DHEA replacement for postmenopausal women: placebo or panacea?

In adults, dehydroepiandrosterone (DHEA) is the most abundant steroid found in serum and its levels fall with age. It can be converted into androgens and estrogens by peripheral tissues. Thus it may be considered to be a pro-hormone. Many websites are promoting oral DHEA as an anti-aging tonic and in some countries it is sold as a supplement. Recent clinical trials of oral DHEA and reviews of those trials have failed to show any health benefits for postmenopausal women. However, there may be a role for vaginal DHEA.

A double-blind, randomized, placebo-controlled trial of the effect of testosterone cream on the sexual motivation of menopausal hysterectomized women with hypoactive sexual desire disorder.

OBJECTIVES: To assess the safety and efficacy of 10 mg topical testosterone therapy daily (2 cm Andro-Feme cream) as a treatment for low sexual desire in postmenopausal hysterectomized women who were already on transdermal estrogen. METHODS: A double-blind, randomized, placebo-controlled, cross-over study (each period being of 3 months' duration) was performed in the research center of a tertiary referral women's hospital. Thirty-six menopausal healthy women were recruited who had undergone a hysterectomy, who were not depressed, were in a stable relationship and who fulfilled diagnostic criteria for low sexual desire, as measured by the Brief Index of Sexual Function for Women (BISF-W). MAIN OUTCOME MEASURES: The primary outcome measure was improvement in the sexuality score as measured by a validated tool (BISF-W); secondary measures were sub-scores of the BISF-W, effect on mood and energy, lipids and testosterone levels. RESULTS: Testosterone cream significantly improved sexual desire, frequency of sex, receptivity and initiation as measured by the BISF-W score. It did not change mood, energy, lipids, blood pressure or weight over the study period. CONCLUSIONS: Testosterone cream significantly improved sexual scores in menopausal women with low sexual desire. It was effective, easy to use and had no side-effects over the 3-month period of active treatment. It offers a novel and acceptable method of administering testosterone to menopausal women.

Breast cancer in premenopausal women: recurrence and survival rates and relationship to hormone replacement therapy.

OBJECTIVES: To determine any association between hormonal replacement therapy (HRT) usage and breast cancer recurrence and survival rates in women who were premenopausal at the time of diagnosis of breast cancer. METHODS: The study group comprised 524 women who were diagnosed with breast cancer when they were premenopausal. Of these, 277 women reached menopause before recurrence of the disease, being lost to follow-up, or reaching the end of the study. In this group, 119 women took HRT to control menopausal symptoms. The majority took combined continuous estrogen-progestin treatment. Times from diagnosis to cancer recurrence or new breast cancer, to death from all causes, and to death from primary tumor were compared between HRT users and non-users. RESULTS: Women who used HRT after their menopause had an adjusted relative risk of recurrence or new breast cancer of 0.75 (95% confidence interval (CI), 0.29-1.95) compared to that of non-users. The relative risk of death from all causes was 0.36 (95% CI, 0.11-1.16) and that of death from primary tumor was 0.24 (95% CI, 0.05-1.14). CONCLUSION: HRT use in women who were premenopausal at the diagnosis of primary invasive breast cancer is not associated with worse outcomes in terms of breast cancer recurrence or mortality.

Serenoa repens extract for benign prostate hyperplasia: a randomized controlled trial.

OBJECTIVE: To compare the effect of a Serenoa repens extract with placebo for symptoms of benign prostatic hyperplasia (BPH). PATIENTS AND METHODS: In a double-blind placebo-controlled randomized trial between January 1999 and March 2000, 100 men with symptoms of BPH, aged < 80 years, with a maximum urinary flow rate of 5-15 mL/s for a voiding volume of 150 mL, were randomly and equally allocated to 320 mg S. repens extract or placebo (paraffin oil). The main outcome measures were the International Prostate Symptom Score (IPSS), peak urinary flow rate, and the Rosen International Index of Erectile Function (IIEF) questionnaire. RESULTS: There was no significant difference between the treatments over the 12 weeks of the study in the IPSS, peak urinary flow rate or for the IIEF questionnaire. CONCLUSIONS: During the trial all participants had some improvement in their symptoms of BPH but there was no significant beneficial effect of this S. repens extract over placebo in this 12-week trial.

A cohort study of topical vaginal estrogen therapy in women previously treated for breast cancer.

OBJECTIVE: To estimate the risk of recurrence of breast cancer associated with the use of topical vaginal estrogen therapy in the management of vaginal atrophy in women previously treated for breast cancer. METHODS: The study group comprised 1472 women with histologically confirmed breast cancer. In 69 of these subjects (4.7%) their only bothersome menopausal problems were vaginal symptoms. In these women, poorly absorbed topical vaginal estrogen cream or tablets were used. The response of these patients was compared with that of the rest of the database. A Cox regression analysis was performed using sex hormone usage after diagnosis as a time-dependent covariate. Disease-free interval was the outcome measured. Results are expressed as a hazard ratio with 95% confidence intervals. The hazard rate is defined as the probability of disease recurrence or of a subject dying from breast cancer over the study period. A second analysis was performed adjusting for factors known to affect breast cancer prognosis. RESULTS: Hormone usage was entered as a time-dependent covariate with disease-free interval as the outcome. Subjects who used a topical estrogen alone for menopausal symptoms had an uncorrected hazard ratio of 0.30 (95% confidence interval (CI) 0.11-0.80, p = 0.02). The corrected hazard ratio was 0.57 (95% CI 0.20-1.58, p = 0.28). The hazard rate for a subject dying was not analyzed, as there were too few numbers. CONCLUSIONS: Although the small numbers of this study preclude a definitive result, topical estrogen usage does not appear to be associated with an increased risk of recurrence of breast cancer.

Quality of life of breast cancer survivors: the impact of hormonal replacement therapy.

OBJECTIVES: The aims of this non-randomized qualitative study were to compare the quality of life (QOL) of breast cancer survivors who received hormone replacement therapy (HRT) and those who did not, and to describe the impact of breast cancer on their social, physical, psychological and spiritual domains. A QOL self-evaluation questionnaire was used to determine the most important concerns and changes described by women that affected, or were likely to affect, their QOL as a result of breast cancer. METHODS: In total, 220 patients who had finished treatment for breast cancer were contacted; 190 agreed to participate, of whom 123 (64.8%) completed and returned their questionnaires, which comprised demographic data, Quality of Life Breast Cancer Version Questionnaire and Quality of Life Self Evaluation Questionnaire. The results for women taking HRT were compared with results for those who were not. RESULTS: There were no significant differences in time between surgery for breast cancer and the survey, age at last birthday, number of pregnancies and live births, employment, breast cancer surgery and adjuvant therapy between HRT and non-HRT groups. No differences were found in the social, physical, psychological and spiritual domains between the two groups; however, significant differences were found between survival time and quality of life in some domains. During the study, none of the 123 women developed a recurrence of their breast cancer. CONCLUSION: There were no significant differences in any demographic variables between the users of HRT and the non-users. The same level of QOL was observed between HRT and non-HRT groups in the four domains of well-being. The majority of women with breast cancer recovered to a near normal level of QOL after a 4-year adjustment period, and lead fulfilling lives. This adjustment period cannot be quantified, as individual factors such as emotional, social and financial concerns will differ for each individual.

Tamoxifen, hormone receptors and hormone replacement therapy in women previously treated for breast cancer: a cohort study.

OBJECTIVE: To determine the risk of recurrence of breast cancer associated with the use of hormone replacement therapy (HRT) in the management of menopausal symptoms in women previously treated for breast cancer who were taking concurrent tamoxifen or who were estrogen receptor-positive. METHODS: The study group comprised 1472 women with histologically confirmed breast cancer, of whom 342 subjects (23.2%) elected to use hormonal therapy in the management of their menopausal symptoms. Women were not excluded from treatment with hormonal therapy if they were taking adjuvant tamoxifen or if they had receptor-positive breast cancer. The response of these patients was compared with that of the rest of the database. A Cox regression analysis was performed with sex hormone usage as time-dependent covariate. Disease-free interval was the outcome measured. RESULTS: Subjects who took concurrent tamoxifen with combined continuous estrogen-progestogen therapy had a hazard ratio of 0.67 (95% confidence interval (CI) 0.14-3.24, p = 0.62), while concurrent tamoxifen and topical vaginal estrogen users had a hazard ratio of 0.31 (95% CI 0.10-2.57, p = 0.28). The hazard ratio for the estrogen-progestogen users who were estrogen receptor-positive was 0.24 (95% CI 0.10-1.49, p = 0.14). CONCLUSIONS: The use of HRT was not associated with an increased risk of recurrence of breast cancer in women taking concurrent tamoxifen or who were estrogen receptor-positive.

Effects on menopausal symptoms and acceptability of isoflavone-containing soy powder dietary supplementation.

OBJECTIVES: To assess the acceptability of the delivery of an isoflavone supplementation in the form of a powdered drink, and whether the supplementation of dietary isoflavones in this manner decreased the incidence of menopausal flushes. The secondary aims included assessment of other symptoms or parameters of estrogen deficiency and responses to isoflavones. METHODS: A randomized, double-blind, placebo-controlled, parallel-group trial comprising 24 postmenopausal women with symptoms of estrogen deficiency was performed over a 12-week period. The women were randomized to receive a dietary beverage containing isoflavones or an isoflavone-free, isocaloric placebo preparation. RESULTS: Although there was a high compliance rate among individual patients, there was a 25% withdrawal rate from the study in the active group. The incidence of complaints of bad taste tended to be higher in the active group (p = 0.07), and the total number of adverse events was significantly higher in this group (p < 0.001). There was no statistically significant difference in the incidence of flushes between the groups. There was no difference between the groups in Greene Menopause Symptom Scores, vaginal maturation value, levels of follicle stimulating hormone (FSH) or sex hormone-binding globulin (SHBG), or bone turnover markers. CONCLUSIONS: Powdered energy drinks are not commonly consumed in Australia and were poorly tolerated in this study. The high withdrawal rate and reporting of side-effects suggests that other methods of isoflavone delivery may be more appropriate in this culture, in future trials. At the dose used no benefit was seen in relief from menopausal symptoms, although for the sample size, the study could only have been expected to detect major differences between the groups.

Managing the menopause: phyto-oestrogens or hormone replacement therapy?

Menopause is a natural event, and understandably many women would like to take a natural therapy rather than a drug for managing their menopause symptoms as well as preventing the long-term sequelae of oestrogen deficiency. In this respect phyto-oestrogens show a lot of promise. However, at this point in time clinical data are inconclusive. There are some data supporting the contention that isoflavones improve hot flushes; however, there are also negative studies. Soy protein has been shown to lower cholesterol, and isoflavones improve arterial compliance. Clinical studies suggest that isoflavones have little impact on menopause-induced bone loss.

The effects of dietary supplementation with isoflavones from red clover on the lipoprotein profiles of post menopausal women with mild to moderate hypercholesterolaemia.

The effects of dietary isoflavone supplementation using a purified extract of red clover containing approximately biochanin A 26 mg, formononetin 16 mg, daidzein 0.5 mg and genistein 1 mg per tablet at doses of one or two tablets per day were compared to placebo in a three-period, randomised, double blind, ascending dose study in 66 post menopausal women with plasma cholesterol levels between 5.0 and 9.0 mmol/l. Each treatment period lasted 4 weeks and a further nine women received placebo for the full 12-week period. All women consumed a low isoflavone diet for 2 weeks preceding the commencement of the study and for the 12-week study period. Urinary isoflavone excretion was very low in subjects receiving placebo but increased in a dose-dependent manner during therapy with one and two of isoflavone tablets. Dietary supplementation with isoflavones did not significantly alter total plasma cholesterol, LDL cholesterol, HDL cholesterol or plasma triglyceride levels. However, inverse correlations were found between urinary genistein excretion and plasma triglyceride levels and between urinary O-DMA excretion (an isoflavone metabolite) and plasma triglyceride levels in subjects receiving one isoflavone tablet, suggesting a weak relationship between isoflavone intake and plasma triglycerides which may be influenced by individual differences in isoflavone absorption or metabolism. The results suggest that isoflavone phytoestrogens from red clover in the proportions and quantities studied do not significantly alter plasma lipids in post menopausal women with moderately elevated plasma cholesterol levels.

Effects of estrogens and hormone replacement therapy on breast cancer risk and on efficacy of breast cancer therapies.

This review summarises preclinical and clinical data on effects of endogenous and exogenous estrogens on probability of breast cancer diagnosis, and on the course and efficacy of breast cancer therapies. The data indicate that higher endogenous estrogen exposure (e.g. pregnancy, early menarche and late menopause, estrogen levels in future breast cancer patients, obesity) or exogenous estrogens (oral contraceptives; hormone replacement therapies) may be associated with an increased probability of breast cancer diagnosis. However, there is little evidence that estrogens have deleterious effects on the course of breast cancer. Moreover, increased incidence of breast cancer diagnosis after prolonged hormone replacement therapy (HRT) use seems to be associated with clinically less advanced disease. In studies assessing both diagnosis and mortality, HRT is frequently associated with reduced mortality compared to never users. The interaction of progestagens and estrogens on the probability of breast cancer diagnosis is complex and dependent on type of progestagens and regimens employed. Efficacy of current treatment modalities for breast cancer (surgery, irradiation, adjuvant therapy or chemotherapy) is not negatively influenced by estrogens at concentrations considerably higher than those attained with current HRT preparations. Although it cannot be excluded that estrogens increase the probability of breast cancer diagnosis, available data fail to demonstrate that, once breast cancer has been diagnosed, estrogens worsen prognosis, accelerate the course of the disease, reduce survival or interfere with the management of breast cancer. It may therefore be concluded that the prevalent opinion that estrogens and estrogen treatment are deleterious for breast cancer, needs to be revisited. However, results of ongoing prospective, randomised clinical trials with different HRT regimens in healthy women or breast cancer survivors are needed to provide more definite conclusions about risks and benefits of HRT.

The effects of soy protein in women and men with elevated plasma lipids.

Fifty four postmenopausal women with elevated cholesterol were recruited for a randomised, double-blind controlled trial of soy protein containing isoflavones. (ISP+) or a soy protein with a low isoflavone content (ISP-), taken daily for 12 weeks. There was an overall reduction after 12 weeks in total cholesterol (TC), LDL cholesterol (LDL-C), sex hormone binding globulin (SHBG), and luteinizing hormone (LH). There were no significant differences between treatment groups. In a separate study 27 male subjects with a TC > 5.5 mmol/l were given ISP+ for 12 weeks. In this male study there was a significant increase in HDL cholesterol (HDL-C) and SHBG. Soy protein has a cholesterol lowering effect in both women and men. These studies suggest that this effect is independent of isoflavones. Soy protein also reduces SHBG levels in both sexes.

Effect of sequential transdermal progesterone cream on endometrium, bleeding pattern, and plasma progesterone and salivary progesterone levels in postmenopausal women.

BACKGROUND: Transdermal progesterone is being used in some countries as a purported treatment for menopausal symptoms, either alone or prescribed in conjunction with estrogen, but little information exists regarding the biological activity and effectiveness of this method of delivery of progesterone in protecting the endometrium from excess proliferation. This study was designed to evaluate the use of sequential transdermal progesterone. End-points evaluated included endometrial cellular response and bleeding pattern as well as plasma hormone levels and salivary progesterone estimations. METHOD: Twenty-seven postmenopausal women were treated with continuous transdermal estrogen (28-day cycle) and a cream containing 16, 32 or 64 mg of progesterone in each 4-cm extrusion from a tube of Pro-Feme administered daily in a sequential (days 15-28 of cycle) regimen. Blood and endometrial samples were analyzed for progesterone response prior to therapy, after the first 14 days of unopposed transdermal estrogen and following 14 days of transdermal progesterone. Saliva samples were taken during the last 14 days of the 84-day study, when the final progesterone cream therapy was being applied. RESULTS: Hormone assay indicated that physiological levels of estradiol were achieved, but progesterone levels were insufficient to induce any detectable change in the endometrium. Only one patient experienced bleeding during the study period. Levels of salivary progesterone were so variable as to be considered completely unreliable in determining the potential influence on biological activity. INTERPRETATION: Pro-Feme transdermal progesterone administered in a 16-, 32- or 64-mg daily dose for 14 days in a sequential regimen does not appear to be effective in inducing a secretory change in a proliferative endometrium. Salivary progesterone levels were not of value in managing the therapy of postmenopausal women.

The effect of Promensil, an isoflavone extract, on menopausal symptoms.

OBJECTIVES: The primary aim was to assess whether the use of an isoflavone extract containing 40 mg or 160 mg of total isoflavones affects the frequency of menopausal flushes and other symptoms. The secondary aims were assessments of possible effects on menopause symptom scores and biological measures of estrogen activity. METHODS: A randomized, double-blind, placebo-controlled prospective trial of 37 postmenopausal women with symptoms of estrogen deficiency was performed over a 12-week period. The women were randomized to three treatment groups: placebo, 40 mg or 160 mg, delivered in tablet form. RESULTS: There was no significant difference in the incidence of flushes between the three groups at trial conclusion. There was no difference between the groups in Greene Menopause Symptom Scores, vaginal pH, levels of follicle stimulating hormone (FSH), sex hormone binding globulin (SHBG) or total cholesterol, liver function or blood parameters. A statistically significant increase in high-density lipoprotein (HDL) cholesterol of 18.1% (p = 0.038) occurred in the 40-mg group. CONCLUSION: A large placebo response and inadvertent use of dietary isoflavones in the placebo group may have obscured a significant change in flushing frequency. Previous uncontrolled studies claiming a beneficial effect of foods with a high isoflavone content on menopausal symptoms may have been confounded by a large placebo response.

A review of 1019 consecutive cases of polycystic ovary syndrome demonstrated by ultrasound.

Analysis of a cohort of 1019 consecutive subjects with ultrasonically demonstrable polycystic ovary (PCO) syndrome demonstrated a significant relationship between biochemical parameters and clinical symptoms such as menstrual frequency and severity of hirsutism. One hundred and forty-four subjects presented with involuntary infertility and only eight cases had unexplained infertility apart from PCO.

Isoflavone content of infant foods and formulas.

OBJECTIVE: The purpose of this study was to investigate the phytoestrogen content of different foods, formulas and drinks that may be consumed by infants during their first year of life in an attempt to define levels of exposure on different feeding regimens. METHODOLOGY: High performance liquid chromatography (HPLC) was used to determine the levels of genistein, daidzein, biochanin A, formononetin and equol in samples purchased from Australian supermarkets. Single lots of duplicate or triplicate samples of soy beverages, cow's milks, infant formulas and infant yoghurts were analysed. RESULTS: All foods tested contained isoflavones, at varying levels, suggesting that exposure to these compounds is almost ubiquitous. Casein-based infant formulas contained between 0.001 and 0.03 mg L(-1). Soy-based infant formulas ranged from 17.2 to 21.9 mg L(-1) with the values detected in yoghurt at similar levels to that of cow's milk. For comparison, the soy-based beverages (which are not recommended for use under 12 months of age) contained levels of isoflavones from 22.9 to 71.5 mg L(-1). CONCLUSIONS: Given the relatively broad choice of infant foods becoming available, exposure to dietary isoflavones during the first year of life is virtually ubiquitous. The exposure may be higher if soy infant formulas are consumed, however, the levels attained appear to fall within normal physiological boundaries.

A twin study of polycystic ovary syndrome and lipids.

Our objective was to assess the relative contribution of genetic and environmental factors (particularly androgens) on circulating levels of lipid fractions and to determine the effect, if any, of polycystic ovary syndrome (PCOS) on lipid fractions. The study was carried out in the outpatient clinic of the Royal Hospital for Women, Paddington, Sydney, Australia. A group of 19 monozygotic (MZ) and 15 dizygotic (DZ) twin pairs was identified from the National Twin Register. Ultrasound clinical and biochemical parameters were used to define polycystic ovaries. Serum androgen and lipid fractions were also measured. Eleven pairs of twins (five MZ, six DZ) were scan discordant (i.e. one twin had polycystic ovaries and the co-twin did not). Serum levels of the lipoprotein fractions in twins with polycystic ovaries were not significantly different from the levels found for their co-twins with normal ovaries. There were no significant correlations between androgen-related hormones and any of the lipid measurements. Body mass index (BMI) was positively correlated with triglycerides and lipoprotein (a), and negatively correlated with high-density lipoprotein cholesterol (HDL-C). Sex hormone-binding globulin (SHBG) levels were negatively correlated with triglycerides and lipoprotein (a) and positively associated with HDL-C. Fasting insulin levels were significantly correlated with triglycerides and negatively with HDL-C. The MZ intraclass correlation exceeded that of the DZ twin pairs for all the lipid variables measured. The heritability estimates for lipoprotein (a), apolipoprotein B, total cholesterol and HDL-C were 0.95, 0.56, 0.48 and 0.54, respectively. However, the intraclass correlation coefficient for triglycerides was not significantly different between MZ and DZ twins, but maximum likelihood analysis indicated that at least 10% of the variance of the circulating triglyceride concentration is determined by genetic factors. We conclude that twins discordant for the PCOS do not have significantly different lipid fractions.