Hormonal modulation of interleukin-6, tumor necrosis factor and associated receptor secretion in postmenopausal women

Hormone replacement therapy (HRT) reduces the risk for osteoporosis but transiently increases cardiovascular risk for some postmenopausal women. This study investigated the hypothesis that these risks are associated with HRT-induced changes in mononuclear cell secretion of interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-alpha), and associated soluble receptors. Compared to the untreated condition (n=8), estrogen therapy (n=7) and estrogen+progestin therapy (n=7) both caused 2-fold elevations in TNF-alpha secretion. IL-6 secretion was increased (48%, P=0.04) only by estrogen+progestin therapy. Although soluble receptor secretion was not different among groups, soluble TNF receptor type I and IL-6 receptor secretion were inversely related to plasma follicle stimulating hormone (P<0.05). Both therapies reduced plasma osteocalcin (a marker for osteoporosis) by approximately 50% (P<0.002). Plasma C-reactive protein (CRP, a marker for cardiovascular risk) was 3-fold higher in women receiving only estrogen, compared to untreated women (P=0.01), and twice as high as those receiving estrogen+ progestin (P=0.045). Simple linear relationships were not observed between cytokine secretion and these markers, but a significant HRT/TNF-alpha interaction with osteocalcin (P=0.022) and an HRT/IL-6 interaction with CRP (P =0.016) indicated more complex relationships between hormone replacement, cytokine activity, and health risks associated with menopause.     

Hormone replacement therapy and risk of venous thromboembolism: population based case-control study.

OBJECTIVE: To evaluate the association between use of hormone replacement therapy and the risk of idiopathic venous thromboembolism. DESIGN: Population based case-control study. SETTING: Population enrolled in the General Practice Research Database, United Kingdom. SUBJECTS: A cohort of 347,253 women aged 50 to 79 without major risk factors for venous thromboembolism was identified. Cases were 292 women admitted to hospital for a first episode of pulmonary embolism or deep venous thrombosis; 10,000 controls were randomly selected from the source cohort. MAIN OUTCOME MEASURES: Adjusted relative risks estimated from unconditional logistic regression. RESULTS: The adjusted odds ratio of venous thromboembolism for current use of hormone replacement therapy compared with non-users was 2.1 (95% confidence interval 1.4 to 3.2). This increased risk was restricted to first year users, with odds ratios of 4.6 (2.5 to 8.4) during the first six months and 3.0 (1.4 to 6.5) 6-12 months after starting treatment. No major risk differences were observed between users of low and high doses of oestrogens, unopposed and opposed treatment, and oral and transdermal preparations. The risk of idiopathic venous thromboembolism among non-users of replacement therapy was estimated to be 1.3 per 10,000 women per year. Among current users, idiopathic venous thromboembolism occurs at two to three times the rate in non-users, resulting in one to two additional cases per 10,000 women per year. CONCLUSIONS: Current use of hormone replacement therapy was associated with a higher risk of venous thromboembolism, although the risk seemed to be restricted to the first year of use.     

High-risk premenopausal women's experiences of undergoing prophylactic oophorectomy: a descriptive study

Women who are at increased risk of developing ovarian cancer because of their family history may need to make decisions about the medical management of their cancer risk--whether to have ovarian screening or undergo prophylactic surgery. This qualitative study explores the perceived physical and emotional implications of undergoing preventative surgery using data collected during interviews with 23 high-risk premenopausal women who had undergone prophylactic oophorectomy because of their family history of cancer. Despite the fact that all of these women regarded their decision to undergo surgery extremely positively, 20 women also described what they regarded as the costs of undergoing surgery. These included post-operative complications, the onset of menopausal symptoms, side effects of hormone replacement therapy, and negative effects on body image and gender identity. The perceived benefits of surgery were described as risk reduction, enabling one to fulfil family obligations, removing the need for gynecological screening, cessation of menstruation, and positive side effects of hormone replacement therapy. This study suggests there is a need to inform women about potential physical and emotional sequelae of oophorectomy prior to undergoing this procedure.     

Should symptomatic menopausal women be offered hormone therapy?

Many physicians remain uncertain about prescribing hormone therapy for symptomatic women at the onset of menopause. The American Society for Reproductive Medicine (ASRM) convened a multidisciplinary group of healthcare providers to discuss the efficacy and risks of hormone therapy for symptomatic women, and to determine whether it would be appropriate to treat women at the onset of menopause who were complaining of menopausal symptoms. MAJOR FINDINGS: Numerous controlled clinical trials consistently demonstrate that hormone therapy, administered via oral, transdermal, or vaginal routes, is the most effective treatment for vasomotor symptoms. Topical vaginal formulations of hormone therapy should be preferred when prescribing solely for the treatment of symptoms of vulvar and vaginal atrophy. Data from the Women's Health Initiative indicate that the overall attributable risk of invasive breast cancer in women receiving estrogen plus progestin was 8 more cases per 10,000 women-years. No increased risk for invasive breast cancer was detected for women who never used hormone therapy in the past or for those receiving estrogen only. Hormone therapy is not effective for the treatment of cardiovascular disease and that the risk of cardiovascular disease with hormone therapy is principally in older women who are considerably postmenopause. CONCLUSIONS: Healthy symptomatic women should be offered the option of hormone therapy for menopausal symptoms. Symptom relief with hormone therapy for many younger women (at the onset of menopause) with menopausal symptoms outweighs the risks and may provide an overall improvement in quality of life. Hormone therapy should be individualized for symptomatic women. This involves tailoring the regimen and dose to individual needs.     

Should symptomatic menopausal women be offered hormone therapy?

Many physicians remain uncertain about prescribing hormone therapy for symptomatic women at the onset of menopause. The American Society for Reproductive Medicine (ASRM) convened a multidisciplinary group of healthcare providers to discuss the efficacy and risks of hormone therapy for symptomatic women, and to determine whether it would be appropriate to treat women at the onset of menopause who were complaining of menopausal symptoms. MAJOR FINDINGS: Numerous controlled clinical trials consistently demonstrate that hormone therapy, administered via oral, transdermal, or vaginal routes, is the most effective treatment for vasomotor symptoms. Topical vaginal formulations of hormone therapy should be preferred when prescribing solely for the treatment of symptoms of vulvar and vaginal atrophy. Data from the Women's Health Initiative indicate that the overall attributable risk of invasive breast cancer in women receiving estrogen plus progestin was 8 more cases per 10,000 women-years. No increased risk for invasive breast cancer was detected for women who never used hormone therapy in the past or for those receiving estrogen only. Hormone therapy is not effective for the treatment of cardiovascular disease and that the risk of cardiovascular disease with hormone therapy is principally in older women who are considerably postmenopause. CONCLUSIONS: Healthy symptomatic women should be offered the option of hormone therapy for menopausal symptoms. Symptom relief with hormone therapy for many younger women (at the onset of menopause) with menopausal symptoms outweighs the risks and may provide an overall improvement in quality of life. Hormone therapy should be individualized for symptomatic women. This involves tailoring the regimen and dose to individual needs.     

Cardioprotective effect of hormone replacement therapy in postmenopausal women: is the evidence biased?

OBJECTIVE--To quantify the effect of selection of relatively healthy women in studies reporting reduced relative risk for cardiovascular disease in postmenopausal women taking hormone replacement therapy. DESIGN--Review of the follow up studies reported in three recent meta-analyses to determine the effect of oestrogen therapy on both total cancer and cardiovascular disease. The same standard statistical methods as in the original analyses were used. MAIN OUTCOME MEASURES--Relative risks of total cancer and cardiovascular disease. RESULTS--In most of the follow up studies the relative risk for total cancer was below 1. The studies that showed the largest reduction in cardiovascular disease also showed the largest reduction in cancer, indicating a healthy cohort effect. Although heterogeneity within the studies prevented pooling, the best estimate for the protective effect on total cancer was a relative risk of 0.83 among women taking oestrogen (95% confidence interval 0.71 to 0.96), while in the same studies the relative risk for cardiovascular disease was 0.57 (0.50 to 0.64). CONCLUSIONS--Unintended selection of relatively healthy women for oestrogen therapy may have influenced the reported beneficial effect of oestrogen therapy on cardiovascular disease. It is unclear how much of the cardioprotection is due to this selection. Universal preventive hormonal replacement therapy for postmenopausal women is unwarranted at present.     

Utilisation of hormone replacement therapy by women doctors.

OBJECTIVES--To ascertain the prevalence and duration of use of hormone replacement therapy by menopausal women doctors. DESIGN--Postal questionnaire. SETTING--General practices in the United Kingdom. SUBJECTS--Randomised stratified sample of women doctors who obtained full registration between 1952 and 1976, taken from the current principal list of the Medical Register. MAIN OUTCOME MEASURES--Prevalence and duration of use of hormone replacement therapy; menopausal status. RESULTS--Overall, 45.7% (436/954) of women doctors aged between 45 and 65 years had ever used hormone replacement therapy. When the results from women still menstruating regularly were excluded, 55.2% (428) were ever users and 41.2% (319) current users. The cumulative probability of remaining on hormone replacement therapy was 0.707 at five years and 0.576 at 10 years. CONCLUSIONS--Women doctors have a higher prevalence of use of hormone replacement therapy than has been reported for other women in the United Kingdom, and most users seem to be taking hormone replacement therapy for more than five years. The results may become generalisable to the wider population as information on the potential benefits of hormone replacement therapy is disseminated.     

Socioeconomic position and lifestyle in relation to breast cancer incidence among postmenopausal women: a prospective cohort study, Denmark, 1993-2006

Background: In Denmark, the incidence of breast cancer is higher among women with higher socioeconomic position. We investigated whether differences in exposure to certain risk factors contribute to this gradient, as measured from education, income and occupation. Methods: We conducted a cohort study of 23 111 postmenopausal women aged 50–65 years who were enrolled in the prospective Danish ‘Diet, Cancer and Health’ study between 1993 and 1995. At baseline, all women filled in a questionnaire on lifestyle and food frequency. The results were analysed in Cox proportional hazard models. Results: Part of the association with socioeconomic position is due to the potential mediators reproductive pattern, use of hormone replacement therapy and alcohol consumption. After simultaneous adjustment for these factors, the hazard ratios were 1.06 (95% confidence interval [CI], 0.88–1.27) for women with higher education and 1.07 (95% CI, 0.85–1.34) for women with higher income. The HR ratio for women working as higher officials when compared with unskilled workers was 1.23 (0.96–1.59). Conclusion: The results support the hypothesis that the higher incidence of breast cancer among socially advantaged women is mediated partly by differences in exposure to reproductive factors, hormone replacement therapy and alcohol.     

Pre-existing risk factor profiles in users and non-users of hormone replacement therapy: prospective cohort study in Gothenburg,Sweden

ObjectiveTo assess whether risk factor profiles for cardiovascular disease differed, before starting treatment, between women who would subsequently use hormone replacement therapy and those who would remain untreated.DesignProspective population study, initiated in 1968-9, with follow ups in 1974, 1980, and 1992.SettingGothenburg, Sweden.Participants1201 women born in 1918, 1922, and 1930, representative of women of the same age in the general population.Results179 of the 1202 women (14.9%) used hormone replacement therapy sometime during the 24 year follow up period. Multivariate models indicated that these women had significantly lower blood pressure, had less obesity, and belonged to a higher social group before the start of treatment than women who would remain untreated.ConclusionWomen who would subsequently use hormone replacement therapy were already at lower cardiovascular risk before the start of treatment than women who would remain untreated. Some of the claimed beneficial effects of treatment may thus be explained by women who would use hormone replacement therapy representing a healthier cohort than women who would remain untreated.

Key messages

• Many retrospective epidemiological studies have shown that hormone replacement therapy reduces the risk of cardiovascular disease
• Results from the prospective population study in Gothenburg show that there were already differences in risk factor profile of women before hormone replacement therapy was considered
• It is too early to recommend hormone replacement therapy for prevention of cardiovascular disease before controlled randomised studies have been performed

     

Incidence of and risk factors for Motor Neurone Disease in UK women: a prospective study

ABSTRACT: BACKGROUND: Motor neuron disease (MND) is a severe neurodegenerative disease with largely unknown etiology. Most epidemiological studies are hampered by small sample sizes and/or the retrospective collection of information on behavioural and lifestyle factors. METHODS: 1.3 million women from the UK Million Women Study, aged 56 years on average at recruitment, were followed up for incident and/or fatal MND using NHS hospital admission and mortality data. Adjusted relative risks were calculated using Cox regression models. FINDINGS: During follow-up for an average of 9.2 years, 752 women had a new diagnosis of MND. Age-specific rates increased with age, from 1.9 (95% CI 1.3 - 2.7) to 12.5 (95% CI 10.2 - 15.3) per 100,000 women aged 50-54 to 70-74, respectively, giving a cumulative risk of diagnosis with the disease of 1. 74 per 1000 women between the ages of 50 and 75 years. There was no significant variation in risk of MND with region of residence, socio-economic status, education, height, alcohol use, parity, use of oral contraceptives or hormone replacement therapy. Ever-smokers had about a 20% greater risk than never smokers (RR 1.19 95% CI 1.02 to 1.38, p=0.03). There was a statistically significant reduction in risk of MND with increasing body mass index (pfor trend=0.009): obese women (body mass index, 30 kg/m2 or more) had a 20% lower risk than women of normal body mass index (20 to <25 Kg/m2)(RR 0.78 95% CI 0.65-0.94; p=0.03). This effect persisted after exclusion of the first three years of follow-up. Interpretation. MND incidence in UK women rises rapidly with age, and an estimated 1 in 575 women are likely to be affected between the ages of 50 and 75 years. Smoking slightly increases the risk of MND, and adiposity in middle age is associated with a lower risk of the disease.     

Hormone therapy after endometrial cancer

Endometrial carcinoma is listed among the absolute contra-indications to hormone therapy. After all the existing opinions so far, hormone therapy after FIGO stage I or II endometrial cancer is still thought of as a possibility, and up to now the continuous combined oestrogen/progestogen replacement therapy would be recommended. However, until today, only observational studies have been put forward. Although no study has established an increased rate of recurrences or mortality, alternatives such as phytopreparations, tibolone, or, in, particular, psychotherapeutic drugs such as venlafaxine should be considered for the relief of climacteric complaints. Progestogen-only therapy also comes particularly into question. Indeed, the wider discussion about the gestagen effects regarding the risks of breast cancer is to be considered. Generally, after hysterectomy, at least for patients with cardiovascular risk factors, the preference today is to use low-dose oestrogen therapy (patches, gels) instead of continuous combined oestrogen/progestogen replacement therapy, and this also is now recommended for patients after endometrial cancer. This is to be noted because of the risk factors for endometrial carcinomas, such as hypertension, obesity, polycystic ovary syndrome, diabetes mellitus, etc. However, each form of hormone therapy should only be exceptionally recommended, and the patients must be informed about the risks that exist and the use of alternatives.     

Estrogen, alcohol and breast cancer risk

Estrogen replacement has been used for many years to reverse the hypoestrogenic symptoms of menopause and prevent osteoporosis. Studies have found that estrogen replacement also decreases cardiovascular risk. In addition, social use of alcohol has been found to decrease cardiovascular risk. Therefore, both estrogen replacement therapy and alcohol use have been proposed to have cardiovascular benefits, and are often used in combination. Epidemiologic evidence indicates that estrogen replacement therapy after menopause increases breast cancer risk. Regular alcohol consumption is also associated with increase in risk. However, interactions between the two are poorly understood. In addition, if alcohol alters circulating estrogen levels in estrogen users, this may have implications in terms of altering the risks:benefit ratio of estrogen replacement in an undesirable direction. For example, there are data suggesting that the use of both alcohol and estrogen may increase breast cancer risk more than the use of either one alone. Data support both acute and chronic effects of alcohol in raising circulating estrogen levels in premenopausal women on no hormonal medications. In postmenopausal women studies focusing on acute effects of alcohol on estrogen metabolism indicate that alcohol has a much more pronounced effect in women using estrogen replacement than in those who do not. Studies evaluating chronic effects of alcohol ingestion on circulating estrogens in postmenopausal women are needed.     

Use of proton pump inhibitors and risk of osteoporosis-related fractures

Background

The use of proton pump inhibitors has been associated with an increased risk of hip fracture. We sought to further explore the relation between duration of exposure to proton pump inhibitors and osteoporosis-related fractures.

Methods

We used administrative claims data to identify patients with a fracture of the hip, vertebra or wrist between April 1996 and March 2004. Cases were each matched with 3 controls based on age, sex and comorbidities. We calculated adjusted odds ratios (OR) for the risk of hip fracture and all osteoporosis-related fractures for durations of proton pump inhibitor exposure ranging from 1 or more years to more than 7 years.

Results

We matched 15 792 cases of osteoporosis-related fractures with 47 289 controls. We did not detect a significant association between the overall risk of an osteoportic fracture and the use of proton pump inhibitors for durations of 6 years or less. However, exposure of 7 or more years was associated with increased risk of an osteoporosis-related fracture (adjusted OR 1.92, 95% confidence interval [CI] 1.16–3.18, p = 0.011). We also found an increased risk of hip fracture after 5 or more years of exposure (adjusted OR 1.62, 95% CI 1.02–2.58, p = 0.04), with even higher risk after 7 or more years exposure (adjusted OR 4.55, 95% CI 1.68–12.29, p = 0.002).

Interpretation

Use of proton pump inhibitors for 7 or more years is associated with a significantly increased risk of an osteoporosis-related fracture. There is an increased risk of hip fracture after 5 or more years exposure. Further study is required to determine the clinical importance of this finding and to determine the value of osteoprotective medications for patients with long-term use of proton pump inhibitors.Osteoporosis is a common condition throughout the developed world, affecting up to 16% of women and 7% of men aged 50 years and older.¹ The presence of underlying osteoporosis is a major risk factor for the development of fractures of the hip, proximal femur, spinal vertebra and forearm. In 2000, the estimated number of people with fractures worldwide was 56 million, and about 9 million new osteoporotic fractures occur each year.² In 1993/94, the number of hip fractures in Canada was 23 375.³ This number is predicted to increase to 88 124 by the year 2041, with a parallel increase in the number of days in hospital (465 000 patient-days in 1993/94 to 1.8 million in 2041).³ Moreover, the case-fatality rate for hip fractures can exceed 20%,⁴ and all osteoporosis-related fractures can lead to substantial long-term disability and decreased quality of life.⁵Many risk factors for the development of osteoporosis-related fracture have been identified, including white ethnic background, low body mass index, physical inactivity and female sex.^6–8 There are also a number of medication classes, including corticosteroids and serotonin selective reuptake inhibitors, whose use has been linked to higher rates of osteoporosis.^9–11 Furthermore, any condition or drug that increases the risk of falls and injury also increases the risk of an osteoporosis-related fracture.^12,13One medication class that may affect bone mineral metabolism is proton pump inhibitors. This class of drugs inhibits the production and intragastric secretion of hydrochloric acid, which is believed to be an important mediator of calcium absorption in the small intestine.¹⁴ Recent studies have suggested that the use of proton pump inhibitors for 1 or more years is associated with hip fracture and other osteoporotic fractures; however, there is limited data on additional risk beyond 4 years exposure.^15,16Because proton pump inhibitors are commonly prescribed to control and prevent symptoms of chronic unrelenting conditions, it is likely that many patients will use these medications for more than 4 years. Therefore, we used an adminstrative database to examine the effects of longer durations of proton pump inhibitor use on the development of osteoporosis-related fractures.     

The action of ovarian hormones in cardiovascular disease

The incidence of cardiovascular disease (CAD) differs between men and women, in part because of differences in risk factors and hormones. This sexual dimorphism means a lower incidence in atherosclerotic diseases in premenopausal women, which subsequently rises in postmenopausal women to eventually equal that of men. These observations point towards estrogen and progesterone playing a lifetime protective role against CAD in women. As exogenous estrogen and estrogen plus progesterone preparations produce significant reductions in low-density lipoprotein (LDL) cholesterol levels and significant increases in high-density lipoprotein (HDL) cholesterol, this should in theory lower the risk of CAD. However, results from oral contraceptive (OC) use and combined estrogen and progesterone hormone replacement therapy (HRT) have suggested that hormone replacement regimes do not provide cardiovascular protection. In fact, depending on the preparation and the presence or absence of genetic risk factors, an increased risk of cardiovascular diseases such as venous thrombosis, myocardial infarction (MI) and stroke have been observed. Interestingly, in the majority of studies the increase in risk was highest in the first year, after which an increase in risk was not observed, and in some studies a lower risk of CAD was evident after four or five years of exogenous hormone administration. While the debate continues about the merits of HRT, and several good reviews exist on the statistics of CAD in relation to exogenous hormones, we have decided to review the literature to piece together the physiological actions of estrogen and progesterone preparations on the individual mechanistic components leading to CAD; namely, the altered endothelium and the haemostatic balance between coagulation and fibrinolysis. We present possible mechanisms for how HRT and OCs protect against MI in the absence of cardiovascular risk factors but increase the incidence of MI in their presence. We also speculate on the roles played by hormones on the short- and long-term risks of cardiovascular disease.     

Menopausal Hormone Therapy and Chronic Disease Risk in the Women’S Health Initiative: is Timing Everything?

ObjectiveThis review provides a comprehensive overview of the most recent findings from the Women’s Health Initiative (WHI) hormone therapy (HT) trials and highlights the role of age and other clinical risk factors in risk stratification.MethodsWe review the findings on cardiovascular disease, cancer outcomes, all-cause mortality, and other major endpoints in the two WHI HT trials (conjugated equine estrogens [CEEs, 0.625 mg/day] with or without medroxyprogesterone acetate [MPA, 2.5 mg/day]).ResultsThe hazard ratio (HR) for coronary heart disease (CHD) was 1.18 (95% confidence interval [CI], 0.95 to 1.45) in the CEE + MPA trial and 0.94 (95% CI, 0.78 to 1.14) in the CEE-alone trial. In both HT trials, there was an increased risk of stroke and deep vein thrombosis and a lower risk of hip fractures and diabetes. The HT regimens had divergent effects on breast cancer. CEE + MPA increased breast cancer risk (cumulative HR, 1.28; 95% CI, 1.11 to 1.48), whereas CEE alone had a protective effect (cumulative HR, 0.79; 95% CI, 0.65 to 0.97). The absolute risks of HT were low in younger women (ages 50 to 59 years) and those who were within 10 years of menopause onset. Furthermore, for CHD, the risks were elevated for women with metabolic syndrome or high low-densitylipoprotein cholesterol concentrations but not in women without these risk factors. Factor V Leiden genotype was associated with elevated risk of venous thromboembolism on HT.ConclusionHT has a complex pattern of benefits and risks. Women in early menopause have low absolute risks of chronic disease outcomes on HT. Use of HT for management of menopausal symptoms remains appropriate, and risk stratification will help to identify women in whom benefits would be expected to outweigh risks. (Endocr Pract. 2014;20:1201-1213)     

Hormone replacement therapy increases renal kallikrein excretion in healthy postmenopausal women

Hypertension and its related increase in cardiovascular morbidity in postmenopausal women is a major public health problem. The hypotensive property of urinary kallikrein has been described since 1909. Despite the controversy surrounding the effects of hormone replacement therapy on blood pressure regulation, its mechanisms remain incompletely understood, and no evidence has yet been provided for its effects on renal kallikrein excretion in postmenopausal women. In a double-blind, randomized study we examined the effects of hormone replacement therapy in the form of 2 mg 17-beta estradiol (ERT) or 2 mg 17-beta estradiol combined with continuous 5 mg medroxyprogesterone acetate (HRT) on urinary kallikrein excretion in postmenopausal women. Thirty-nine postmenopausal women collected their urine for 24 hours on two separate occasions 3 months apart. During the 3 month period women were randomized to placebo, ERT, or HRT. Urine samples were assayed for kallikrein activity, normalized to urine creatinine and expressed as mU/gm creatinine. Urinary kallikrein excretion increased significantly after 3 months in the ERT (p < 0.001) and HRT (p < 0.01) groups, and decreased non-significantly in the placebo group (p > 0.06). There were no significant blood pressure changes after 3 months of therapy. The findings demonstrate that hormone replacement therapy in the form of estrogen or estrogen combined with continuous medroxyprogesterone is effective in increasing urinary kallikrein excretion. Given that a decrease in kallikrein excretion may mark risk for development of hypertension, the findings of this study are of value in demonstrating a novel mechanism underlying cardioprotective properties of postmenopausal hormone replacement therapy in women without pre-existing coronary disease.     

Anabolic Therapy and Optimal Treatment Sequences for Patients With Osteoporosis at High Risk for Fracture

Objective: Provide an update regarding anabolic medications for osteoporosis, which are often considered to be the last resort for patients with osteoporosis, after multiple fractures have already occurred and other medications have already been administered.Methods: Literature review and discussion.Results: Recent pivotal trial data for anabolic agents and randomized trials comparing anabolic and antiresorptive medications suggest that three anabolic agents (teriparatide, abaloparatide, and romosozumab) reduce nonvertebral and vertebral fractures faster and to a greater extent than potent antiresorptive treatments. Furthermore, bone density accrual is maximized when patients are given anabolic agents first, followed by potent antiresorptive therapy. Since total hip bone density during or after osteoporosis treatment has emerged as an excellent surrogate for future fracture risk, attaining a greater hip bone mineral density is a treatment goal for high-risk osteoporosis patients.Conclusion: This review defines the highest-risk patients and summarizes the rationale for the evolving role of anabolic therapy in the management of postmenopausal women at high risk for fracture.Abbreviations: ACTIVE = Abaloparatide Comparator Trial in Vertebral Endpoints; ARCH = Active Controlled Fracture Study in Postmenopausal Women with Osteoporosis at High Risk; BMD = bone mineral density; FRAME = Fracture Study in Postmenopausal Women with Osteoporosis; FRAX = Fracture Risk Assessment Tool; PTH = parathyroid hormone; TBS = trabecular bone score     

Risk factors for acute myocardial infarction in women: evidence from the Royal College of General Practitioners' oral contraception study.

To determine the pattern of risk factors for acute myocardial infarction associated solely with women a nested case-control study was carried out on cohort data collected during the Royal College of General Practitioners'' oral contraception study. Smoking (adjusted relative risk 1.7 for light smokers and 4.3 for heavy smokers), hypertension (2.4), toxaemia of pregnancy (2.8), and diabetes mellitus (6.9) were associated with a significantly increased risk of myocardial infarction. There was no significant trend of risk with social class. Current use of the pill increased the risk only among women who also smoked (relative risk 20.8 for heavy smokers). Previous use of the pill did not influence the risk of myocardial infarction. If heavy smokers also had a history of toxaemia of pregnancy their risk of myocardial infarction was further increased (relative risk 41.0). Other variables associated solely with women, such as parity, hysterectomy, and hormone replacement therapy, had little effect on the risk of having a myocardial infarction. Overall, smoking was the most important independent risk factor and had a strong influence on risks associated with other factors.     

Assessing and Addressing the Risk of Venous Thromboembolism Across the Spectrum of Gender Affirming Care: A Review

ObjectiveAccumulating evidence demonstrates that gender affirming hormone therapy (GAHT) improves mental health outcomes in transgender persons. Data specific to the risks associated with GAHT for transgender persons continue to emerge, allowing for improvements in understanding, predicting, and mitigating adverse outcomes while informing discussion about desired effects. Of particular concern is the risk of venous thromboembolism (VTE) in the context of both longitudinal GAHT and the perioperative setting. Combining what is known about the risk of VTE in cisgender individuals on hormone therapy (HT) with the evidence for transgender persons receiving HT allows for an informed approach to assess underlying risk and improve care in the transgender community.ObservationsHormone formulation, dosing, route, and duration of therapy can impact thromboembolic risk, with transdermal estrogen formulations having the lowest risk. There are no existing risk scores for VTE that consider HT as a possible risk factor. Risk assessment for recurrent VTE and bleeding tendencies using current scores may be helpful when assessing individual risk. Gender affirming surgeries present unique perioperative concerns, and certain procedures include a high likelihood that patients will be on exogenous estrogens at the time of surgery, potentially increasing thromboembolic risk.Conclusions and RelevanceWithholding GAHT due to potential adverse events may cause negative impacts for individual patients. Providers should be knowledgeable about the management of HT in transgender individuals of all ages, as well as in the perioperative setting, to avoid periods in which transgender individuals are off GAHT. Treatment decisions for both anticoagulation and HT should be individualized and tailored to patients’ overall goals and desired outcomes, given that the physical and mental health benefits of gender affirming care may outweigh the risk of VTE.