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.
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.
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.
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.
ClinicalTrials.gov registration #NCT01089049.
herbal supplement; breast health; estrogen metabolites
Estrogen exposure and metabolism may play an important role in the development of estrogen-sensitive cancers in postmenopausal women. In this study we investigated whether past oral contraceptive (OC) administration or current dietary isoflavonoids (IF) affected expression and/or activity of steroid hormone-metabolizing cytochrome P450 (CYP) enzymes using complementary primate and cell culture models. One-hundred-eighty-one female cynomolgus macaques were randomized to receive OC or nothing for 26 months premenopausally, then ovariectomized and randomized to one of three diets for 36 months: an IF-depleted soy protein isolate (Soy−) diet, a Soy diet with IF (Soy+), or a Soy− diet supplemented with conjugated equine estrogens (CEE). Prior OC-treatment significantly reduced CYP gene expression in the mammary gland (≤60% of OC−). Dietary IFs had no effect on CYP expression, while CEE-treatment decreased CYP1A1 and increased CYP3A4 mRNA in a tissue-specific manner. For in vitro studies, we measured effects of the isoflavonoids genistein, daidzein and equol on CYP activity using intact V79 cells stably transfected to express CYP1A1, CYP1B1, or CYP3A4. All three IFs significantly altered CYP activity in a dose-dependent and isoform-specific manner (20–95% inhibition vs. controls). These results suggest potential mechanisms for prior OC and dietary IF effects on cancer risk in estrogen-responsive tissues.
estrogen metabolism; cytochrome P450; oral contraceptive; isoflavonoids; mammary gland; Macaca fascicularis
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.
estrogen; phytoestrogens; estrogen receptor; endothelium; vascular smooth muscle; hypertension; progesterone; testosterone
The potential effects of oral contraceptive (OC) and post-menopausal hormone (PMH) use are not well understood among BRCA1 or BRCA2 deleterious mutation carriers with a history of breast cancer. In this study, we investigated the association between OC and PMH use and risk of contralateral breast cancer (CBC) in the WECARE (Women’s Environment, Cancer and Radiation Epidemiology) Study. The WECARE Study is a population-based case-control study of 705 women with asynchronous CBC and 1,398 women with unilateral breast cancer, including 181 BRCA1/2 mutation carriers. Risk factor information was assessed by telephone interview. Mutation status was measured using denaturing high-performance liquid chromatography followed by direct sequencing in all participants. Outcomes, treatment and tumor characteristics were abstracted from medical records. Ever use of OCs was not associated with risk among non-carriers (RR=0.87; 95% CI=0.66–1.15) or BRCA2 carriers (RR=0.82; 95% CI=0.21–3.13). BRCA1 carriers who used OCs had a non-significant greater risk than non-users (RR=2.38; 95% CI=0.72–7.83). Total duration of OC use and at least five years of use before age 30 were associated with a non-significant increased risk among mutation carriers, but not among non-carriers. Few women had ever used PMH and we found no significant associations between lifetime use and CBC risk among carriers and non-carriers. In conclusion, the association between OC/PMH use and risk of CBC does not differ significantly between carriers and non-carriers; however, because carriers have a higher baseline risk of second primaries even a potential small increase in risk as a result of OC use may be clinically relevant.
breast cancer; asynchronous bilateral; contralateral; oral contraceptives; postmenopausal hormones; BRCA1; BRCA2
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.
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.
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.
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
Menopause; botanical supplements; dietary supplements
Estrogen metabolism may play an important role in mammary carcinogenesis in postmenopausal women. We evaluated the effects of prior oral contraceptive (OC) treatment and current soy isoflavone consumption on endogenous estrogen metabolite concentration and biomarkers of tissue estrogen exposure in a monkey model. One hundred eighty-one female cynomolgus macaques were randomized to receive OC or placebo for 26 months premenopausally, then ovariectomized and randomized to one of three diets for 36 months: an isoflavone-depleted soy protein isolate (Soy−) diet, a diet containing soy protein isolate with a human equivalent of 129 mg isoflavone/d (Soy+), or a Soy− diet supplemented with conjugated equine estrogens (CEE+) at a human equivalent dose of 0.625 mg/d. Reverse-phase high-performance liquid chromatography directly coupled with tandem mass spectrometry was used to measure the concentrations of estrogen species in urine samples. Generally, prior OC treatment was associated with significantly reduced urinary estrogen metabolites (25–55% reduction; P < 0.05 for each versus OC−). Animals that consumed isoflavones postmenopausally had increased urinary 2-hydroxyestrone and 16α-hydroxyestrone (50% and 56% increases, respectively), but reduced levels of 2-hydroxyestradiol, 2-methoxyestradiol, and 17-epiestriol (92%, 63%, and 66%, respectively), compared with animals fed a Soy− diet. Isoflavones did not have widespread effects on uterine or mammary proliferation biomarkers, whereas prior OC significantly reduced two of three proliferation end points in the endometrium. Premenopausal OCs may have long-term systemic effects on response to estrogen and its metabolism whereas postmenopausal dietary isoflavones may alter endogenous estrogen metabolism in a modest but selective manner.
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).
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.
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.
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.
Contraceptive hormones, most commonly prescribed as oral contraceptives (OC), are a widely utilized method to prevent ovulation, implantation and therefore pregnancy. The Women’s Health Initiative demonstrated cardiovascular risk linked to menopausal hormone therapy among women without pre-existing cardiovascular disease, prompting review of the safety, efficacy and side effects of other forms of hormone therapy. A variety of basic science, animal and human data suggest that contraceptive hormones have anti-atheromatous effects, however relatively less is known regarding the impact on atherosclerosis, thrombosis, vasomotion and arrhythmogenesis. Newer generation OC formulations currently in use indicate no increased myocardial infarction (MI) risk for current users, but a persistent increased risk of venous thrombo-embolism (VTE). There are no cardiovascular data available for the newest generation contraceptive hormone formulations, including those that contain newer progestins that lower blood pressure, as well as the non-oral routes (topical and vaginal). Current guidelines indicate that, as with all medication, contraceptive hormones should be selected and initiated by weighing risks and benefits for the individual patient. Women 35 years and older should be assessed for cardiovascular risk factors including hypertension, smoking, diabetes, nephropathy and other vascular diseases including migraines, prior to use. Existing data are mixed with regard to possible protection from OC for atherosclerosis and cardiovascular events; longer-term cardiovascular follow-up of menopausal women with regard to prior OC use, including subgroup information regarding adequacy of ovulatory cycling, the presence of hyperandrogenic conditions, and the presence of prothrombotic genetic disorders is needed to address this important issue.
Hormones; Contraception; Cardiovascular Disease
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.
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.
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.
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).
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.
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.
alternative to HRT; blood hormones; Maca (Lepidium peruvianum); perimenopause
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.
tissue selective estrogen complex; menopause; bone mineral density; bone turnover markers; climacteric symptoms
during adulthood, most studies have reported that oral contraceptive (OC) pills had neutral, or possibly beneficial effect on bone health. We proposed this study of pre and post menopausal women assessing BMD, bone biochemical markers and physical performance among OC past users and comparable women who have never use Ocs.
A cross-sectional study comparing the bone density, bone biochemical markers (osteocalcin, CTX) and three measures to assess physical performance: timed get-up-and-go test "TGUG", five-times-sit-to-stand test "5 TSTS" and 8-feet speed walk "8 FSW" of users and never users OC. We were recruited 210 women who used OC for at least 2 years with that of 200 nonusers was carried out in pre and postmenopausal women (24-86 years).
when analysing the whole population, BMD and biochemical markers values were similar for Ocs past users and control subjects. However when analysing the subgroup of premenopausal women, there was a statistically significant difference between users and never-users in osteocalcin (15,5 ± 7 ng/ml vs 21,6 ± 9 ng/ml; p = 0,003) and CTX (0,30 ± 0,1 ng/ml vs 0,41 ± 0,2 ng/ml; p = 0,025). This difference persisted after adjustment for age, BMI, age at menarche and number of pregnancies. In contrast, in post menopausal women, there was no difference in bone biochemical markers between OC users and the control. On the other hand OC past users had a significant greater performance than did the never users group. And when analysing the physical performance tests by quartile OC duration we found a significant negative association between the three tests and the use of OC more than 10 years.
the funding show no evidence of a significant difference in BMD between Ocs users and never user control groups, a decrease in bone turn over in OC pre menopausal users and a greater physical performances in patients who used OC up than 10 years.
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.
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.
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.
The study is registered at the Netherlands Trial Register (NTR1165) and ClinicalTrials.gov (NCT00582244).
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.
sex hormones; progesterone; testosterone; phytoestrogens; estrogen receptor; endothelium; vascular smooth muscle; hypertension
Emergency contraception (EC) can prevent unintended pregnancy. However, many women continue to lack information needed to use EC effectively and clinician time to counsel women about EC is limited.
To evaluate whether computer-assisted provision of EC can increase knowledge and use of EC among women able to access EC without a prescription.
We conducted a randomized controlled trial in which the intervention group received a 15-minute computerized educational session and 1 pack of EC. The control group received education about periconception folate supplementation, but no information about EC. Participants were contacted 7 months after enrollment.
Four hundred forty-six women recruited from 2 urgent care clinics in San Francisco in 2005.
Knowledge of EC, use of EC, and self-reported pregnancy.
At follow-up, women in the intervention group answered an average of 2 more questions about EC correctly than they had at baseline, whereas women in the control group answered only 1 more item correctly (2.0 vs 1.2, p < .001). There was a trend toward more use of EC during the study period in the intervention group (10% vs 4% of women followed, p = .06; 6% vs 3%, p = .09 of women enrolled). Fewer women in the intervention group were pregnant at the time of follow-up (0.8% vs 6.5%, p = .01 of women followed; 0.5% vs 4.0%, p = .01 of women enrolled).
Computer-assisted provision of EC in urgent care waiting areas increased knowledge of EC in a state where EC had been available without a prescription for 3 years.
women’s health; computerized counseling; contraception; emergency contraception
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.
estrogen; menopause; blood pressure; diabetes; lipids; hypertension
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.
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.
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).
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.
soy foods; isoflavones; estradiol; sex hormone-binding globulin; gonadotrophins
One of the biggest problem today that most developing countries are faced with is the uncontrolled population growth; a serious threat to the international community. One of the most accessible contraceptive methods is the hormonal methods in which low-dose estrogen (LD) combined pills are considered as the most common among them. The most important reason for discontinuation of the combination pills is the side effects and following the discontinuation, it can lead to unwanted pregnancy. Promotion of more new methods and providing better methods with lesser side effects can be an important step towards solving some of the problems and increasing the usage percentages of contraceptive methods. This study therefore aimed to compare the effects of Yasmin and LD on menstrual cycle changes.
In this clinical trial study, 60 women referred to the Family Planning Health Center of Isfahan in 2008 were studied that finally after the sample loss, 27 and 24 samples were placed in Yasmin and LD groups, respectively. A questionnaire was used in order to collect the data. Content validity test and re-test also were used to confirm the validity and reliability of the questionnaire. To analyze the data, SPSS software and descriptive and inferential statistical methods were used.
The results of this study indicated that the bleeding rate in the Yasmin group within the next six month compared to taking them before was significantly lower than that in LD group (p = 0.02); but there was no significant difference in terms of menstrual bleeding duration and the two menstruation interval between the two groups (p = 0.2). There was no significant difference between the Yasmin and LD groups in terms of delay in menstruation and dysmenorrheal. Spotting rate significantly was higher in Yasmin group than that in LD group (p = 0.02). There was a significant reduction in terms of bleeding rate changes and menstrual bleeding duration in both Yasmin and LD group at the following next six months in comparison with before the consumption (p < 0.05).
According to the results obtained, the oral combination of Yasmin pills has fewer side effects than LD pills. Therefore, it is recommended to start using Yasmin pill in the family planning units in Iran.
LD; side effects; contraceptive pill; Yasmin
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.
Black cohosh; botanical; complementary and alternative medicine; estrogen; inflammatory; nitric oxide
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.
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
Folate is a generic term for a water-soluble B-complex vitamin which plays an important role in protein synthesis and metabolism and other processes related to cell multiplication and tissue growth. Pregnant and lactating women are at increased risk of folic acid deficiency because generally their dietary folate is insufficient to meet their physiological requirements and the metabolic demands of the growing fetus. The evidence pertaining to the reduction of the risk of neural tube defects (NTDs) due to folate is so compelling that supplementation with 400 μg of folic acid to all women trying to conceive until 12 weeks of pregnancy has been recommended by every relevant authority. A recent Cochrane review has also found protective effects of folate supplementation in occurrence and reoccurrence of NTDs. Despite food fortification and targeted public health campaigns promoting folic acid supplementation, 4,300,000 new cases occur each year worldwide resulting in an estimated 41,000 deaths and 2.3 million disability-adjusted life years (DALYS). This article will review the burden and risk factors of NTDS, and the role of folate in preventing NTDs. It will also describe different modes of supplementing folate and the newer evidence of the effectiveness of adding folate in oral contraceptives for raising serum and red blood cell folate levels.
folate; folate-containing oral contraceptives; oral contraceptives; contraceptives
Progesterone receptor modulators (PRMs) delivered by contraceptive vaginal rings provide an opportunity for development of an estrogen-free contraceptive that does not require daily oral intake of steroids. The objective of this proof-of-concept study was to determine whether continuous delivery of 600–800 mcg of ulipristal acetate (UPA) from a contraceptive vaginal ring could achieve 80% to 90% inhibition of ovulation.
This was a prospective, controlled, open-labeled, multicenter international trial to examine the effectiveness and safety of this prototype vaginal ring. Thirty-nine healthy women, 21–40 years old and not at risk of pregnancy, were enrolled at three clinic sites. Volunteers participated in a control cycle, a 12-week treatment period and a post-treatment cycle. Pharmacodynamic effects on follicular function and inhibition of ovulation, effects on endometrium, bleeding patterns and serum UPA levels were evaluated.
Mean UPA levels during treatment were nearly constant, approximately 5.1 ng/mL throughout the study. Ovulation was documented in 32% of 111 “4-week treatment cycles.” A correlation was observed between serum UPA and degree of inhibition of ovarian activity. There was no evidence of hyperplasia of endometrium, but PRM-associated endometrial changes were frequently observed (41%).
In this study, the minimum effective contraceptive dose was not established. Further studies are required testing higher doses of UPA to attain ovulation suppression in a higher percentage of subjects.
Progesterone receptor modulators; Ulipristal acetate; Contraceptive vaginal ring; Ovulation inhibition; Follicular development; PRM-associated endometrial changes
Removal or impairment of ovaries before menopause may affect a woman's breast cancer risk by altering her cumulative exposure to ovarian hormones. The Women's Contraceptive and Reproductive Experiences Study, a population-based, multicenter case-control study of incident invasive breast cancer, recruited women aged 35–64 years (4,490 cases and 4,611 controls) who provided data on ovariectomy, hysterectomy, and tubal sterilization during in-person interviews. Controls were frequency-matched to cases by age, race, and study site. Unconditional logistic regression analysis was used. Women who had not undergone premenopausal reproductive surgery were the referent group. Bilateral ovariectomy was associated with reduced breast cancer risk overall (odds ratio (OR) = 0.59, 95% confidence interval (CI): 0.50, 0.69) and among women <45 years of age (ORs ranged from 0.31 to 0.52), but not among those who were older at surgery. It was also associated with a reduced risk for estrogen and progesterone receptor–positive tumors (OR = 0.63, 95% CI: 0.52, 0.75) but not receptor-negative tumors. Hysterectomy with ovarian conservation (OR = 0.83, 95% CI: 0.72, 0.96) and hysterectomy with partial ovary removal (OR = 0.73, 95% CI: 0.59, 0.91) were also associated with lower risk. No association with breast cancer risk was observed with tubal sterilization only or partial ovariectomy without hysterectomy. Reproductive organ surgeries may alter ovarian hormone levels, thereby affecting breast cancer risk.
breast neoplasms; case-control studies; hysterectomy; ovariectomy; sterilization, tubal
We describe the rationale and protocol for a randomized controlled trial (RCT) to assess whether intrauterine contraception placed immediately after a second trimester abortion will result in fewer pregnancies than current recommended practice of intended placement at 4 weeks post-abortion. Decision analysis suggests the novel strategy could substantially reduce subsequent unintended pregnancies and abortions. This paper highlights considerations of design, implementation and evaluation of a trial expected to provide rigorous evidence for appropriate insertion timing and health economics of intrauterine contraception after second trimester abortion.
Consenting women choosing to use intrauterine contraception after abortion for a pregnancy of 12 to 24 weeks will be randomized to insertion timing groups either immediately (experimental intervention) or four weeks (recommended care) post abortion. Primary outcome measure is pregnancy rate at one year. Secondary outcomes include: cumulative pregnancy rates over five year follow-up period, comprehensive health economic analyses comparing immediate and delayed insertion groups, and device retention rates, complication rates (infection, expulsion) and, contraceptive method satisfaction. Web-based Contraception Satisfaction Questionnaires, clinical records and British Columbia linked health databases will be used to assess primary and secondary outcomes. Enrolment at all clinics in the province performing second trimester abortions began in May 2010 and is expected to complete in late 2011. Data on one year outcomes will be available for analysis in 2014.
The RCT design combined with access to clinical records at all provincial abortion clinics, and to information in provincial single-payer linked administrative health databases, birth registry and hospital records, offers a unique opportunity to evaluate such an approach by determining pregnancy rate at one through five years among enrolled women. We highlight considerations of design, implementation and evaluation of a trial expected to provide rigorous evidence for appropriate insertion timing and health economics of intrauterine contraception after second trimester abortion.
Current Controlled Trials ISRCTN19506752
Obese women have higher rates of pregnancy complications, making the prevention of unintended pregnancies in this group of particular importance.
We performed a secondary analysis of data from Active Mothers Postpartum (AMP), a randomized controlled trial aimed at postpartum weight reduction. We assessed contraceptive use among 361 overweight/obese women 12 months postpartum. Logistic regression was used to model the effect of BMI categories on effective contraceptive use (intrauterine, hormonal, or sterilization methods) while adjusting for potential confounders including age, race, parity, breastfeeding, education, and chronic illness.
Effective contraceptive use was reported by 45% of women. In the multivariable model, women with a BMI ≥ 35 kg/m2 were less likely to use effective contraception than women with a BMI <30 kg/m2 (OR 0.5, 95% CI 0.3–0.8). There was a trend towards less use of effective contraception among women with a BMI 30–34.9 kg/m2 as compared to women with a BMI <30 kg/m2.
At 12 months postpartum, obese women were less likely to use effective contraceptive methods than overweight women. Although certain contraceptive methods may be preferred over others in this population, providers should reinforce the importance of effective contraception to avoid unintended pregnancies in obese women.