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1.  Effects of A Breast-Health Herbal Formula Supplement on Estrogen Metabolism in Pre- and Post-Menopausal Women not Taking Hormonal Contraceptives or Supplements: A Randomized Controlled Trial 
Introduction
Both indole-3-carbinol and dietary lignans have beneficial effects on estrogen metabolism and breast cancer risk. There is no published literature on the effects of a combination product. This study was designed to investigate the impact of a combination product on estrogen metabolism. The major trial objective was to determine whether a breast health supplement containing indole-3-carbinol and hydroxymatairesinol lignan would alter estrogen metabolism to favour C-2 hydroxylation and reduce C-16 hydroxylation. Higher concentrations of C-2 metabolites and lower concentrations of C-16 metabolites may reduce breast cancer risk and risk for other hormonally-related cancers.
Methods
Forty-seven pre-menopausal and forty-nine post-menopausal women were recruited for this study, and were divided by random allocation into treatment and placebo group. The treatment supplement contained HMR lignan, indole-3-carbinol, calcium glucarate, milk thistle, Schisandra chinesis and stinging nettle, and each woman consumed either treatment or placebo for 28 days. At day 0 and day 28, blood samples were analysed for serum enterolactone concentrations, and first morning random urine samples were assessed for estrogen metabolites. Repeated measures ANOVA statistical testing was performed.
Results
In pre-menopausal women, treatment supplementation resulted in a significant increase (P < 0.05) in urinary 2-OHE concentrations and in the 2:16α-OHE ratio. In post-menopausal women, treatment supplementation resulted in a significant increase in urinary 2-OHE concentrations. In pre- and post-menopausal women combined, treatment supplementation produced a significant increase in urinary 2-OHE concentration and a trend (P = 0.074) toward an increased 2:16α-OHE ratio. There were no significant increases in serum enterolactone concentrations in the treatment or placebo groups.
Conclusions
Supplementation with a mixture of indole-3-carbinol and HMR lignan in women significantly increased estrogen C-2 hydroxylation. This may constitute a mechanism for the reduction of breast cancer risk as well as risk for other estrogen-related cancers. Further studies with higher numbers of subjects are indicated.
Trial registration
ClinicalTrials.gov registration #NCT01089049.
doi:10.4137/BCBCR.S6505
PMCID: PMC3018890  PMID: 21234288
herbal supplement; breast health; estrogen metabolites
2.  Impact of Sex Hormone Metabolism on the Vascular Effects of Menopausal Hormone Therapy in Cardiovascular Disease 
Current drug metabolism  2010;11(8):693-714.
Epidemiological studies have shown that cardiovascular disease (CVD) is less common in pre-menopausal women (Pre-MW) compared to men of the same age or post-menopausal women (Post-MW), suggesting cardiovascular benefits of estrogen. Estrogen receptors (ERs) have been identified in the vasculature, and experimental studies have demonstrated vasodilator effects of estrogen/ER on the endothelium, vascular smooth muscle (VSM) and extracellular matrix. Several natural and synthetic estrogenic preparations have been developed for relief of menopausal vasomotor symptoms. However, whether menopausal hormone therapy (MHT) is beneficial in postmenopausal CVD remains controversial. Despite reports of vascular benefits of MHT from observational and experimental studies, randomized clinical trials (RCTs), such as the Heart and Estrogen/progestin Replacement Study (HERS) and the Women’s Health Initiative (WHI), have suggested that, contrary to expectations, MHT may increase the risk of CVD. These discrepancies could be due to age-related changes in sex hormone synthesis and metabolism, which would influence the effective dose of MHT and the sex hormone environment in Post-MW. Age-related changes in the vascular ER subtype, structure, expression, distribution, and post-ER signaling pathways in the endothelium and VSM, along with factors related to the design of RCTs, preexisting CVD condition, and structural changes in the blood vessels architecture have also been suggested as possible causes of MHT failure in CVD. Careful examination of these factors should help in identifying the causes of the changes in the vascular effects of estrogen with age. The sex hormone metabolic pathways, the active versus inactive estrogen metabolites, and their effects on vascular function, the mitochondria, the inflammatory process and angiogenesis should be further examined. Also, the genomic and non-genomic effects of estrogenic compounds should be viewed as integrated rather than discrete responses. The complex interactions between these factors highlight the importance of careful design of MHT RCTs, and the need of a more customized approach for each individual patient in order to enhance the vascular benefits of MHT in postmenopausal CVD.
PMCID: PMC3063102  PMID: 21189141
estrogen; phytoestrogens; estrogen receptor; endothelium; vascular smooth muscle; hypertension; progesterone; testosterone
3.  Contemporary Alternatives to Plant Estrogens for Menopause 
Maturitas  2006;55(Suppl 1):S3-13.
Objectives
Every year, millions of women begin the peri-menopause and may experience a number of symptoms related to this transition. Many women are reluctant to use exogenous hormone therapy for treatment of menopausal symptoms and are turning to botanical and dietary supplements (BDS) for relief. This paper reviews the literature on alternatives to plant estrogens for relief of menopausal symptoms.
Methods
The MEDLINE database was searched for clinical trials of non-estrogenic plant extracts for menopausal symptoms. To be included, studies had to include peri- or postmenopausal women as subjects. All clinical trials (randomized-controlled trials, open trials, and comparison group studies) were included for this review.
Results
Black Cohosh appears to be one of the most effective botanicals for relief of vasomotor symptoms, while St. John’s wort can improve mood disorders related to the menopausal transition. Many other botanicals have limited evidence to demonstrate safety and efficacy for relief of symptoms related to menopause.
Conclusions
A growing body of evidence suggests that some botanicals and dietary supplements could result in improved clinical outcomes. Health care providers should discuss these issues with their patients so they can assist them in managing these alternative therapies through an evidence-based approach.
doi:10.1016/j.maturitas.2006.06.012
PMCID: PMC1780040  PMID: 16884867
Menopause; botanical supplements; dietary supplements
4.  Menopausal Hormone Therapy and Risks of Melanoma and Nonmelanoma Skin Cancers: Women’s Health Initiative Randomized Trials 
Background
Case–control studies have reported that exogenous estrogen use is associated with increased risk of skin cancer. The effects of menopausal hormone therapy on incidence of nonmelanoma skin cancer and melanoma were evaluated in post hoc analyses of the Women’s Health Initiative randomized placebo-controlled hormone therapy trials of combined estrogen plus progestin (E + P) and estrogen only (E-alone).
Methods
Postmenopausal women aged 50–79 years were randomly assigned to conjugated equine estrogen (0.625 mg/d) plus medroxyprogesterone acetate (2.5 mg/d) or placebo in the E + P trial if they had an intact uterus (N = 16 608) or to conjugated equine estrogen alone or placebo in the E-alone trial if they had a hysterectomy (N =10 739); the mean follow-up was 5.6 and 7.1 years, respectively. Incident nonmelanoma skin cancers (n = 980 [E + P trial]; n = 820 [E-alone trial]) and melanomas (n = 57 [E + P trial]; n =38 [E-alone trial]) were ascertained by self-report. Incident cases of cutaneous malignant melanoma were confirmed by physician review of medical records. Incidences of nonmelanoma skin cancer and melanoma were compared between the two randomization groups within each trial using hazard ratios (HRs), with corresponding 95% confidence intervals (CIs) and Wald statistic P values from Cox proportional hazards models. All statistical tests were two-sided.
Results
Rates of incident nonmelanoma skin cancer and melanoma were similar between the active hormone (combined analysis of E + P and E-alone) and placebo groups (nonmelanoma skin cancer: HR = 0.98, 95% CI = 0.89 to 1.07; melanoma: HR = 0.92, 95% CI = 0.61 to 1.37). Results were similar for the E + P and E-alone trials when analyzed individually.
Conclusions
Menopausal hormone therapy did not affect overall incidence of nonmelanoma skin cancer or melanoma. These findings do not support a role of menopausal estrogen, with or without progestin, in the development of skin cancer in postmenopausal women.
doi:10.1093/jnci/djr333
PMCID: PMC3186783  PMID: 21878677
5.  Changing Concepts: Menopausal Hormone Therapy and Breast Cancer 
Hormone therapy is still used by millions of women for menopausal symptoms. Concerns regarding hormone therapy and breast cancer were initially based on case reports and retrospective case–control studies. However, recent results from large prospective cohort studies and the Women’s Health Initiative (WHI) randomized placebo-controlled hormone therapy trials have substantially changed concepts regarding how estrogen alone and estrogen plus progestin influence breast cancer. The preponderance of observational studies suggested that estrogen alone and estrogen plus progestin both increased the risk of breast cancer, with cancers commonly diagnosed at an early stage. However, substantially different results emerged from the WHI randomized hormone therapy trials. In the WHI trial evaluating estrogen plus progestin in postmenopausal women with an intact uterus, combined hormone therapy statistically significantly increased the risk of breast cancer and hindered breast cancer detection, leading to delayed diagnosis and a statistically significant increase in breast cancer mortality. By contrast, estrogen alone use by postmenopausal women with prior hysterectomy in the WHI trial did not substantially interfere with breast cancer detection and statistically significantly decreased the risk of breast cancer. Differential mammography usage patterns may explain differences between observational study and randomized trial results. In clinical practice, hormone therapy users have mammograms more frequently than nonusers, leading to more and earlier stage cancer detection. By contrast, in the WHI randomized trials, mammogram frequency was protocol mandated and balanced between comparison groups. Currently, the different effects of estrogen plus progestin vs estrogen alone on breast cancer are not completely understood.
doi:10.1093/jnci/djs014
PMCID: PMC3317878  PMID: 22427684
6.  Profile of bazedoxifene/conjugated estrogens for the treatment of estrogen deficiency symptoms and osteoporosis in women at risk of fracture 
Decreasing levels of estrogens during menopause are associated with reduced bone density and an increased risk of osteoporosis. Many women also experience bothersome vasomotor and vaginal symptoms during the menopausal transition. Results of systematic reviews and meta-analyses of randomized controlled trials have shown that both systemic estrogen therapy or hormone therapy (estrogen combined with a progestin) are useful to prevent bone loss, and they are the most effective treatment for such climacteric symptoms as hot flushes, sweating, vaginal dryness, and dyspareunia. Unfortunately, estrogen therapy and hormone therapy increase the risk of endometrial and breast cancer, respectively. The selective estrogen receptor modulators (SERMs) result in positive estrogenic effects on bone, with no negative effects on the endometrium and breast but do not provide relief from postmenopausal symptoms. The combination of a SERM with estrogen as a tissue selective estrogen complex (TSEC) is a new strategy for the prevention of bone loss and the treatment of climacteric symptoms. This combination is particularly interesting from a clinical point of view, taking into account that estrogen alone did not increase breast cancer risk by the Women’s Health Initiative. TSEC is hypothesized to provide the benefits of estrogen-alone therapy, with an improved tolerability profile because the SERM component can make possible the elimination of progestin. The objective of this review was to critically evaluate the evidence from the reports published to date on the use of bazedoxifene (a third-generation SERM) in combination with conjugated estrogens in postmenopausal women. The conclusion is that effectively, the combination of bazedoxifene and conjugated estrogens may be a promising alternative to hormone therapy for the prevention of osteoporosis and the treatment of postmenopausal symptoms in non-hysterectomized postmenopausal women.
doi:10.2147/DDDT.S47807
PMCID: PMC3724601  PMID: 23901263
tissue selective estrogen complex; menopause; bone mineral density; bone turnover markers; climacteric symptoms
7.  Therapeutic Effects of Pre-Gelatinized Maca (Lepidium Peruvianum Chacon) used as a Non-Hormonal Alternative to HRT in Perimenopausal Women - Clinical Pilot Study 
Background:
Roots of cruciferous plant Lepidium peruvianum Chacon cultivated in high plateaus of Andes and known under its common name Maca, have been traditionally-used as an energizing vegetable with therapeutic properties for both men and women. Maca has been recognized by natives of Peru as herbal remedy helping to treat conditions affecting menopausal women.
Objective:
The effects of Pre-Gelatinized Organic Maca (Maca-GO) on quantitative physiological responses and alleviation of symptoms contributing to menopausal discomfort in perimenopausal women was examined.
Methods:
In this, four months, double blind, crossover, randomized pilot trial, monthly measurements of the following blood serum constituents were taken: Estrogen (E2), Follicle Stimulating Hormone (FSH), Luteinizing Hormone (LH) and Progesterone (PGS), Cortisol (CT), Adrenocorticotropic Hormone (ACTH), Thyroid Hormones (TSH, T3, T4), minerals (Ca, K, Fe) and lipid profile (Triglicerides, Total Cholesterol, LDL, HDL). In monthly interviews conducted by gynecologist, body weight and blood pressure were registered and Menopausal Index according to Kupperman’s was determined. Toxicity of Maca -GO determined on rats showed its safe use at the level of 7.5mg/kg body weight. A group of 20 women (aged 41-50 years), who fulfilled criteria of being in perimenopausal stage (E2 above 40pg/ml and FSH below 30IU/ml), were randomly allocated to two even groups, one receiving for two months Maca-GO and the other Placebo capsules followed by a crossover with treatment change for another two months period. All participants signed informed consent to participate. Two 500mg hard capsules with Maca-GO or Placebo were self-administered by participants twice daily with meals (total 2g/day).
Results:
Two months administration of Maca-GO significantly alleviated symptoms of discomfort observed in majority of women involved in the study (74%-87%) as assessed by Kupperman’s Menopausal index. This was associated with significant increase in E2 and FSH, Progesterone and ACTH levels, and reduction in blood pressure, body weight, Triglycerides and Cholesterol levels. There was a distinctive placebo effect observed at the beginning of the study.
Conclusions:
The results showed that in addition to reduction in body weight, blood pressure and increasing serum HDL and Iron, pre-gelatinized Maca-GO may be a valuable non-hormonal plant preparation for balancing levels of hormones (FSH, E2, PG and ACTH) and alleviating negative physiological and psychological symptoms (frequency of hot flushes, incidence in night sweating, interrupted sleep pattern, nervousness, depression and heart palpitations) experienced by women in perimenopausal stage. It appears that Maca-GO may act as a toner of hormonal processes, leading to alleviation of discomfort felt by perimenopausal women, hence, its potential use as non-hormonal alternative to HRT program.
PMCID: PMC3614596  PMID: 23674976
alternative to HRT; blood hormones; Maca (Lepidium peruvianum); perimenopause
8.  Cognitive behavioral therapy and physical exercise for climacteric symptoms in breast cancer patients experiencing treatment-induced menopause: design of a multicenter trial 
BMC Women's Health  2009;9:15.
Background
Premature menopause is a major concern of younger women undergoing adjuvant therapy for breast cancer. Hormone replacement therapy is contraindicated in women with a history of breast cancer. Non-hormonal medications show a range of bothersome side-effects. There is growing evidence that cognitive behavioral therapy (CBT) and physical exercise can have a positive impact on symptoms in naturally occurring menopause. The objective of this study is to investigate the efficacy of these interventions among women with breast cancer experiencing treatment-induced menopause.
Methods/design
In a randomized, controlled, multicenter trial, we are evaluating the effectiveness of CBT/relaxation, of physical exercise and of these two program elements combined, in reducing menopausal symptoms, improving sexual functioning, reducing emotional distress, and in improving the health-related quality of life of younger breast cancer patients who experience treatment-induced menopause. 325 breast cancer patients (aged < 50) are being recruited from hospitals in the Amsterdam region, and randomly allocated to one of the three treatment groups or a 'waiting list' control group. Self-administered questionnaires are completed by the patients at baseline, and at 12 weeks (T1) and 6 months (T2) post-study entry. Upon completion of the study, women assigned to the control group will be given the choice of undergoing either the CBT or physical exercise program.
Discussion
Cognitive behavioral therapy and physical exercise are potentially useful treatments among women with breast cancer undergoing treatment-induced, premature menopause. For these patients, hormonal and non-hormonal therapies are contraindicated or have a range of bothersome side-effects. Hence, research into these interventions is needed, before dissemination and implementation in the current health care system can take place.
Trial registration
The study is registered at the Netherlands Trial Register (NTR1165) and ClinicalTrials.gov (NCT00582244).
doi:10.1186/1472-6874-9-15
PMCID: PMC2706817  PMID: 19500403
9.  Potential Approaches to Enhance the Effects of Estrogen on Senescent Blood Vessels and Postmenopausal Cardiovascular Disease 
Cardiovascular disease (CVD) is more common in postmenopausal than premenopausal women, suggesting vascular protective effects of estrogen. Vascular estrogen receptors ERα, ERβ and a transmembrane estrogen-binding protein GPR30 have been described. Also, experimental studies have demonstrated vasodilator effects of estrogen on the endothelium, vascular smooth muscle and extracellular matrix. However, randomized clinical trials have not supported vascular benefits of menopausal hormone therapy (MHT), possibly due to the subjects' advanced age and age-related changes in estrogen synthesis and metabolic pathways, the vascular ERs number, distribution and integrity, and the post-ER vascular signaling pathways. Current MHT includes natural estrogens such as conjugated equine estrogen, as well as synthetic and semi-synthetic estrogens. New estrogenic formulations and hormone combinations have been developed. Phytoestrogens is being promoted as an alternative MHT. Specific ER modulators (SERMs), and selective agonists for ERα such as PPT, ERβ such as DPN, and GPR30 such as G1 are being evaluated. In order to enhance the vascular effectiveness of MHT, its type, dose, route of administration and timing may need to be customized depending on the subject's age and pre-existing CVD. Also, the potential interaction of estrogen with progesterone and testosterone on vascular function may need to be considered in order to maximize the vascular benefits of MHT on senescent blood vessels and postmenopausal CVD.
PMCID: PMC2853974  PMID: 20210774
sex hormones; progesterone; testosterone; phytoestrogens; estrogen receptor; endothelium; vascular smooth muscle; hypertension
10.  The effects of botanical dietary supplements on cardiovascular, cognitive and metabolic function in males and females 
Gender medicine  2008;5(Suppl A):S76-S90.
The onset of menopause marks a pivotal time in which the incidence of hypertension and cardiovascular disease begins to increase dramatically in women. Prior to menopause, the incidence of these diseases is significantly lower than in similarly aged men, but following menopause the rates rise rapidly until paralleling that in men. The loss of endogenous estrogen at menopause has traditionally been thought to be the primary factor involved in these changes and resulted in the widespread use of hormone replacement therapy (HRT) to reduce cardiovascular risk factors and decrease the affective symptoms of menopause. However, the adverse effects of HRT reported in recent large-scale trials (e.g., the Women’s Health Initiative) have greatly decreased the use of HRT by postmenopausal women.
Many women are seeking alternatives to HRT, including the use of dietary supplements that have a long history of use in traditional medicine, particularly in Asia. Examples of frequently used botanicals are soy, black cohosh, red clover, grape derivatives, St. John’s wort, Ginko biloba and Echinacea. While many of these botanicals appear to ameliorate some postmenopausal symptoms (i.e., bone loss, hot flushes/flashes and night sweats), none of the tested botanicals has proven as effective as HRT in decreasing the affective disorders of menopause. Further, despite the increasing usage of botanical supplements, their efficacy and safety have not been well documented by critical research studies. This review summarizes recent findings related to the utility of botanicals for menopause-related cardiovascular and metabolic disorders, specifically hypertension, diabetes, progressive cognitive decline and hyperlipidemia. While great caution should be exercised in the translation of animal findings to the human, these studies, along with those of others, suggest that some commonly used botanical supplements may be useful adjuvants for providing protection to women (and men) against cardiovascular risk.
doi:10.1016/j.genm.2008.03.008
PMCID: PMC2675052  PMID: 18395685
estrogen; menopause; blood pressure; diabetes; lipids; hypertension
11.  Effects of soy protein and isoflavones on circulating hormone concentrations in pre- and post-menopausal women: a systematic review and meta-analysis 
Human Reproduction Update  2009;15(4):423-440.
BACKGROUND
Hormonal effects of soy and isoflavones have been investigated in numerous trials with equivocal findings. We aimed to systematically assess the effects of soy and isoflavones on circulating estrogen and other hormones in pre- and post-menopausal women.
METHODS
The Cochrane Library, MEDLINE and EMBASE (plus reviews and experts) were searched to December 2007. Inclusion of randomized or residential crossover trials of soy or isoflavones for 4 or more weeks on estrogens, SHBG, FSH, LH, progesterone and thyroid hormones in women was assessed independently in duplicate. Six percent of papers assessed were included. Data concerning participants, interventions, outcomes, potential effect modifiers and trial quality characteristics were extracted independently in duplicate.
RESULTS
Forty-seven studies (11 of pre-, 35 of post- and 1 of perimenopausal women) were included. In premenopausal women, meta-analysis suggested that soy or isoflavone consumption did not affect primary outcomes estradiol, estrone or SHBG concentrations, but significantly reduced secondary outcomes FSH and LH [by ∼20% using standardized mean difference (SMD), P = 0.01 and 0.05, respectively]. Menstrual cycle length was increased by 1.05 days (95% CI 0.13, 1.97, 10 studies). In post-menopausal women, there were no statistically significant effects on estradiol, estrone, SHBG, FSH or LH, although there was a small statistically non-significant increase in total estradiol with soy or isoflavones (∼14%, SMD, P = 0.07, 21 studies).
CONCLUSIONS
Isoflavone-rich soy products decrease FSH and LH in premenopausal women and may increase estradiol in post-menopausal women. The clinical implications of these modest hormonal changes remain to be determined.
doi:10.1093/humupd/dmp010
PMCID: PMC2691652  PMID: 19299447
soy foods; isoflavones; estradiol; sex hormone-binding globulin; gonadotrophins
12.  Hormonal treatment, mild cognitive impairment and Alzheimer's disease 
A plethora of in vitro and in vivo studies have supported the neuroprotective role of estrogens and their impact on the neurotransmitter systems implicated in cognition. Recent hormonal replacement therapy trials in non-demented post-menopausal women suggest a temporary positive effect (notably on verbal memory), and four meta-analyses converge to suggest a possible protective effect in relation to Alzheimer’s disease (reducing risk by 29 to 44%). However, data from the only large randomized controlled trial published to date, the Women’s Health Initiative Memory Study, did not confirm these observations and have even suggested an increase in dementia risk for women using hormonal replacement therapy compared to controls. Apart from methodological differences, one key short-coming of this trial has probably been the focus on late-onset (postmenopausal) hormonal changes, i.e. at a time when the neurodegenerative process has already begun and without taking into account individual lifetime exposure to hormone variability. Multifactorial models based on an exhaustive view of all hormonal events throughout the reproductive life (rather than on a specific exposure to a given steroid) together with other risk factors (notably genetic risk factors related to estrogen receptor polymorphisms) should be explored to clarify the role of hormonal risk factors, or protective factors for cognitive dysfunction and dementia.
doi:10.1017/S1041610207006485
PMCID: PMC2662345  PMID: 18072983
Administration, Cutaneous; Aged; Alzheimer Disease; diagnosis; drug therapy; prevention & control; Cognition Disorders; diagnosis; drug therapy; prevention & control; Estradiol; administration & dosage; therapeutic use; Estrogen Replacement Therapy; methods; Estrogens; administration & dosage; therapeutic use; Estrogens, Conjugated (USP); therapeutic use; Female; Humans; Memory Disorders; diagnosis; drug therapy; prevention & control; Middle Aged; Neuroprotective Agents; administration & dosage; therapeutic use; Progestins; therapeutic use; Randomized Controlled Trials as Topic; statistics & numerical data; Receptors, Estrogen; genetics; Research Design; standards; trends; Severity of Illness Index; Treatment Outcome; Cognition; equine estrogens; transdermal estradiol; estrogen receptor; lifetime hormonal status; observation study; randomized controlled trial
13.  Black Cohosh: Insights into its Mechanism(s) of Action 
The Women’s Health Initiative found that combination estrogen and progesterone hormone replacement therapy increases breast cancer and cardiovascular disease risk, which compelled many women to seek herbal alternatives such as black cohosh extract (BCE) to relieve their menopausal symptoms. While several clinical trials document the efficacy of BCE in alleviating menopausal symptoms, preclinical studies to determine how BCE works have yielded conflicting results. Part of this is because there is not a universally accepted method to standardize the dose of black cohosh triterpenes, the presumed active ingredients in the extract. Although the mechanism by which BCE relieves symptoms is unknown, several hypotheses have been proposed: it acts 1) as a selective estrogen receptor modulator, 2) through serotonergic pathways, 3) as an antioxidant, or 4) on inflammatory pathways. We found that while the most prominent triterpene in BCE, 23-epi-26-deoxyactein, suppresses cytokine-induced nitric oxide production in brain microglial cells, the whole BCE extract actually enhanced this pathway. A variety of activities have been reported for black cohosh and its compounds, but the absorption and tissue distribution of these compounds is unknown.
PMCID: PMC3046019  PMID: 21614156
Black cohosh; botanical; complementary and alternative medicine; estrogen; inflammatory; nitric oxide
14.  Correlation of Common Biochemical Markers for Bone Turnover, Serum Calcium, and Alkaline Phosphatase in Post-Menopausal Women 
The quality of life for women after menopause is one of the key health issues today, and osteoporosis is a silently progressing metabolic bone disease widely prevalent in post-menopausal women in India. Rapid bone loss occurs in post-menopausal women due to hormonal factors that lead to an increased risk of fractures. Thus, the present study was undertaken to observe the serum calcium and alkaline phosphatase (ALP) levels in post-menopausal women as these substances are biochemical markers of bone metabolism. In this small-scale cross-sectional study, 100 samples were taken. Of these, 50 were taken from post-menopausal women (experimental group) and 50 were taken from pre-menopausal women (control group). Serum calcium and serum ALP were measured in the blood samples of both groups. The findings demonstrated that the serum calcium level was significantly lower in the post-menopausal group than in the pre-menopausal group, while the ALP level was slightly higher. Therefore, an increase in bone turnover accelerates bone mass reduction in post-menopausal women, whereas a decrease in bone turnover is associated with the preservation of bone mass.
PMCID: PMC3952340  PMID: 24639613
alkaline phosphatase; calcium; menopause; osteoporosis
15.  Soy use and vasomotor symptoms: Soy Estrogen Alternative follow-up study 
Purpose
To evaluate vasomotor symptoms and soy and hormone therapy use in women who had previously participated in the Soy Estrogen Alternative (SEA) study, a trial conducted to compare the effects of soy protein supplements containing differing levels of isoflavones on menopausal symptoms, chronic disease risk factors, and health-related quality of life in perimenopausal and postmenopausal women.
Participants and methods
Two years after the SEA study ended participants were recontacted to complete questionnaires to quantify their health status, medications, menopausal symptoms, and their use of hormone therapy and soy-based foods and supplements. Participants were also asked to record vasomotor symptoms for seven days.
Results
Surveys were collected from 182 of the 241 participants who had been enrolled in the SEA study (76% response rate). Women were 55 ± 2.8 years of age, well educated (80% more than high school), and 93% reported good to excellent health. All but six reported experiencing at least one menopausal symptom, and 56% reported one or more hot flashes on one or more days. Eighty-one women (45%) continued to use soy for menopausal symptom relief, and 58 (32%) were using hormone therapy. Women taking hormone therapy were experiencing fewer and less severe hot flashes than those who were not taking hormone therapy (P < 0.001); hot flash frequency and severity did not differ significantly between those who did and did not use soy, after controlling for hormone therapy use.
Conclusion
Most participants reported they were still experiencing menopausal symptoms. Additionally, half of the most symptomatic women (not taking hormone therapy) were still consuming soy products for vasomotor symptoms.
doi:10.2147/IJWH.S12863
PMCID: PMC2990907  PMID: 21151685
menopause; vasomotor symptoms; soy consumption; survey
16.  Clinical practice guidelines for the care and treatment of breast cancer: 14. The role of hormone replacement therapy in women with a previous diagnosis of breast cancer 
Objective
To provide information and recommendations to women with a previous diagnosis of breast cancer and their physicians regarding hormone replacement therapy (HRT).
Outcomes
Control of menopausal symptoms, quality of life, prevention of osteoporosis, prevention of cardiovascular disease, risk of recurrence of breast cancer, risk of death from breast cancer.
Evidence
Systematic review of English-language literature published from January 1990 to July 2001 retrieved from MEDLINE and CANCERLIT.
Recommendations
· Routine use of HRT (either estrogen alone or estrogen plus progesterone) is not recommended for women who have had breast cancer. Randomized controlled trials are required to guide recommendations for this group of women. Women who have had breast cancer are at risk of recurrence and contralateral breast cancer. The potential effect of HRT on these outcomes in women with breast cancer has not been determined in methodologically sound studies. However, in animal and in vitro studies, the development and growth of breast cancer is known to be estrogen dependent. Given the demonstrated increased risk of breast cancer associated with HRT in women without a diagnosis of breast cancer, it is possible that the risk of recurrence and contralateral breast cancer associated with HRT in women with breast cancer could be of a similar magnitude. · Postmenopausal women with a previous diagnosis of breast cancer who request HRT should be encouraged to consider alternatives to HRT. If menopausal symptoms are particularly troublesome and do not respond to alternative approaches, a well-informed woman may choose to use HRT to control these symptoms after discussing the risks with her physician. In these circumstances, both the dose and the duration of treatment should be minimized.
Validation
Internal validation within the Steering Committee on Clinical Practice Guidelines for the Care and Treatment of Breast Cancer; no external validation.
Sponsor
The steering committee was convened by Health Canada.
Completion date
October 2001.
PMCID: PMC100875  PMID: 12002977
17.  Experiences of a long-term randomized controlled prevention trial in a maiden environment: Estonian Postmenopausal Hormone Therapy trial 
Background
Preventive drugs require long-term trials to show their effectiveness or harms and often a lot of changes occur during post-marketing studies. The purpose of this article is to describe the research process in a long-term randomized controlled trial and discuss the impact and consequences of changes in the research environment.
Methods
The Estonian Postmenopausal Hormone Therapy trial (EPHT), originally planned to continue for five years, was planned in co-operation with the Women's International Study of Long-Duration Oestrogen after Menopause (WISDOM) in the UK. In addition to health outcomes, EPHT was specifically designed to study the impact of postmenopausal hormone therapy (HT) on health services utilization.
Results
After EPHT recruited in 1999–2001 the Women's Health Initiative (WHI) in the USA decided to stop the estrogen-progestin trial after a mean of 5.2 years in July 2002 because of increased risk of breast cancer and later in 2004 the estrogen-only trial because HT increased the risk of stroke, decreased the risk of hip fracture, and did not affect coronary heart disease incidence. WISDOM was halted in autumn 2002. These decisions had a major influence on EPHT.
Conclusion
Changes in Estonian society challenged EPHT to find a balance between the needs of achieving responses to the trial aims with a limited budget and simultaneously maintaining the safety of trial participants. Flexibility was the main key for success. Rapid changes are not limited only to transiting societies but are true also in developed countries and the risk must be included in planning all long-term trials.
The role of ethical and data monitoring committees in situations with emerging new data from other studies needs specification. Longer funding for preventive trials and more flexibility in budgeting are mandatory. Who should prove the effectiveness of an (old) drug for a new preventive indication? In preventive drug trials companies may donate drugs but they take a financial risk, especially with licensed drugs. Public funding is crucial to avoid commercial biases. Legislation to share the costs of large post-marketing trials as well as regulation of manufacturer's participation is needed. [ISRCTN35338757]
doi:10.1186/1471-2288-8-51
PMCID: PMC2529341  PMID: 18673555
18.  Breast Cancer after Use of Estrogen plus Progestin in Postmenopausal Women 
The New England journal of medicine  2009;360(6):573-587.
BACKGROUND
Following the release of the 2002 report of the Women’s Health Initiative (WHI) trial of estrogen plus progestin, the use of menopausal hormone therapy in the United States decreased substantially. Subsequently, the incidence of breast cancer also dropped, suggesting a cause-and-effect relation between hormone treatment and breast cancer. However, the cause of this decrease remains controversial.
METHODS
We analyzed the results of the WHI randomized clinical trial — in which one study group received 0.625 mg of conjugated equine estrogens plus 2.5 mg of medroxy-progesterone acetate daily and another group received placebo — and examined temporal trends in breast-cancer diagnoses in the WHI observational-study cohort. Risk factors for breast cancer, frequency of mammography, and time-specific incidence of breast cancer were assessed in relation to combined hormone use.
RESULTS
In the clinical trial, there were fewer breast-cancer diagnoses in the group receiving estrogen plus progestin than in the placebo group in the initial 2 years of the study, but the number of diagnoses increased over the course of the 5.6-year intervention period. The elevated risk decreased rapidly after both groups stopped taking the study pills, despite a similar frequency of mammography. In the observational study, the incidence of breast cancer was initially about two times as high in the group receiving menopausal hormones as in the placebo group, but this difference in incidence decreased rapidly in about 2 years, coinciding with year-to-year reductions in combined hormone use. During this period, differences in the frequency of mammography between the two groups were unchanged.
CONCLUSIONS
The increased risk of breast cancer associated with the use of estrogen plus progestin declined markedly soon after discontinuation of combined hormone therapy and was unrelated to changes in frequency of mammography.
doi:10.1056/NEJMoa0807684
PMCID: PMC3963492  PMID: 19196674
19.  The effects of postmenopausal hormone therapy on serum estrogen, progesterone and sex hormone binding globulin levels in healthy post-menopausal women 
Menopause (New York, N.Y.)  2010;17(3):622-629.
Objective
Differences in disease outcomes between users and non-users of hormone therapy (HT) and between users of estrogen alone (ET) and users of estrogen plus progesterone therapy (EPT) may relate to differences in serum hormone concentrations between these populations. In this study, we examine the response of serum hormone levels in healthy post-menopausal women after one year of HT.
Methods
A representative sub-sample of 200 healthy adherent participants from the active and placebo groups of the Women's Health Initiative randomized, controlled clinical trials of ET (conjugated equine estrogen 0.625 mg daily) or EPT (ET plus medroxyprogesterone actetate 2.5 mg daily) were selected for determination of selected sex hormone levels at baseline and one year after randomization.
Results
In participants receiving active ET intervention compared to placebo, estrogenic hormone levels increased from baseline to year 1 by 3.6-fold for total estrone, 2.7-fold for total estradiol, and 1.8-fold for bioavailable and free estradiol concentrations. Serum SHBG concentrations also increased 2.5-fold. In contrast, progesterone levels decreased slightly in women taking exogenous EPT. The response of serum estrogens and SHBG did not differ substantially with the addition of progesterone. In subgroup analyses, hormone response varied by age, ethnicity, BMI, smoking, vasomotor symptoms, and baseline hormone levels.
Conclusions
These data provide a reference point for the serum hormone response to HT, and demonstrate that response of serum estrogens is similar for ET and EPT. The implications of the slight decrease in serum progesterone levels with EPT therapy are uncertain. Potential treatment interactions for estrogenic hormones were identified, which suggest a larger response to HT in women with low endogenous levels.
doi:10.1097/gme.0b013e3181cb49e9
PMCID: PMC2866828  PMID: 20215977
Hormone therapy; estrogen; progesterone; estradiol; hormone levels; sex hormone binding globulin; Women's Health Initiative
20.  Hypnosis for hot flashes among postmenopausal women study: A study protocol of an ongoing randomized clinical trial 
Background
Hot flashes are a highly prevalent problem associated with menopause and breast cancer treatments. The recent findings from the Women's Health Initiative have important implications for the significance of a non-hormonal, mind-body intervention for hot flashes in breast cancer survivors. Women who take hormone therapy long-term may have a 1.2 to 2.0 fold increased risk of developing breast cancer. In addition, it is now known that hormone therapy with estrogen and progestin is associated with increased risk of cardiovascular disease and stroke. Currently there are limited options to hormone replacement therapy as non-hormonal pharmacological agents are associated with only modest activity and many adverse side effects. Because of this there is a need for more alternative, non-hormonal therapies. Hypnosis is a mind-body intervention that has been shown to reduce self-reported hot flashes by up to 68% among breast cancer survivors, however, the use of hypnosis for hot flashes among post-menopausal women has not been adequately explored and the efficacy of hypnosis in reducing physiologically measured hot flashes has not yet been determined.
Methods/design
A sample of 180 post-menopausal women will be randomly assigned to either a 5-session Hypnosis Intervention or 5-session structured-attention control with 12 week follow-up. The present study will compare hypnosis to a structured-attention control in reducing hot flashes (perceived and physiologically monitored) in post-menopausal women in a randomized clinical trial. Outcomes will be hot flashes (self-report daily diaries; physiological monitoring; Hot Flash Related Daily Interference Scale), anxiety (State-Trait Anxiety Inventory; Hospital Anxiety and Depression Scale (HADS); anxiety visual analog scale (VAS rating); depression (Center for Epidemiologic Studies Depression Scale), sexual functioning (Sexual Activity Questionnaire), sleep quality (Pittsburgh Sleep Quality Index) and cortisol.
Discussion
This study will be the first full scale test of hypnosis for hot flashes; one of the first studies to examine both perceived impact and physiologically measured impact of a mind-body intervention for hot flashes using state-of-the-art 24 hour ambulatory physiological monitoring; the first study to examine the effect of hypnosis for hot flashes on cortisol; and the first investigation of the role of cognitive expectancies in treatment of hot flashes in comparison to a Structured-Attention Control.
Trial Registration
This clinical trial has been registered with ClinicalTrials.gov, a service of the U.S. National Institutes of Health, ClinicalTrials.gov Identifier: NCT01293695.
doi:10.1186/1472-6882-11-92
PMCID: PMC3200173  PMID: 21989181
21.  The effects of red clover on quality of life in post-menopausal women 
Background:
Due to symptoms and its complications, menopause influences the mental, psychological and physical health, social performance and familial relationships. Because of the undesirable side effects of hormone replacement therapy, tendency and desire toward alternative treatments in relieving menopausal symptoms have increased. Among the alternative therapies are herbs and among those, herbs with phytoestrogens are more preferable. Red clover is a rich source of phytoestrogens. The present study investigated the effect of red clover on quality of life in post-menopausal women.
Materials and Methods:
In a randomized, triple-blind, placebo-controlled clinical trial, 72 menopausal women who at least obtained 15 scores in Kupperman Menopausal Index, after two weeks of monitoring, were randomly allocated to receive either placebo or 45 mg of red clover isoflavones for eight weeks. Before the treatment and at the end of the study, menopause-specific quality of life questionnaire (MENQOL) was completed in the two groups.
Findings:
A total of 55 women completed the study, 28 subjects in red clover and 27 in placebo group. Mean score of total quality of life (p < 0.001 in both groups), mean score of quality of life in vasomotor domain (p < 0.001 in both groups), psycho-social domain (p < 0.001 in red clover and p = 0.02 in placebo group) and physical domain (p < 0.001 red clover and p = 0.01 placebo group) significantly reduced compared to the baseline values. However, the differences between two groups were significant neither for total quality of life nor for its domains. Red clover had no side effects and all the subjects in the red clover group were satisfied with the prescribed administration
Conclusions:
In the present study, the effect of red clover supplementation on menopausal women's quality of life showed no difference with the placebo. Further clinical trials are recommended.
PMCID: PMC3590693  PMID: 23493172
Menopause; phytoestrogens; quality of life; red clover; symptoms
22.  Treatment options for vasomotor symptoms in menopause: focus on desvenlafaxine 
Vasomotor symptoms (VMS), including hot flashes and night sweats, occur in as many as 68.5% of women as a result of menopause. While the median duration of these symptoms is 4 years, approximately 10% of women continue to experience VMS as many as 12 years after their final menstrual period. As such, VMS have a significant impact on the quality of life and overall physical health of women experiencing VMS, leading to their pursuance of treatment to alleviate these symptoms. Management of VMS includes lifestyle modifications, some herbal and vitamin supplements, hormonal therapies including estrogen and tibolone, and nonhormonal therapies including clonidine, gabapentin, and some of the serotonin and serotonin–norepinephrine reuptake inhibitors. The latter agents, including desvenlafaxine, have been the focus of increased research as more is discovered about the roles of serotonin and norepinephrine in the thermoregulatory control system. This review will include an overview of VMS as they relate to menopause. It will discuss the risk factors for VMS as well as the proposed pathophysiology behind their occurrence. The variety of treatment options for VMS will be discussed. Focus will be given to the role of desvenlafaxine as a treatment option for VMS management.
doi:10.2147/IJWH.S24614
PMCID: PMC3410701  PMID: 22870045
menopause; vasomotor symptoms; hot flashes; vasomotor symptom treatment; desvenlafaxine
23.  Lessons Learned From the Women’s Health Initiative Trials of Menopausal Hormone Therapy 
Obstetrics and gynecology  2013;121(1):172-176.
We re-evaluate the Women’s Health Initiative (WHI) findings and their implications for clinical practice. Menopausal hormone therapy (HT) was effective for relief of vasomotor symptoms, and the risk of coronary heart disease (CHD) tended to be reduced in women close to menopause compared to the increased risk in women more distant from menopause. In recently menopausal women, short-term absolute risks of stroke and venous thromboembolism were small. Estrogen plus progestin therapy, but not estrogen therapy (ET), increased the risk of breast cancer, with a suggestion of greater risk when initiated close to the menopause. Menopausal HT increased the risk of CHD in women more than 20 years distant from menopause, particularly in women with vasomotor symptoms. It remains unknown whether the suggestive benefit for CHD in younger women will translate into benefits or harms if menopausal HT is continued into older ages. Based on WHI data, the use of menopausal HT for fewer than 5 years is a reasonable option for the relief of moderate to severe vasomotor symptoms. The risks seen with EPT suggest careful periodic re-assessment of the ongoing therapy needs for women taking estrogen plus progestin therapy. The more favorable profile of ET allows for individualized management with respect to duration of use when symptoms persist. For both ET and estrogen plus progestin therapy the baseline risk profile of the individual woman needs to be taken into account. Menopausal HT is not suitable for long-term prevention of CHD given risks of stroke, venous thromboembolism, and breast cancer (for estrogen plus progestin therapy) found in both clinical trials and in observational studies.
PMCID: PMC3547645  PMID: 23262943
24.  Estrogenic effects of herbal medicines from Costa Rica used for the management of menopausal symptoms 
Menopause (New York, N.Y.)  2009;16(4):748-755.
Objective
Outcomes from the Women's Health Initiative have demonstrated adverse effects associated with hormone therapy (HT), and have prioritized the need to develop new alternative treatments for the management of menopause and osteoporosis. To this end, we have been investigating natural herbal medicines used by Costa Rican women to manage menopausal symptoms.
Design
Seventeen plant species were collected and extracted in Costa Rica. To establish possible mechanisms of action, and determine their potential future use for menopause or osteoporosis, the estrogenic activities of the herbal extracts were investigated in an estrogen reporter gene ERβ-CALUX® assay in U2-OS cells, and in reporter and endogenous gene assays in MCF-7 cells.
Results
Six of the plant extracts bound to the estrogen receptors. Four of the six extracts stimulated reporter gene expression in the ERβ-CALUX® assay. All six extracts modulated expression of endogenous genes in MCF-7 cells, with four extracts acting as estrogen agonists and two extracts, Pimenta dioica and Smilax domingensis, acting as partial agonist/antagonists by enhancing E2-stimulated pS2 mRNA expression, but reducing E2-stimulated PR and PTGES mRNA expression. Both P. dioica and S. domingensis induced a 2ERE-luciferase reporter gene in transient transfected MCF-7 cells, which was inhibited by the ER antagonist ICI 182780.
Conclusions
This work presents a plausible mechanism of action for many of the herbal medicines used by Costa Rican women to treat menopausal symptoms. However, it further suggests that studies of safety and efficacy are needed before these herbs should be used as alternative therapies to HT.
doi:10.1097/gme.0b013e3181a4c76a
PMCID: PMC2756988  PMID: 19424091
Costa Rica; herbal medicine; menopause; ER-CALUX; pS2; PTGES; PR; reporter gene; safety
25.  Evaluation of Salivary Flow Rate, pH and Buffer in Pre, Post & Post Menopausal Women on HRT 
Background: Climateric is considered to be a natural phase of life which by definition is the period of life starting from decline in ovarian activity until after the end of ovarian function. It is accompanied by various health consequences that include the changes in saliva too. This study was carried out to evaluate the salivary flow rate, pH, buffering capacity in pre-menopausal, post-menopausal and post-menopausal women on HRT.
Aims and objectives: (1) To evaluate the salivary flow rate, pH of resting saliva and stimulated saliva and buffer capacity of stimulated saliva in pre-menopausal, post-menopausal and post-menopausal women on Hormone Replacement Therapy (HRT). (2) To compare the above salivary findings between pre-menopausal, post-menopausal and post-menopausal women on HRT.
Materials and Methods: The study was carried out on 60 patients. These patients were divided into three groups of 20 patients: Group 1: Pre-menopausal women (control), Group 2: post-menopausal women (case), Group 3: post-menopausal women on HRT (case).
The control group consisted of 20 women volunteers, having regular ovulatory menstrual cycles with no known systemic illness and deleterious habits and Group 2 consists of 20 post-menopausal women and Group 3 will consist of 20 post-menopausal women on HRT.
After clearing the mouth by swallowing, stimulated saliva was collected after chewing paraffin for 10 mins in to a glass centrifuge tube graded in 0.1 mL increments up to 10mL.in rare cases the collection time will be reduced or extended (5-15 min), salivary flow rate will be determined as ml/min, immediately after collection, pH was determined by dipping pH test paper directly into the sample of oral fluid, salivary buffer capacity was determined by using saliva check buffer kit (GC corporation).
The data obtained was statistically evaluated using chi-square test, fisher exact test ANOVA analysis.
Results: In our study we found salivary flow rate significantly lower in the post-menopausal women in comparison with the menstruating women and also there was improvement in the flow rate in individuals who were on HRT, it was also observed that salivary pH of the post-menopausal group was significantly lower than that of the control group, statistically significant difference in buffer capacity values was found between the groups however buffer capacity values were higher in the post-menopausal group than the control group.
Conclusion: From the above study it is clear that post-menopausal women will present with oral discomfort, while HRT can improve the same. Hence our role as physicians and health care providers is to incorporate preventive dental health care in post-menopausal women and clearly inform patients about both the benefits and the limitations of HRT.
doi:10.7860/JCDR/2014/8158.4067
PMCID: PMC3972571
Postmenopause; Saliva & HRT; Hormonal fluctuations

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