in the estrogen treated group (P < 0.01). Mitogen-induced IL-6 production was reduced in the estrogen treated group in contrast to an increase in the placebo group, leading to a significant difference (P < 0.01) between the groups after 12 weeks of treatment. This difference was eliminated after an addition of progestagens for 2 weeks. No significant changes were noted for IFN-gamma, IL-4 or IL-10 in relation to estrogen or placebo treatment. CONCLUSIONS: In the present controlled study, the main in vivo effect of estrogens was a decrease in IL-6 production, indicating a possible beneficial effect of estrogen therapy.     

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.     

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.     

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].     

Endometrial response to raloxifene compared with placebo, cyclical hormone replacement therapy, and unopposed estrogen in postmenopausal women.

OBJECTIVE: To determine the endometrial effects of raloxifene 60 mg/day in postmenopausal women as assessed by vaginal bleeding and endometrial thickness. DESIGN: Data from 1157 postmenopausal women were analyzed from a database consisting of four independent, double-blind, randomized, placebo-controlled trials (range = 6-30 months duration), a 24-month open-label randomized, cyclical hormone replacement therapy (HRT)-controlled trial, and a 6-month double-blind, randomized, unopposed estrogen-controlled trial. Vaginal bleeding rate was derived from self-reported adverse events collected at least every 6 months. Endometrial thickness was measured by ultrasonography at regular intervals. RESULTS: Raloxifene 60 mg/day was not significantly different from placebo with regard to the incidence of vaginal bleeding, the baseline-to-endpoint change in endometrial thickness, or the proportion of women experiencing an increase in endometrial thickness above baseline after either 12 or 24 months of therapy. Unexpected bleeding was reported significantly more frequently in the unopposed estrogen groups compared with the raloxifene group (raloxifene 60 mg/day, 0% versus estrogen, 50%; p = 0.002). A significantly greater baseline-to-endpoint increase in endometrial thickness was observed in both the HRT and estrogen groups compared with their respective raloxifene comparison group (raloxifene 60 mg/day, 0.01 +/- 2.0 mm versus HRT, 1.8 +/- 3.2; p < 0.001; raloxifene 60 mg/day, 1.1 +/- 1.7 mm versus estrogen, 7.8 +/- 3.8; p < 0.001). No cases of endometrial hyperplasia or cancer were diagnosed in the placebo or raloxifene 60 mg/day groups. Endometrial hyperplasia was diagnosed in one case in the HRT group and in two cases in the estrogen group. CONCLUSION: Raloxifene 60 mg/day for up to 30 months is not associated with vaginal bleeding or increased endometrial thickness in postmenopausal women.