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“Risks and Benefits of Estrogen Plus Progestin in Healthy Postmenopausal Women: Principal Results From the Women's Health Initiative Randomized Controlled Trial” Writing Group for the Women's Health Initiative Investigators (WHI) JAMA 2002 288 3 321 333 10.1001/jama.288.3.321
... This highlights the importance of developing new antiprogestins with high specificity and lower toxicity than those currently available. The fact that progestins have been shown to increase breast cancer risk [187,188], and that antiprogestins, such as MFP, were shown to act as PR agonists in PRB contexts [189] may be some of the reasons to explain the hampered interest in PR ligands. Nowadays, the attention has been focused on exploring new targets that might be used together with standard endocrine therapy. ...
Progesterone receptors (PR) play a pivotal role in many female reproductive tissues such as the uterus, the ovary, and the mammary gland (MG). Moreover, PR play a key role in breast cancer growth and progression. This has led to the development and study of different progestins and antiprogestins, many of which are currently being tested in clinical trials for cancer treatment. Recent reviews have addressed the role of PR in MG development, carcinogenesis, and breast cancer growth. Thus, in this review, in addition to making an overview on PR action in normal and tumor breast, the focus has been put on highlighting the still unresolved topics on hormone treatment involving PR isoforms and breast cancer prognosis.
... It would be of great clinical value to know whether estrogens and progestogens actually are harmless when it comes to recurrence risk in TNBC patients. While generally considered detrimental for ER-positive BC patients based on prospective studies [4][5][6], hormonal replacement therapy (HRT) could still be an option for HR-negative BC/TNBC patients, many of whom are young and at high risk of premature ovarian insufficiency (POI) due to toxicity of chemotherapy [7]. The excess morbidity, and perhaps even mortality [8], associated with iatrogenic/early menopause warrants a careful re-examination of the feasibility of HRT for these patients. ...
Triple-negative breast cancers (TNBC) occur more frequently in younger women and do not express estrogen receptor (ER) nor progesterone receptor (PR), and are therefore often considered hormone-insensitive. Treatment of premenopausal TNBC patients almost always includes chemotherapy, which may lead to premature ovarian insufficiency (POI) and can severely impact quality of life. Hormone replacement therapy (HRT) is contraindicated for patients with a history of hormone-sensitive breast cancer, but the data on safety for TNBC patients is inconclusive, with a few randomized trials showing increased risk-ratios with wide confidence intervals for recurrence after HRT. Here, we review the literature on alternative pathways from the classical ER/PR. We find that for both estrogens and progestogens, potential alternatives exist for exerting their effects on TNBC, ranging from receptor conversion, to alternative receptors capable of binding estrogens, as well as paracrine pathways, such as RANK/RANKL, which can cause progestogens to indirectly stimulate growth and metastasis of TNBC. Finally, HRT may also influence other hormones, such as androgens, and their effects on TNBCs expressing androgen receptors (AR). Concluding, the assumption that TNBC is completely hormone-insensitive is incorrect. However, the direction of the effects of the alternative pathways is not always clear, and will need to be investigated further.
Purpose
To present a case with a woman with Turner syndrome (TS) with acromegaly and breast cancer, in her medical history.
Method
A descriptive case report of a single patient.
Results
The woman had short stature and lack of puberty and was not treated with hormones. When she was 36-year-old, acromegaly was diagnosed. She was treated with transsphenoidal surgery, followed by external radiation on the adenoma, without any affection on the pituitary gland. Annual controls revealed ordinary pituitary axes during 40 years’ follow-up. She was treated for hypertension, had an aortic dilatation and started menopausal hormone therapy (MHT),1 mg estradiol and 0.5 mg norethisterone acetate daily, at the age of 50, due to osteoporosis. At the age of 60, she was diagnosed with breast cancer at the mammography screening. After, mastectomy, neoadjuvant radiation, and treatment with tamoxifen citrate were given due to the tubular breast cancer.
Conclusions
Despite a possible growth hormone (GH) resistance and lack of endogenous estradiol in women with TS, this patient was diagnosed with acromegaly and breast cancer. This case demonstrates the potential for co-occurring two hormonally active tumors in a woman with TS with monosomy karyotype.
Objective
To evaluate the actual perceptions of postmenopausal hormone therapy (HT) in BRCA mutation carriers (BRCAmc) in comparison with women from the general population.
Methods
Questionnaire-based study of 83 BRCAmc and a control group of 89 women without a genetic mutation. Perceptions were evaluated by specific questions and Likert scales (- 5 to + 5).
Results
Present and past users of HT were more frequent in the control group (p=0.01), with a longer time of use (p=0.03). The preferred route of administration of HT was “oral” (54.6%). The most frequently reported adverse effect of HT was venous thrombosis (0.8), while a protective effect on bone health was reported. No noticeable beneficial effects of HT have been recognised for hot flushes (0.2) and vaginal dryness (0.1). The most frequently perceived beneficial and adverse effects of HT were not significantly different between BRCA mutation carriers and controls. The greatest oncological fear was breast cancer (1.0). The protective role of HT on colorectal cancer was not known (0.1). These oncological impacts were mostly overestimated in BRCAmc, however this was not significant. Few BRCAmc would think of taking HT after risk-reducing surgeries.
Conclusions
Knowledge of the effects of HT on BRCAmc is relatively poor and they are likely to overstate its negative effects and underestimate its health benefits; however, this is not significant in comparison to the general population. More and better information should be given to BRCAmc to allow them to make informed decisions about the use of HT, especially before undergoing risk-reducing surgeries.
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Background:
Among non-hormonal treatments, herbal products are frequently used by women. Korean red ginseng (KRG) is one of the popular herbal medicines. KRG could be one option for relieving menopausal symptoms. However, there are still concerns about the safety for long-term use. In order to be used for alleviating menopausal symptoms, the safety of KRG on breast must be ensured. The purpose of this study was to investigate the effects of KRG on breast cells.
Methods:
MCF-7 and MCF-10A cells were treated with different concentrations of KRG extracts for 48 h. Cell viability was evaluated by MTT assay, and apoptosis by flow cytometry. The expression of apoptosis-related proteins was determined by western blot analysis and estrogen receptor (ER) affinity by ER binding assay.
Results:
KRG extract inhibited growth and induced apoptosis of both MCF-7 and MCF-10A cells in dose-dependent manner. KRG extract increased the expression of pro-apoptotic proteins BAX, BAK, and BAD and decreased the expression of anti-apoptotic proteins Bcl-2 and Bcl-XL in both cells. The expressions of Fas and FasL were increased in lower doses, but decreased in higher doses in both cells. Activities of caspase-3, -8 and -9 increased in MCF-10A, while caspase-8 and -9 showed increase in MCF-7. Competition of KRG to E2 was significant in MCF-7 as KRG dose increased, whereas ER binding was hardly shown in MCF-10.
Conclusion:
KRG induced apoptosis via extrinsic and intrinsic pathway in MCF-7 breast cancer cells and MCF-10A non-malignant cells. KRG may be safely used with regard to breast cancer risk in postmenopausal women to reduce the vasomotor symptoms.
Introduction: Menopausal symptoms can be very overwhelming for women. Over the years, many pharmacotherapeutic options have been tested, and others are still being developed. Hormone therapy (HT) is the most efficient therapy for managing vasomotor symptoms and related disturbances. The term HT comprises estrogens and progestogens, androgens, tibolone, the tissue-selective estrogen complex (TSEC), a combination of bazedoxifene and conjugated estrogens, and the selective estrogen receptor modulators, such as ospemifene. Estrogens and progestogens and androgens may differ significantly for chemical structure and can be delivered through different routes, thereby displaying various pharmacological and clinical properties. Tibolone, TSEC and SERM also exhibit unique pharmacodynamics that can be exploited to obtain distinctive therapeutic effects. Non-hormonal options fall mainly into the selective serotonin reuptake inhibitor (SSRI) and selective noradrenergic reuptake inhibitor (SNRI), GABA-analogue drug classes.
Areas covered: Herein, the authors describe the pharmacokinetics and pharmacodynamics of hormonal (androgens, estrogens, progestogens, tibolone, TSEC, SERMs) and non-hormonal (SSRIs, SNRIs, Gabapentin, Pregabalin, Oxybutynin, Neurokinin antagonists) treatments for menopausal symptoms and report essential clinical trial data in humans.
Expert opinion: Patient tailoring of treatment is key to managing symptoms of menopause. Physicians must have in-depth knowledge of the pharmacology of compounds to tailor therapy to the individual patient’s characteristics and needs.
NAFLD/NASH is a sex dimorphic disease, with a general higher prevalence in men. Women are at reduced risk of NAFLD compared to men in fertile age, whereas after menopause women have a comparable prevalence of NAFLD as men. Indeed, sexual category, sex hormones and gender habits interact with numerous NAFLD factors including cytokines, stress, and environmental factors and alter the risk profiles and phenotypes of NAFLD. In the present review, we summarized the last findings about the influence of sex on epidemiology, pathogenesis, progression in cirrhosis, indication for liver transplantation and alternative therapies, including life styles modification and pharmacological strategies. We are confident that an appropriate consideration of sex, age, hormonal status, and sociocultural gender differences will lead to a better understanding of sex differences in NAFLD risk, therapeutic targets, and treatment responses and will aid in achieving sex‐specific personalized therapies.
Successful aging includes good health and low levels of disability. To that end, primary prevention is far better than managing subsequent organ damage. When medication is needed to prevent or manage disease, the preferred choice should be associated with the greatest benefits and fewest adverse effects. Cardiovascular diseases are the leading cause of morbidity and mortality in postmenopausal women worldwide. Considering disease-adjusted life years, other leading causes are chronic obstructive pulmonary disease, diabetes mellitus, dementias, hearing loss, cancers of the breast, lung and bowel, osteoporosis, fractures and falls, depression, osteoarthritis, refractive errors of the eye and non-diabetic chronic kidney disease. This review explores the global prevalence of these diseases in women aged 50 years and older, and medications commonly used for them, and contrasts the effects of menopausal hormone therapy (MHT) with others. When initiated early, there is good evidence for MHT benefit in all-cause mortality and primary prevention of cardiovascular disease, diabetes and osteoporosis; fair evidence for benefit in dementias, depression and osteoarthritis; limited evidence for benefit in chronic obstructive pulmonary disease, hearing loss, non-diabetic chronic kidney disease and colorectal cancer; null effects on lung cancer and refractive errors; and varied effects on breast cancer and stroke. Relative benefits and adverse effects of other medications warrant consideration.
Aglycone isoflavones are estrogen‐like bioactive compounds found in low amounts in soybean, which are increased by biotransformation processes. This study investigated two biotransformation processes of soybean extracts with Aspergillus awamori fungus, evaluating aglycone content and capability of stimulation of collagen‐I deposition. Isoflavones were quantified via HPLC; cytotoxicity of biotransformed extracts towards mouse and human fibroblasts was evaluated via NRU and apoptosis/necrosis assays; and collagen‐I deposition was measured through Western Blot, immunofluorescence, and immunoassay. BSE‐2 was the biotransformed soybean extract with the highest aglycone content and did not decrease viability or demonstrated cytotoxicity to either L929 or HDFa cells. BSE‐2, at the optimal concentration of 1.33μg/mL, increased substantially collagen‐I amount in HDFa intracellular matrix compared to non‐biotransformed soybean extract (NBSE) and immunoassay demonstrated that the extracellular deposition was mostly inhibited by BSE‐2 concentrations, except at 1.33μg/mL. Hence, biotransformed soybean extract by the enzymatic filtrate of Aspergillus awamori fungus demonstrated a high nutricosmetic potential, showing safeness and effective collagen‐I augmentation.
Background
Randomized controlled trials on menopausal hormone therapy in humans have not confirmed the benefit of estrogens on cardiovascular disease found in animal studies. Flawed methodology or publication bias in animal studies may explain the dicrepancy.
Objectives
The aim of this study was to investigate whether publication of the randomized controlled trials Heart and Estrogen/Progestin Replacement Study and Women’s Health Initiative influenced study authors’ assessment of research findings (confirmation bias) as well as to investigate publication bias and small‐study effects in animal studies of estrogen effects on atherosclerosis.
Methods
The data source for this study was PubMed from inception to 2018. We selected animal studies with cardiovascular outcomes comparing 17‐β‐estradiol, its natural metabolites, or conjugated equine estrogen with control. Qualitative data were extracted on authors’ conclusions about estrogen effects on cardiovascular disease, as well as quantitative data for atherosclerosis outcomes. Fixed‐ and random‐effects meta‐analyses were used. Publication bias/small‐study effects were assessed using funnel plots and Egger’s regression. Trim‐and‐fill plots and extrapolation from Egger’s regression were used to adjust for publication bias. The main outcomes and measures were the primary study authors' interpretation of their own results, and estrogen effects on cardiovascular disease in general before and after publication of the Women’s health Initiative study (2003). The effects of estrogens on atherosclerosis were measured as standardized mean difference between intervention and control.
Results
Of 1925 studies retrieved, 360 were eligible for analyses. Study‐specific statements concluded that estrogens were protective against cardiovascular disease in 75% of studies before 2003 and 78% after, but the percentage of general statements about estrogens being cardioprotective changed from 70% to 40%. Meta‐analyses showed less atherosclerosis in estrogen‐treated animals. Extremely skewed funnel plots and P < .01 in Egger’s regression suggested publication bias and/or exaggerated effects in small studies, which was more pronounced after 2002. There was substantial heterogeneity of effects (I² = 68%‐86%) overall and in all subgroups except cynomolgus monkeys (I² = 9%), the only animal subgroup without clear bias. Adjusting for publication bias, overall estimates of estrogen effects on atherosclerosis were close to null effect.
Conclusions
We found substantial evidence of publication bias but not of confirmation bias. Publication bias and flawed small studies may partly explain why findings differ between animal studies and clinical trials on the effect of estrogens on cardiovascular disease.
Introduction: Endocrine disrupting chemicals (EDCs) are chemicals that alter the actions of hormones. In the 21st Century, numerous expert groups of clinicians, scientists, and environmental activists have called for action to protect present and future generations from the harm induced by EDC exposures. These demands for regulatory responses come because of the strong weight of the evidence from epidemiology, wildlife, and controlled laboratory studies.
Areas covered: In this review, we examine the conclusions drawn by experts from different scientific and medical disciplines. We also address several areas where recent findings or work has changed the landscape of EDC work including new approaches to identify and evaluate the evidence for EDCs using a key characteristics approach, the need to expand our understanding of vulnerable periods of development, and the increasing concern that traditional methods used to evaluate toxicity of environmental chemicals are insufficient for EDCs and how collaborative science could help to address these gaps.
Expert opinion: The science is clear: there is more than enough evidence to demonstrate that EDCs affect the health of humans and wildlife. Waiting to act is a decision that puts the health of current and future generations at risk.
Hormonal contraception exposes women to synthetic progesterone receptor (PR) agonists, progestins, and transiently increases breast cancer risk. How progesterone and progestins affect the breast epithelium is poorly understood because we lack adequate models to study this. We hypothesized that individual progestins differentially affect breast epithelial cell proliferation and hence breast cancer risk. Using mouse mammary tissue ex vivo, we show that testosterone-related progestins induce the PR target and mediator of PR signaling-induced cell proliferation receptor activator of NF-κB ligand (Rankl), whereas progestins with anti-androgenic properties in reporter assays do not. We develop intraductal xenografts of human breast epithelial cells from 36 women, show they remain hormone-responsive and that progesterone and the androgenic progestins, desogestrel, gestodene, and levonorgestrel, promote proliferation but the anti-androgenic, chlormadinone, and cyproterone acetate, do not. Prolonged exposure to androgenic progestins elicits hyperproliferation with cytologic changes. Androgen receptor inhibition interferes with PR agonist- and levonorgestrel-induced RANKL expression and reduces levonorgestrel-driven cell proliferation. Thus, different progestins have distinct biological activities in the breast epithelium to be considered for more informed choices in hormonal contraception.
Due to advances in understanding the immune microenvironment of colorectal cancer (CRC), microsatellite classification (dMMR/MSI‐H and pMMR/MSS) has become a key biomarker for the diagnosis and treatment of CRC patients and therefore has important clinical value. Microsatellite status is associated with a variety of clinicopathological features and affects drug resistance and the prognosis of patients. CRC patients with different microsatellite statuses have different compositions and distributions of immune cells and cytokines within their tumor microenvironments (TMEs). Therefore, there is great interest in reversing or reshaping CRC TMEs to transform immune tolerant "cold" tumors into immune sensitive "hot" tumors. This requires a thorough understanding of differences in the immune microenvironments of MSI‐H and MSS type tumors. This review focuses on the relationship between CRC microsatellite status and the immune microenvironment. It focuses on how this relationship has value for clinical application in diagnosis and treatment, as well as exploring the limitations of its current application. The main differences of TME among different MSI types.
The regeneration potential of implantable organ model hydrogels is applied to treat a loss of ovarian endocrine function in women experiencing menopause and/or cancer therapy. A rat ovariectomy model is used to harvest autologous ovary cells while subsequently producing a layer-by-layer form of follicle spheroids. Implantation of a microchannel network hydrogel with cell spheroids [vascularized hydrogel with ovarian spheroids (VHOS)] into an ischemic hindlimb of ovariectomized rats significantly aids the recovery of endocrine function with hormone release, leading to full endometrium regeneration. The VHOS implantation effectively suppresses the side effects observed with synthetic hormone treatment (i.e., tissue overgrowth, hyperplasia, cancer progression, deep vein thrombosis) to the normal levels, while effectively preventing the representative aftereffects of menopause (i.e., gaining fatty weight, inducing osteoporosis). These results highlight the unprecedented therapeutic potential of an implantable VHOS against menopause and suggest that it may be used as an alternative approach to standard hormone therapy.
We thank the authors for taking the time to evaluate our study. While we disagree with several of their comments, we do agree with their conclusion that a randomized controlled trial would answer most of our shared concerns.
Regarding the authors’ first point, our study size indeed decreased with increasing confounding control, but this was because addition of additional control factors in effect highlighted the ways in which the treated and control populations were distinct from one another. We would argue the potential loss of external validity — that is, generalizability to a specific target population— while improving internal validity — that is, estimation of the true causal treatment effect in the study sample — is a necessary trade-off, as results that are generalizable but remain biased do not advance patient care. It’s a trade-off that exists even for randomized trials, in which many more patients are screened than are enrolled. , While this selectivity may limit generalizability, it is selection, but not selection bias. In our study, the population of our final analysis A5 is described in Table 1, with full transparency on the variable selection methodology included in the Supplement. Readers can judge whether this population is representative of their patients, as they would by inspecting the Table 1 of any randomized trial publication.
Regarding the authors’ second point, we disagree that additional covariate adjustment implies over-adjustment, which has a specific definition that includes, for example, adjusting for causal intermediates, instrumental variables, or colliders. Our study avoids such over-adjustment by design, by collecting all covariate data prior to exposure and by explicitly screening for instrumental variables and colliders. Further, with the observed point estimate of 0.99, we do not see how increased statistical power from a larger patient population would change the interpretation of the result. We also disagree that a hazard ratio of 1.72 for risk of cholelithiasis, with a confidence interval that includes the null, invalidates the inspection of this tracer outcome. The study was not powered to detect the tracer outcome, and if it were, dichotomously interpreting a 72% increased risk of cholelithiasis (0.94-3.13) as “non-existent” based on a criterion of p < 0.05 is explicitly discouraged. Rather, we are reassured by the consistent demonstration of the expected increased risk of our two tracer outcomes, cholelithiasis and B12 deficiency anemia across analyses A1 through A5.
Regarding the authors’ third point, the letter omits the key reasons why we employed an active comparator: to overcome substantial and demonstrated information imbalance in EHR data comparing patients undergoing surgery versus not (Figures S3 and S4), and to introduce a specific “time 0” inception point in the non-surgical control group. As noted above, the inclusion of an active comparator may limit generalizability, but its inclusion will not contribute to bias. Further, while the established treatment guidelines around joint replacement are thoughtful and meaningful, they are not followed consistently (Table 1). In our A5 analysis, 56.3% of arthroplasty controls had a BMI ≥40. So while these control patients may indeed be highly selected, they are as highly selected as the treated patients. We achieve the apples-to-apples comparison needed for an unbiased estimate by constructing an active comparator design, by extensive capture of risk factors, and in the application of propensity-score matching.
Taken together, our study does not support a 40-50% reduction in MACE shortly after bariatric surgery. We agree that the previously observed association was unlikely fully explained by unmeasured confounding, yet we remain aware that such strong biases due to unmeasured confounding are not unheard of — including reports of spurious effect of statins on hip fractures, statins on colorectal cancer, and flu vaccines or SGLT-2 inhibitors on all-cause mortality. , Rather, in this case several design-related biases may also have contributed. Note that unlike unmeasured confounding, these design biases would not be captured in an e-value.
Finally, the existence of many studies with consistent results does not guarantee validity. The noted 30 published observational studies that showed positive cardiovascular effects of bariatric surgery bring to mind the many observational studies of hormone replacement therapy (HRT) and the risk of coronary heart disease which, except for the Framingham study, consistently found a clinically meaningful benefit. In the HRT example, the many studies were subsequently refuted by clinical trial evidence and a re-analysis of the real-world data based on principles of causal inference. In the end, we agree that a randomized trial could shed much-needed light on the important question of the cardiovascular benefits of bariatric surgery. Should that trial fail to emerge — or should it under-represent at-risk populations such as Hispanic and non-Hispanic Black adults — real-world evidence, generated as described in our study, offers the best information available about the effect of bariatric surgery on reduction in MACE.
To analyse published evidence on the economic evaluation of risk‐based screening (RBS), a full systematic literature review was conducted. After a quality appraisal, we compared the cost‐effectiveness of risk‐based strategies (low‐risk, medium‐risk, and high‐risk) with no screening and age‐based screening. Studies were also analysed for modelling, risk stratification methods, input parameters, data sources, and harms and benefits.
The ten modelling papers analysed were based on screening performance of film‐based mammography (FBM) (three), digital mammography (DM) & FBM (two), DM alone (three), DM, ultrasound (US) and magnetic resonance imaging (one) and DM & US (one). Seven studies did not include cost of risk‐stratification, and one did not consider the cost of diagnosis. Disutility was incorporated in only six studies (one for screening and five for diagnosis). None of the studies reported disutility of risk‐stratification (being considered as high‐risk). Risk‐stratification methods varied from only breast density (BD) to the combination of familial risk, genetic susceptibility, lifestyle, previous biopsies, Jewish ancestry, and reproductive history. Less or no screening in low‐risk women and more frequent mammography screening in high‐risk women was more cost‐effective compared to no screening and age‐based screening. High‐risk women screened annually yielded a higher mortality rate reduction and more quality‐adjusted life years at the expense of higher cost and false positives.
RBS can be cost effective compared to the alternatives. However, heterogeneity among risk‐stratification methods, input parameters, and weaknesses in the methodologies hinder the derivation of robust conclusions. Therefore, further studies are warranted to assess newer technologies and innovative risk‐stratification methods.
Sanguisorba officinalis L. (Rosaceae) is a perennial herbaceous plant and its roots have been used as an important traditional medicine for over 2000 years. Ziyuglycoside I (Ziyu), an active compound isolated from the roots of S. officinalis L., has shown biological effects such as anti-oxidant, antiviral, and antiwrinkle activities. This study aimed to elucidate the underlying mechanisms of action of Ziyu on cytotoxicity, migration, and differentiation of pre-osteoblasts. Herein, at concentrations ranging from 1 to 100 [Formula: see text]M, Ziyu was not cytotoxic against pre-osteoblasts. Alkaline phosphatase activity assay and staining, and migration assay showed that Ziyu increased cell migration and promoted early osteoblast differentiation, followed by the enhancement of mineralized nodule formation in a dose-dependent manner, as indicated by Alizarin Red S staining. In addition, Ziyu increased the protein levels of runt-related transcription factor 2 (RUNX2) during osteoblast differentiation, whereas it did not affect the phosphorylation of Smad1/5/8 and GSK3b and expression of [Formula: see text]-catenin. Ziyu also activated ERK1/2 and mitogen-activated protein kinase during osteoblast differentiation, and ERK1/2 inhibitor attenuated Ziyu-mediated RUNX2 expression and nuclear accumulation. Furthermore, Ziyu-mediated early and late osteoblast differentiation was significantly suppressed by the inhibition of ERK1/2, which was accompanied by attenuation in the mRNA levels of osteoblast-related genes including bone sialoprotein, osteopontin, and osteocalcin. Taken together, the findings of this study provide evidence that Ziyu promotes cell migration, osteoblast differentiation, and bone mineralization and suggest a potential role for Ziyu in the treatment of bone diseases.
Background:
The Global Consensus Position Statement on the Use of Testosterone Therapy for Women (Global Position Statement) recommended testosterone therapy for postmenopausal women with hypoactive sexual desire disorder (HSDD).
Aim:
To provide a clinical practice guideline for the use of testosterone including identification of patients, laboratory testing, dosing, post-treatment monitoring, and follow-up care in women with HSDD.
Methods:
The International Society for the Study of Women's Sexual Health appointed a multidisciplinary panel of experts who performed a literature review of original research, meta-analyses, review papers, and consensus guidelines regarding testosterone use in women. Consensus was reached using a modified Delphi method.
Outcomes:
A clinically useful guideline following a biopsychosocial assessment and treatment approach for the safe and efficacious use of testosterone in women with HSDD was developed including measurement, indications, formulations, prescribing, dosing, monitoring, and follow-up.
Results:
Although the Global Position Statement endorses testosterone therapy for only postmenopausal women, limited data also support the use in late reproductive age premenopausal women, consistent with the International Society for the Study of Women's Sexual Health Process of Care for the Management of HSDD. Systemic transdermal testosterone is recommended for women with HSDD not primarily related to modifiable factors or comorbidities such as relationship or mental health problems. Current available research supports a moderate therapeutic benefit. Safety data show no serious adverse events with physiologic testosterone use, but long-term safety has not been established. Before initiation of therapy, clinicians should provide an informed consent. Shared decision-making involves a comprehensive discussion of off-label use, as well as benefits and risks. A total testosterone level should not be used to diagnose HSDD, but as a baseline for monitoring. Government-approved transdermal male formulations can be used cautiously with dosing appropriate for women. Patients should be assessed for signs of androgen excess and total testosterone levels monitored to maintain concentrations in the physiologic premenopausal range. Compounded products cannot be recommended because of the lack of efficacy and safety data.
Clinical Implications:
This clinical practice guideline provides standards for safely prescribing testosterone to women with HSDD, including identification of appropriate patients, dosing, and monitoring.
Strengths & Limitations:
This evidence-based guideline builds on a recently published comprehensive meta-analysis and the Global Position Statement endorsed by numerous societies. The limitation is that testosterone therapy is not approved for women by most regulatory agencies, thereby making prescribing and proper dosing challenging.
Conclusion:
Despite substantial evidence regarding safety, efficacy, and clinical use, access to testosterone therapy for the treatment of HSDD in women remains a significant unmet need.
Aim
To provide a clinical practice guideline for the use of testosterone including identification of patients, laboratory testing, dosing, post-treatment monitoring, and follow-up care in women with hypoactive sexual desire disorder (HSDD).
Methods
The International Society for the Study of Women's Sexual Health appointed a multidisciplinary panel of experts who performed a literature review of original research, meta-analyses, review papers, and consensus guidelines regarding testosterone use in women. Consensus was reached using a modified Delphi method.
Outcomes
A clinically useful guideline following a biopsychosocial assessment and treatment approach for the safe and efficacious use of testosterone in women with HSDD was developed including measurement, indications, formulations, prescribing, dosing, monitoring, and follow-up.
Results
Although the Global Position Statement endorses testosterone therapy for only postmenopausal women, limited data also support the use in late reproductive age premenopausal women, consistent with the International Society for the Study of Women's Sexual Health Process of Care for the Management of HSDD. Systemic transdermal testosterone is recommended for women with HSDD not primarily related to modifiable factors or comorbidities such as relationship or mental health problems. Current available research supports a moderate therapeutic benefit. Safety data show no serious adverse events with physiologic testosterone use, but long-term safety has not been established. Before initiation of therapy, clinicians should provide an informed consent. Shared decision-making involves a comprehensive discussion of off-label use, as well as benefits and risks. A total testosterone level should not be used to diagnose HSDD, but as a baseline for monitoring. Government-approved transdermal male formulations can be used cautiously with dosing appropriate for women. Patients should be assessed for signs of androgen excess and total testosterone levels monitored to maintain concentrations in the physiologic premenopausal range. Compounded products cannot be recommended because of the lack of efficacy and safety data.
Clinical implications
This clinical practice guideline provides standards for safely prescribing testosterone to women with HSDD, including identification of appropriate patients, dosing, and monitoring.
Strengths and limitations
This evidence-based guideline builds on a recently published comprehensive meta-analysis and the Global Position Statement endorsed by numerous societies. The limitation is that testosterone therapy is not approved for women by most regulatory agencies, thereby making prescribing and proper dosing challenging.
Conclusion
Despite substantial evidence regarding safety, efficacy, and clinical use, access to testosterone therapy for the treatment of HSDD in women remains a significant unmet need.
Background
Oral postmenopausal hormone therapy (HT) increases the risk of venous thrombosis (VT). We postulated that activated protein C (APC) resistance induced by HT is one of the mechanisms causing VT, and also assessed the role of one of the main determinants of APC resistance, i.e., tissue factor pathway inhibitor (TFPI).
Methods
We performed a nested case‐control study embedded within two Women’s Health Initiative (WHI) hormone trials. Women were randomized to hormone therapy or placebo. Biomarkers were measured at baseline and after one‐year, in 217 cases and 817 controls.
Results
Increased APC resistance and decreased TFPI at baseline were associated with VT (OR ranging from 1.20 to 2.06). However, women with such prothrombotic profile at baseline did not have further increased risk of VT when randomized to HT compared with placebo.
While there was no change in APC resistance or TFPI in placebo group after one‐year, HT group showed prothrombotic changes in the biomarkers, i.e., an increase in APC resistance (mean(sd):0.39 (0.54)) and decrease in TFPI (‐0.21(0.50): free TFPI, ‐0.24(0.22): TFPI activity and ‐0.22(0.20): total TFPI). However, HT induced prothrombotic change in biomarkers did not increase risk of VT.
Conclusion
Women with prothrombotic levels of APC resistance and TFPI at baseline were not at increased risk of VT when randomized to HT compared with placebo. This suggests that testing for these biomarkers prior to starting HT is not required.
HT led to prothrombotic change in these biomarkers after one year, but this did not relate to increased risk of VT.
Colorectal cancer (CRC) is the second most frequently diagnosed cancer in females worldwide. Menopausal hormone therapy (MHT) has been proposed as a potential protective factor for the development of CRC. Yet, the available evidence is controversial. Thus, we aimed at summarizing the current evidence on the effect of MHT on CRC through a systematic review. A systematic literature search identified 1’001 potentially relevant articles, out of which 57 original studies and nine meta‐analyses were deemed eligible for the final synthesis.
The evidence synthesis showed the following: 1) MHT showed a heterogeneity in findings for CRC risk with a slight tendency to a neutral or protective effect, 2) MHT effect was either neutral or protective on colorectal adenoma, 3) MHT had no impact on tumor grade, subsite and histologic types, 4) MHT was not associated with CRC mortality, and 5) MHT showed heterogenous effects on CRC stage and invasiveness, respectively.
In summary, despite some evidence pointing towards a protective effect of MHT on CRC, MHT is currently not recommended for primary CRC prevention by international guidelines due to several important, potentially harmful effects.
Significance:
NAFLD is a hepatic and systemic disorder with a complex multifactorial pathogenesis. Owing to the rising incidence of obesity and diabetes mellitus, the prevalence of NAFLD and its impact on global healthcare are expected to increase in the future. Differences in NAFLD exist between males and females, and among females depending on their reproductive status. Clinical and preclinical data show that females in the fertile age are more protected against NAFLD and studies in postmenopausal women and ovariectomized animal models support a protective role for estrogens. Recent Advances: An efficient crosstalk between the liver and adipose tissue is necessary to regulate lipid and glucose metabolism, protecting the liver from steatosis and insulin resistance contributing to NALFD. New advances in the knowledge of sexual dimorphism in liver and adipose tissue are providing interesting clues about the sex differences in NAFLD pathogenesis that could inspire new therapeutic strategies.
Critical issues:
Sex hormones influence key master regulators of lipid metabolism and oxidative stress in liver and adipose tissue. All these sex-biased metabolic adjustments shape the crosstalk between liver and adipose tissue, contributing to the higher protection of females to NAFLD.
Future directions:
The development of novel drugs based on the protective action of estrogens, but without its feminizing or undesired side effects, might provide new therapeutic strategies for the management of NAFLD.
In the last decades, there has been great progress in the field of stroke. With the introduction of acute therapies (intravenous thrombolysis and intra-arterial treatment), the outcome after stroke has improved significantly. Better prevention, improved acute therapy, and acute rehabilitation improved the morbidity and mortality rate after stroke. Gender differences in risk factors and epidemiology have been known for a long time, but lately attention to gender differences in stroke has increased. The aim of this mini-review is to demonstrate gender disparities in stroke with a focus on epidemiology, specific risk factors (gender-specific and unspecific), and outcomes. The influence of some risk factors for stroke is stronger in women (atrial fibrillation and hypertension) and there are risk factors exclusive to women such as pregnancy, pregnancy-associated hypertensive disorders, oral contraceptives, and hormonal replacement treatment. Data on the impact of other risk factors are inconsistent. The worse outcome after a stroke is mainly caused by demographic characteristics in women. Specific gender research is needed to better understand gender disparities in stroke to improve prevention strategies and treatment for women.
Sleep disturbances are a pervasive problem among postmenopausal women, with an estimated 40 to 64% reporting poor sleep. Hypnosis is a promising intervention for sleep disturbances. This study examined optimal dose and delivery for a manualized hypnosis intervention to improve sleep. Ninety postmenopausal women with poor sleep were randomized to 1 of 4 interventions: 5 in-person, 3 in-person, 5 phone, or 3 phone contacts. All received hypnosis audio recordings, with instructions for daily practice for 5 weeks. Feasibility measures included treatment satisfaction ratings and practice adherence. Sleep outcomes were sleep quality, objective and subjective duration, and bothersomeness of poor sleep. Results showed high treatment satisfaction, adherence, and clinically meaningful (≥ 0.5 SD) sleep improvement for all groups. Sleep quality significantly improved, p < .05, η2 = .70, with no significant differences between groups, with similar results for the other sleep outcomes across all treatment arms. Comparable results between phone and in-person groups suggest that a unique “dose” and delivery strategy is highly feasible and can have clinically meaningful impact. This study provides pilot evidence that an innovative hypnosis intervention for sleep (5 phone contacts with home practice) reduces the burden on participants while achieving maximum treatment benefit.
Background
Several promising new medications containing low-dose estradiol (E2) in combination with a progestin and an additional component, such as gonadotropin-releasing hormone antagonists, are currently being developed for use in pre-menopausal women.
Objective
This pooled analysis was designed to estimate the thromboembolic safety profile of E2 and its ester, estradiol valerate (E2Val), when used in combined hormonal treatments in a pre-menopausal population.
Methods
Data regarding users of combined oral contraceptives (COCs) and combined menopausal hormonal therapy (MHT) containing either E2/E2Val or ethinylestradiol (EE) ⩽ 30 µg were retrieved from five large prospective, non-interventional, cohort studies in Europe, US, and Canada with similar study design but differing medication cohorts. Propensity score sub-classification was applied to balance baseline parameters between cohorts and time-to-event analysis of venous thromboembolic events (VTE) was carried out based on the extended Cox model to calculate crude and adjusted hazard ratios (HR).
Results
(1) Crude incidence rates of VTE were higher in MHT users compared to pre-menopausal COC users, (2) the VTE risk in menopausal users of E2/E2Val-norethindrone acetate was not higher than that in menopausal users of E2/E2Val-progestin (adjusted HR 0.71; 95% confidence interval, 0.41-1.26) and (3) the VTE risk in pre-menopausal users of E2/E2Val-progestin was similar, or lower, than pre-menopausal users of EE⩽30µg-progestin (adjusted HR 0.49; 95% confidence interval, 0.28–0.84).
Conclusion
Our data presents a solid safety assessment of combined hormonal preparations containing E2/E2Val. We conclude that the risk of E2/E2Val-norethindrone acetate in pre-menopausal users is unlikely to be higher than the known risk of COCs containing EE ⩽ 30 µg-progestin.
Social support is associated prospectively with cognitive decline and dementia among the elderly; however, little is known about the impact of social support on healthy neurological aging. The current study investigates whether perceived social support has an influence on neurological health among a large sample of healthy postmenopausal women. Social support and neuropsychological outcomes were measured annually for six years through the Women’s Health Initiative Study of Cognitive Aging. In postmenopausal women, higher perceived social support was associated with significantly better overall neuropsychological functioning at baseline, especially in the domains of short-delay figural memory, short-delay verbal memory, and semantic fluency. No significant associations were found between social support and longitudinal changes in neuropsychological function over a median follow-up period of six years. Additionally, there was no significant relationship between social support and regional brain volumes. These findings suggest that social support is related to performance in a subset of neuropsychological domains and contributes to the existing literature that points to the importance of social support as a modifiable lifestyle factor that has the potential to help protect against the decline of cognitive aging, specifically among older adult women.
Background
Adhesive small bowel obstruction (ASBO) is one of the major causes of postoperative morbidity. Non-surgical management is generally applied to non-strangulated ASBO. Several factors have been reported to affect the response to non-surgical management in patients with ASBO. However, the association between sex differences and non-strangulated ASBO remains unclear. This study aimed to elucidate the effect of sex differences in non-strangulated postoperative ASBO.
Methods
We divided 139 patients with a first episode of non-strangulated postoperative ASBO into two groups: male group (n = 83) and female group (n = 56). Clinical features and prognosis were compared between the two groups.
Results
Female patients had lower proportions of oesophageal/gastric malignancies (P = 0.044) and colorectal malignancies (P = 0.030) and a higher proportion of uterine/ovarian malignancies (P < 0.001) than male patients did. More female patients required surgical management than male patients (P = 0.003) did. Hospital length of stay (LOS) was longer (P = 0.046) in the female group than in the male group. Multiple logistic regression analysis showed that the female sex was associated with an increased risk of the need for surgical management (odds ratio 5.318, P = 0.006). Cox proportional hazards regression analysis revealed that the female sex was positively associated with increased LOS (hazard ratio 0.687, P = 0.045).
Conclusion
Female sex was associated with failure of non-surgical management and increased LOS in patients with non-strangulated postoperative ASBO.
We report a case of breast cancer in which the size of the tumor shrank rapidly after discontinuation of hormone replacement therapy (HRT). The patient was a 52-year-old woman who noticed a mass in her left breast in March. Echography revealed a hypoechoic mass of 16 mm in size in the upper-inner quadrant of her left breast. The pathological diagnosis by core needle biopsy was invasive ductal carcinoma, ER(+ : 95%), PgR(+ : 80%), and HER2(1+). She continued placing an adhesive skin patch of estradiol and norethisterone for menopausal symptoms since she was 51 years old, but we told her to discontinue it in April. Breast echography just before surgery showed a significant reduction in tumor size from 16 mm to 8 mm. The interruption of HRT seemed to decrease the blood level of estradiol and in effect diminish the size of the tumor. It is clear that long-term HRT increases the risk of breast cancer tumorigenesis, and even short-term HRT, as in this case, may lead to latent tumor growth.
Objectives
Non-traditional risk factors place young women at increased risk of cardiovascular disease (CVD) over their lifetime. The current study undertakes a systematic review and meta-analysis of randomised controlled trials (RCTs) that examined the effectiveness of primary prevention interventions for CVD in premenopausal women.
Methods
An electronic literature search was performed in key databases in July 2018 and updated in May 2020. RCTs that recruited predominately female participants with a proportion aged under 55 years and that compared primary prevention interventions of CVD with usual practice were included. Two reviewers undertook the selection process for study inclusion. Meta-analysis was conducted for studies based on the same intervention in order to synthesise the results.
Results
14 RCTs with sample size ranging from 49 to 39 876 were included. Interventions included diet (2), vitamin E/antioxidants (3), lifestyle modification programme (7) and aspirin (2). The meta-analysis results indicated that diet nor vitamin E/antioxidant did not significantly lower the CVD risk profiles, while lifestyle modification programme involving components of lifestyle education, counselling and multiple follow-ups showed great potential to improve risk profiles. The lifestyle modification intervention improved blood pressure (−2.11 mm Hg, 95% CI −4.32 to 0.11, for systolic and −3.31 mm Hg (95% CI −4.72 to −1.91, for diastolic), physical activity (30.72 MET-min/week, 95% CI 23.57 to 37.87, for moderate physical activity 12.70 MET-min/week, 95% CI 8.27 to 17.14, for vigorous physical activity) and fasting blood glucose (−0.37 mmol/L, 95% CI −0.58 to −0.15). Subgroup meta-analysis in studies with a mean age under 51 years old suggested that lifestyle modification intervention remained to be effective in improving physical activity and fasting blood glucose.
Conclusion
The effective interventions identified in this review although with a small sample size and short duration could potentially inform future design of primary prevention of CVD in premenopausal women.
Agency breast cancer prevention guidelines for other than hereditary cancers have not materially changed in 20 years; endocrine-targeted agents (then, tamoxifen; now, adding raloxifene and aromatase inhibitors) reduce good prognosis estrogen receptor (ER)–positive, progesterone receptor (PR)–positive cancers without reducing deaths from breast cancer. Across three tamoxifen placebo-controlled prevention trials (N = 23,360) begun almost 30 years ago, although there were 226 fewer breast cancer cases, there were nine more deaths from breast cancer in the tamoxifen groups. Following clinical advances, currently more than half of breast cancer cases are solved problems with extremely low risk of death. As endocrine-targeted agents commonly prevent these cancers, widespread implementation of current prevention strategies may not reduce deaths from breast cancer. Compared with other breast cancers, ER-positive, PR-negative cancers and triple-negative cancers have inferior survival (90.6% v 83.8% v 78.1%, respectively; P < .001). Against this background, in the Women's Health Initiative Dietary Modification randomized trial (N = 48,835), ER-positive, PR-negative cancers were statistically significantly reduced in the intervention group (hazard ratio, 0.77; 95% CI, 0.64 to 0.94) and deaths from breast cancer were reduced 21% ( P = .02). In the Women's Health Initiative randomized, placebo-controlled trial evaluating conjugated equine estrogen (N = 10,739), ER-positive, PR-negative cancers were statistically significantly reduced in the intervention group (hazard ratio, 0.44; 95% CI, 0.27 to 0.74) and deaths from breast cancer were reduced 40% ( P = .04). These findings suggest that reexamination of breast cancer risk reduction strategies and clinical practice is needed.
The increasing availability of passively observed data has yielded a growing interest in “data fusion” methods, which involve merging data from observational and experimental sources to draw causal conclusions. Such methods often require a precarious tradeoff between the unknown bias in the observational dataset and the often-large variance in the experimental dataset. We propose an alternative approach, which avoids this tradeoff: rather than using observational data for inference, we use it to design a more efficient experiment. We consider the case of a stratified experiment with a binary outcome and suppose pilot estimates for the stratum potential outcome variances can be obtained from the observational study. We extend existing results to generate confidence sets for these variances, while accounting for the possibility of unmeasured confounding. Then, we pose the experimental design problem as a regret minimization problem subject to the constraints imposed by our confidence sets. We show that this problem can be converted into a concave maximization and solved using conventional methods. Finally, we demonstrate the practical utility of our methods using data from the Women’s Health Initiative.
Aim:
The menopause transition is experienced by women often involves troublesome symptoms due to changes in the level of reproductive hormones. Non-hormonal therapies are more commonly accepted by women than hormonal therapy for coping with the climacteric symptoms. The aim of the study was to evaluate the effects of yoga practice on menopausal symptoms, specific quality of life, and changes in hormonal levels among menopausal women.
Method:
A single-blinded randomized control trial was conducted among 80 participants aged 40 of 50 years and was randomly divided into two study arms, that is, Sudarshan Kriya Yoga (SKY) and brisk walking intervention, to find the effect on the hormonal changes and menopausal quality of life (measured by MENQOL tool). The significant improvements in the outcome measures were measured by using repeated measures analysis of variance and McNemar's test.
Results:
Significant improvements in the menopausal-specific quality of life were observed in the domain of vasomotor, psychosocial, and physical symptoms (p < 0.05). The antioxidant enzymes (superoxide dismutase and glutathione peroxidase (GPX) were significantly elevated after 1 year of regular practice of SKY compared to walking intervention (p < 0.05). In contrast, no significant improvement was observed in follicle-stimulating hormone and dehydroepiandrosterone sulfate levels. The women reported no adverse events after SKY practice or brisk walking.
Conclusion:
The study concluded that 1 year of SKY practice could be one of the preferred non-hormonal, lifestyle-modifying regimens for improving the overall quality of life in menopausal women.
Nuclear receptors, also known as ligand-activated transcription factors, regulate gene expression upon ligand signals and present as attractive therapeutic targets especially in chronic diseases. Despite the therapeutic relevance of some nuclear receptors in various pathologies, their potential in neurodegeneration and neuroinflammation is insufficiently established. This perspective gathers preclinical and clinical data for a potential role of individual nuclear receptors as future targets in Alzheimer's disease, Parkinson's disease, and multiple sclerosis, and concomitantly evaluates the level of medicinal chemistry targeting these proteins. Considerable evidence suggests the high promise of ligand-activated transcription factors to counteract neurodegenerative diseases with a particularly high potential of several orphan nuclear receptors. However, potent tools are lacking for orphan receptors, and limited central nervous system exposure or insufficient selectivity also compromises the suitability of well-studied nuclear receptor ligands for functional studies. Medicinal chemistry efforts are needed to develop dedicated high-quality tool compounds for the therapeutic validation of nuclear receptors in neurodegenerative pathologies.
Sexual dysfunction for women with diabetes is more common than for women without diabetes. The reasons why women with diabetes are a high-risk group are numerous. For example, lack of vaginal lubrication, pain during sex and inability to orgasm can be a consequence of high or low blood glucose levels. Higher rates of depression in people with diabetes can lead to low sexual drive. Wearing of diabetes devices, such as pumps, glucose monitors or lumps from lipohypertrophy around insulin injection sites may affect body image and self-esteem and the inconvenience of self-managing diabetes may affect the spontaneity of sex. This narrative review provides an overview of the problem of sexual dysfunction in women with diabetes, current methods of assessing sexual dysfunction in women, pharmacological and non-pharmacological interventions to treat it and an example of how psychological support for women with diabetes who experience sexual dysfunction can be integrated into a diabetes service. There are still significant gaps in our knowledge in how best to support women with diabetes and sexual dysfunction. However, raising awareness of the problem may help women with diabetes and healthcare professionals to discuss it as part of diabetes clinical consultations.
Introduction
Transgender women have been reported to have a high burden of cardiovascular disease (CVD) and risk factors based largely on surveys. Our aim was to describe the prevalence of CVD and associated comorbidities among a cohort of older transgender women referred to cardiology as part of their gender-affirming care.
Methods
This was a retrospective, cross-sectional study of transgender women at a single institution from 2017-2019.
Results
Fifty-two consecutive patients were included. The most common reasons for referral were cardiac risk factor management (45%) and pre-operative cardiac risk stratification prior to gender-affirming surgery (35%). The mean age was 57 ± 10 years, 87% were white, and 92% had insurance coverage. Forty-eight patients (92%) were taking gender-affirming hormone therapy; 5 had undergone breast augmentation, 4 had undergone orchiectomy, and 2 had undergone vaginoplasty. The most common comorbidities were depression and/or anxiety (63%), obesity (58%), and hyperlipidemia (54%). Excluding aldosterone antagonists, 46% were on cardiac medications; changes were recommended for 25% of patients: new prescriptions in 9, dose adjustments in 5, and discontinuations in 4. According to the pooled cohort equation, the 10-year risk of atherosclerotic CVD was 9.4 ± 7.7% when the study population was calculated as male and 5.2 ± 5.1% when calculated as female (p <.001). For patients who completed exercise testing, the functional aerobic capacity was fair (77.6 ± 21.4%) when calculated as male and average (99.5 ± 27.5%) as female (p<.0001); there was inconsistency in sex used for calculating the result on the formal report.
Conclusions
Older transgender women may have an underestimated prevalence of CVD and its risk factors. More research is needed to identify cardiovascular health profiles, improve practice consistency, and establish normative values for transgender patients.
Menopause is diagnosed clinically after 12 months of amenorrhea that results from the loss of ovarian follicular activity that cannot be attributed to another physiologic or pathologic causes. It marks the end of reproductive life in women and is associated with clinical, physiological and psychological manifestations. This chapter discusses the process of reproductive ageing through the perimenopause and examines the symptomatology of the menopause with the associated hormonal changes and the causal associations between menopause and several symptoms and diseases. It also discusses the principles of managing the menopause with various hormonal and non-hormonal approaches. The use of hormone replacement therapy is discussed in detail including its benefits, risks and casual linkages to neoplasms. It is important to recognise that individuals place different values on various health outcomes associated with hormone therapy, so the decision to use it should be made jointly by each woman and her health-care provider after weighing the risks and benefits.
Objective
This study aimed to explore Australian health-care providers’ knowledge of menopause and its consequences, and their views about menopause-related health care.
Methods
This was a cross-sectional qualitative study of Australian general practitioners (GPs), gynecologists (GYs) and pharmacists (PHs). Recruitment was ultimately achieved through professional networks and cold calling.
Results
There were equal numbers of GPs, GYs and PHs, and equal numbers of males and females in each group. All participants demonstrated sound understanding of menopause and its consequences. A strong theme was recognition of high usage of complementary and alternative medicines (CAMs) by women for menopausal symptoms. Most participants highlighted lack of efficacy evidence for most CAMs, but the majority of GPs and PHs considered CAMs to ‘have a role’. Most supported menopausal hormone therapy (MHT) when symptoms impaired quality of life. Limitations to comprehensive care included knowledge gaps and lack of time.
Conclusions
Australian health-care providers appeared knowledgeable about menopause, but uncertain about its management. MHT prescription appeared limited to women with severe symptoms despite lifestyle modification and a trial of CAMs. The upskilling of clinicians providing care for women at midlife, with respect to the indications for and prescribing of MHT, urgently needs to be addressed.
Objectives
An open-label, randomized trial was conducted to examine the effects of risedronate versus menopausal hormone therapy (MHT) in postmenopausal women with recent hip fracture.
Methods
Among 1165 eligible women, 281 were recruited and randomly assigned to receive oral risedronate (35 mg/week) or percutaneous estradiol gel (1.5 mg/day) plus oral micronized progesterone (100 mg/day) for 4 years. The primary end point was recurrent fracture and the secondary end points were mortality and bone mineral density (BMD).
Results
Kaplan–Meier analyses showed no significant differences in fracture recurrence and mortality between the two groups. The incidence of any new fracture per 100 person-years (PY) was 8.63 in the risedronate group and 12.86 in the MHT group (p = 0.180); that of clinical fracture was 4.75 and 6.99, respectively (p = 0.265); and that of asymptomatic vertebral fracture was 4.87 and 5.58, respectively (p = 0.764). The respective incidence of death per 100 PY was 3.58 and 4.40 (p = 0.503). BMD increased comparably at the lumbar spine in both groups. BMD at the total hip did not change in the risedronate group, but increased significantly by 2.8% in the MHT group.
Conclusions
MHT might not differ from risedronate in the prevention of secondary fractures and death among postmenopausal women with recent hip fracture.
A fixed-dose combination (FDC) formulation of bazedoxifene 20 mg and cholecalciferol 8 mg was developed to increase medication compliance and convenience for osteoporosis patients. This study was conducted to demonstrate bioequivalence by comparing the pharmacokinetic (PK) profiles and tolerability of an FDC tablet and the individual component tablets. A randomized, open-label, single-dosing, 2-treatment, 2-period, 2-sequence crossover study was conducted in 52 healthy subjects. All subjects were randomly assigned to 2 sequences, and they received FDC tablets of bazedoxifene and cholecalciferol and individual component tablets. Serial blood samples for PK evaluation were collected up to 24 hours predose and 120 hours postdose, and the PK parameters were estimated by noncompartmental methods. Throughout the study, tolerability was assessed based on adverse events, vital signs, and clinical laboratory tests. Of the enrolled 52 subjects, 47 subjects completed the study. The results, the geometric mean ratios (GMRs) and 90% confidence intervals (90%CIs), of bazedoxifene Cmax and AUC0-t for FDC to single entities given together were 0.98 (0.91-1.05) and 1.02 (0.97-1.07), respectively. The GMRs (90%CIs) of cholecalciferol Cmax and AUC0-t for FDC to single entities given together were 0.96 (0.91-1.00) and 0.94 (0.90-0.99), respectively. Overall, the GMRs (90%CIs) of the PK parameter of bazedoxifene and cholecalciferol fell within the conventional bioequivalence range of 0.8-1.25. There were no clinically significant differences in the safety profile between the 2 treatments. In conclusion, this study confirmed the development of a new FDC drug by demonstrating that the FDC formulation of bazedoxifene and cholecalciferol is biologically equivalent to the coadministered individual formulations.
Early breast cancer detection decreases mortality. As a result, it is imperative that primary care physicians are able to identify those individuals who are at an increased risk for breast cancer and understand how to help the patients manage that risk. Hereditary cancer syndromes in particular are dangerous and under-recognized. Various risk assessment tools are available for patients who are not at hereditary risk to help determine who may be eligible for enhanced screening or those who may benefit from preventive medication, and many imaging centers have now incorporated a form of risk assessment with associated recommendations into their reporting structure. Some patients even wish to consider risk-reducing surgery, which requires special counseling and support. All women should be risk stratified as early as possible so that those at a high risk can benefit from risk-stratified care. The management of patients at increased risk for the development of breast cancer has become increasingly challenging and nuanced with the exploding field of germline genetic testing and its implications for personalized care, and an increasing number of available options for high-quality supplemental breast imaging, particularly for the patient with dense breast tissue. This chapter aims to outline the identification and management of the high-risk patient, focusing on salient genetic and nongenetic risk factors, available options for risk management, and recommendations for risk modification for all women.
The prevalence of being overweight and obese has been expanded dramatically in recent years worldwide. Obesity usually occurs when the energetic introit overtakes energy expenditure from metabolic and physical activity, leading to fat accumulation mainly in the visceral depots. Excessive fat accumulation represents a risk factor for many chronic diseases, including cancer. Adiposity, chronic low-grade inflammation, and hyperinsulinemia are essential factors of obesity that also play a crucial role in tumor onset. In recent years, several strategies have been pointed toward boundary fat accumulation, thus limiting the burden of cancer attributable to obesity. While remodeling fat via adipocytes browning seems a tempting prospect, lifestyle interventions still represent the main pathway to prevent cancer and enhance the efficacy of treatments. Specifically, the Mediterranean Diet stands out as one of the best dietary approaches to curtail visceral adiposity and, therefore, cancer risk. In this Review, the close relationship between obesity and cancer has been investigated, highlighting the biological mechanisms at the basis of this link. Finally, strategies to remodel fat, including browning and lifestyle interventions, have been taken into consideration as a major perspective to limit excess body weight and tumor onset.
Cardiovascular diseases are the top cause of mortality in the United States, and ischemic heart disease accounts for 16% of all deaths around the world. Modifiable risk factors such as diet and exercise have often been primary targets in addressing these conditions. However, mounting evidence suggests that environmental factors that disrupt physiological rhythms might contribute to the development of these diseases, as well as contribute to increasing other risk factors that are typically associated with cardiovascular disease. Exposure to light at night, transmeridian travel, and social jetlag disrupt endogenous circadian rhythms, which, in turn, alter carefully orchestrated bodily functioning, and elevate the risk of disease and injury. Research into how disrupted circadian rhythms affect physiology and behavior has begun to reveal the intricacies of how seemingly innocuous environmental and social factors have dramatic consequences on mammalian physiology and behavior. Despite the new focus on the importance of circadian rhythms, and how disrupted circadian rhythms contribute to cardiovascular diseases, many questions in this field remain unanswered. Further, neither time-of-day nor sex as a biological variable have been consistently and thoroughly taken into account in previous studies of circadian rhythm disruption and cardiovascular disease. In this review, we will first discuss biological rhythms and the master temporal regulator that controls these rhythms, focusing on the cardiovascular system, its rhythms, and the pathology associated with its disruption, while emphasizing the importance of the time-of-day as a variable that directly affects outcomes in controlled studies, and how temporal data will inform clinical practice and influence personalized medicine. Finally, we will discuss evidence supporting the existence of sex differences in cardiovascular function and outcomes following an injury, and highlight the need for consistent inclusion of both sexes in studies that aim to understand cardiovascular function and improve cardiovascular health.
Sexual and reproductive function are impacted negatively in individuals with chronic kidney disease and end-stage renal disease. Disruption of the hypothalamic–pituitary–gonadal axis plays a pivotal role in contributing to these manifestations as a result of decreasing kidney function and the development of uremia. Early menopause is encountered commonly in women with reduced kidney function, and treatment is problematic as a result of reduced kidney function changing the half-life of medications. Kidney transplantation corrects some of these abnormalities, but medications required after transplantation as well as the persistence of other comorbidities are barriers to normal restoration of gonadal dysfunction.
There are strong indicators that sex hormones have a role in cognition. There has been more than 100 years of dementia research without yielding a disease-modifying therapy or cure and so it is important to explore knowledge gaps in our understanding of this increasingly prevalent fatal disease which currently limit our success. In this paper we discuss the role of sex hormones at the intersection between vascular disease and dementia, in light of the mounting literature covering the shared risk factors, pathological features alongside the timeline of hormonal change with the evolution of vascular and neurodegenerative disease. Interactive risk factors and the role of inflammation over the duration of disease evolution are highlighted. As the prevalence of dementia is rising and is higher in women, it is crucial we advance our knowledge from the “inconclusive” position statement on menopausal hormone therapy of the US Preventive Services Task Force.
The purpose of this cross-sectional study was to examine the relationship between diet and anthropometric measures in postmenopausal women. Data collected from 937 women enrolled in the Minnesota Green Tea Trial (NTC00917735) were used for this analysis. Dietary intake and health-related data were collected via questionnaires. Body weight, height, and waist circumference (WC) were measured by the study staff. The mean age of participants was 59.8 years and mean WC was 83 cm. Approximately 30% of the participants had WC greater than 88 cm. Healthy Eating Index-2015 score was 72.6 and the Dietary Inflammatory Index score was 0. Intakes of whole grains, dairy, protein, sodium, and saturated fat did not meet the dietary guidelines. Only 12.5% consumed the recommended daily amount of calcium (mean intake = 765 mg/day). When calcium supplements were considered, only 35.2% of the participants had adequate intakes, even though 68.9% reported taking a calcium supplement. We found that age and number of medications taken were significantly associated with waist circumference (p = 0.005). Women who reported taking two or more medications had greater WC (85 cm) compared to women who reported not taking any medications (82.2 cm), p = 0.002. Our findings suggest that achieving adequate calcium and vitamin D intake may be challenging to postmenopausal women.
Alzheimer's disease (AD) is a neurodegenerative disease that is characterized by progressive declines in cognitive function. Current epidemiological data indicates significant sex-linked disparities, where females have a higher risk of developing AD compared to male counterparts. This disparity necessitates further investigations to uncover the pathological and molecular factors influencing these sex differences. Although the underlying pathways behind this observed disparity remain elusive, recent research points to menopausal estrogen loss as a potential factor. Estrogen holds a significant role in APP processing as well as overall neuronal health through the regulation of brain derived neurotrophic factor (BDNF) - a factor that is also reduced in post-menopausal women. BDNF is a known contributor to neuronal health, and its reduced expression is typically linked to AD disorders. Exercise is known to increased BDNF and may provide an accessible activity for post-menopausal women to reduce their risk of AD. This review aims to discuss the relationship between estrogen, exercise, and BDNF in AD pathology.
Spinal cord injury (SCI) affects approximately 300,000 people in the United States. Most individuals who sustain severe SCI also develop subsequent osteoporosis. However, beyond immobilization-related lack of long bone loading, multiple mechanisms of SCI-related bone density loss are incompletely understood. Recent findings suggest neuronal impairment and disability may lead to an upregulation of receptor activator of nuclear factor-κB ligand (RANKL), which promotes bone resorption. Disruption of Wnt signaling and dysregulation of RANKL may also contribute to the pathogenesis of SCI-related osteoporosis. Estrogenic effects may protect bones from resorption by decreasing the upregulation of RANKL. This review will discuss the current proposed physiological and cellular mechanisms explaining osteoporosis associated with SCI. In addition, we will discuss emerging pharmacological and physiological treatment strategies, including the promising effects of estrogen on cellular protection.
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