Partisan Perspectives in the Medical Literature, Journal of General Internal Medicine, 2010
2010 Study Abstract
Unfavorable results of major studies have led to a large shrinkage of the market for hormone replacement therapy (HRT) in the last 6 years. Some scientists continue to strongly support the use of HRT.
We analyzed a sample of partisan editorializing articles on HRT to examine their arguments, the reporting of competing interests, the journal venues and their sponsoring societies.
Through Thomson ISI database, we selected articles without primary data written by the five most prolific editorialists that addressed clinical topics pertaining to HRT and that were published in regular journal issues in 2002–2008.
We recorded the number of articles with a partisan stance and their arguments, the number of partisan articles that reported conflicting interests, and the journal venues and their sponsoring societies publishing the partisan editorials.
We analyzed 114 eligible articles (58 editorials, 16 guidelines, 37 reviews, 3 letters), of which 110 (96%) had a partisan stance favoring HRT. Typical arguments were benefits for menopausal and related symptoms (64.9%), criticism of unfavorable studies (78.9%), preclinical data that showed favorable effects of HRT (50%), and benefits for major outcomes such as osteoporosis and fractures (49.1%), cardiovascular disease (31.6%), dementia (24.6%) or colorectal cancer (20.2%), but also even breast cancer (4.4%). All 5 prolific editorialists had financial relationships with hormone manufacturers, but these were reported in only 6 of the 110 partisan articles. Four journals published 15–37 partisan articles each. The medical societies of these journals reported on their websites that several pharmaceutical companies sponsored them or their conferences.
There is a considerable body of editorializing articles favoring HRT use and very few of these articles report conflicts of interest. Full disclosure of conflicts of interest is needed, especially for articles without primary data.
Sources and Press Releases
Partisan Perspectives in the Medical Literature: A Study of High Frequency Editorialists Favoring Hormone Replacement Therapy, Journal of General Internal Medicine, September 2010, Volume 25, Issue 9, pp 914–919, 2010.
Environmental Health Perspectives, Charles W. Schmidt, June 2017
With its associated hot flashes, mood swings, and insomnia, menopause can be a challenging period in a woman’s life. But as much as it marks the end of her childbearing years, menopause—and more specifically the age at which it occurs—can also reflect on a woman’s overall health. An older age at menopause typically reflects good health overall, whereas early menopause—generally defined as occurring before age 40—can reflect poorer health and a greater likelihood of premature mortality.
Now, experts are taking a closer look at how environmental exposures may influence age at menopause and whether exposure-induced changes in menopausal timing put women at greater risk of associated health problems. These are early days in the field, but recent research suggesting a link between potential endocrine-disrupting compounds (EDCs) and early menopausehas raised concerns over how exposures might accelerate hormonal processes involved in female aging.
“We know that going through menopause early increases the risk of osteoporosis, heart disease, and other disorders,
so the long-term health implications of early menopause are considerable.”
says Natalia Grindler, a reproductive and endocrinology fellow at the University of Colorado’s Advanced Reproductive Medicine Division.
There is still much to be learned about the toxicology underlying changes in age at menopause, and isolating chemical effects from the other varied influences that govern when a woman’s reproductive years come to an end is challenging. Nevertheless, this area of study provides a new window on population-level effects from chemical exposures that could have wide-ranging consequences.
Menopause may be a risk factor for hearing loss, and postmenopausal hormone therapy (HT) has been proposed to slow hearing decline; however, there are no large prospective studies. We prospectively examined the independent relations between menopause and postmenopausal HT and risk of self-reported hearing loss.
Prospective cohort study among 80,972 women in the Nurses’ Health Study II, baseline age 27 to 44 years, followed from 1991 to 2013. Baseline and updated information was obtained from detailed validated biennial questionnaires. Cox proportional-hazards regression models were used to examine independent associations between menopausal status and postmenopausal HT and risk of hearing loss.
After 1,410,928 person-years of follow-up, 18,558 cases of hearing loss were reported. There was no significant overall association between menopausal status, natural or surgical, and risk of hearing loss. Older age at natural menopause was associated with higher risk. The multivariable-adjusted relative risk of hearing loss among women who underwent natural menopause at age 50+ years compared with those aged less than 50 years was 1.10 (95% confidence interval [CI] 1.03, 1.17). Among postmenopausal women, oral HT (estrogen therapy or estrogen plus progestogen therapy) was associated with higher risk of hearing loss, and longer duration of use was associated with higher risk (P trend < 0.001). Compared with women who never used HT, the multivariable-adjusted relative risk of hearing loss among women who used oral HT for 5 to 9.9 years was 1.15 (95% CI 1.06, 1.24) and for 10+ years was 1.21 (95% CI 1.07, 1.37).
Older age at menopause and longer duration of postmenopausal HT are associated with higher risk of hearing loss.
Starting periods at a young age is linked to early menopause
Women are more likely to go through menopause early if they started menstruating before their 12th birthday.
This is the conclusion of the largest study of its kind, involving 50,000 postmenopausal women in the UK, Australia, Japan and Scandinavia.
2017 Study Abstract
Are parity and the timing of menarche associated with premature and early natural menopause?
Early menarche (≤11 years) is a risk factor for both premature menopause (final menstrual period, FMP
WHAT IS KNOWN ALREADY
Women with either premature or early menopause face an increased risk of chronic conditions in later life and of early death. Findings from some studies suggest that early menarche and nulliparity are associated with early menopause, however overall the evidence is mixed. Much of the evidence for a direct relationship is hampered by a lack of comparability across studies, failure to adjust for confounding factors and inadequate statistical power.
Early menarche, nulliparity and the risk for premature and early natural menopause, Oxford University Press, doi.org/10.1093/humrep/dew350, 25 January 2017.
STUDY DESIGN, SIZE, DURATION
This pooled study comprises 51 450 postmenopausal women from nine observational studies in the UK, Scandinavia, Australia and Japan that contribute to the International collaboration for a Life course Approach to reproductive health and Chronic disease Events (InterLACE).
PARTICIPANTS/MATERIALS, SETTING, METHODS
Age at menarche (categorized as ≤11, 12, 13, 14 and 15 or more years) and parity (categorized as no children, one child and two or more children) were exposures of interest. Age at FMP was confirmed by at least 12 months of cessation of menses where this was not the result of an intervention (such as surgical menopause due to bilateral oophorectomy or hysterectomy) and categorized as premature menopause (FMP before age 40), early menopause (FMP 40–44 years), 45–49 years, 50–51 years, 52–53 years and 54 or more years. We used multivariate multinomial logistic regression models to estimate relative risk ratio (RRR) and 95% CI for associations between menarche, parity and age at FMP adjusting for within-study correlation.
MAIN RESULTS AND THE ROLE OF CHANCE
The median age at FMP was 50 years (interquartile range 48–53 years), with 2% of the women experiencing premature menopause and 7.6% early menopause. Women with early menarche (≤11 years, compared with 12–13 years) were at higher risk of premature menopause (RRR 1.80, 95% CI 1.53–2.12) and early menopause (1.31, 1.19–1.44). Nulliparity was associated with increased risk of premature menopause (2.26, 1.84–2.77) and early menopause (1.32, 1.09–1.59). Women having early menarche and nulliparity were at over 5-fold increased risk of premature menopause (5.64, 4.04–7.87) and 2-fold increased risk of early menopause (2.16, 1.48–3.15) compared with women who had menarche at ≥12 years and two or more children.
LIMITATIONS, REASONS FOR CAUTION
Most of the studies (except the birth cohorts) relied on retrospectively reported age at menarche, which may have led to some degree of recall bias.
WIDER IMPLICATIONS OF THE FINDINGS
Our findings support early monitoring of women with early menarche, especially those who have no children, for preventive health interventions aimed at mitigating the risk of adverse health outcomes associated with early menopause.
STUDY FUNDING/COMPETING INTEREST(S)
InterLACE project is funded by the Australian National Health and Medical Research Council project grant (APP1027196). G.D.M. is supported by Australian Research Council Future Fellowship (FT120100812). There are no competing interests.
Endocrine disrupting chemicals and reproductive disorders
Cosmetics contain a vast number of chemicals, most of which are not under the regulatory purview of the Food and Drug Administration.
Only a few of these chemicals have been evaluated for potential deleterious health impact: parabens, phthalates, polycyclic aromatic hydrocarbons, and siloxanes.
A review of the ingredients in the best-selling and top-rated products of the top beauty brands in the world, as well as a review of highlighted chemicals by nonprofit environmental organizations, reveals 11 chemicals and chemical families of concern: butylated hydroxyanisole/butylated hydroxytoluene, coal tar dyes, diethanolamine, formaldehyde-releasing preservatives, parabens, phthalates, 1,4-dioxane, polycyclic aromatic hydrocarbons, siloxanes, talc/asbestos, and triclosan.
Age at menopause can be affected by a variety of mechanisms, including endocrine disruption, failure of DNA repair, oxidative stress, shortened telomere length, and ovarian toxicity.
There is a lack of available studies to make a conclusion regarding cosmetics use and age at menopause. What little data there are suggest that future studies are warranted. Women with chronic and consistent use of cosmetics across their lifespan may be a population of concern.
More research is required to better elucidate the relationship and time windows of vulnerability and the effects of mixtures and combinations of products on ovarian health.
British study finds combined HRT nearly triples risk of breast cancer
2% of women monitored for six years got breast cancer – and they were 2.7 times more likely to contract it if they were on combined HRT than if they were not.
Aaccording to the study’s findings, combined HRT increases the risk of breast cancer by 170%.
Menopausal hormone therapy (MHT) increases breast cancer risk; however, most cohort studies omit MHT use after enrolment and many infer menopausal age.
We used information from serial questionnaires from the UK Generations Study cohort to estimate hazard ratios (HRs) for breast cancer among post-menopausal women with known menopausal age, and examined biases induced when not updating data on MHT use and including women with inferred menopausal age.
Menopausal hormone therapy and breast cancer: what is the true size of the increased risk?, nature, 28 July 2016.
Among women recruited in 2003–2009, at 6 years of follow-up, 58 148 had reached menopause and 96% had completed a follow-up questionnaire. Among 39 183 women with known menopausal age, 775 developed breast cancer, and the HR in relation to current oestrogen plus progestogen MHT use (based on 52 current oestrogen plus progestogen MHT users in breast cancer cases) relative to those with no previous MHT use was 2.74 (95% confidence interval (CI): 2.05–3.65) for a median duration of 5.4 years of current use, reaching 3.27 (95% CI: 1.53–6.99) at 15+ years of use. The excess HR was underestimated by 53% if oestrogen plus progestogen MHT use was not updated after recruitment, 13% if women with uncertain menopausal age were included, and 59% if both applied. The HR for oestrogen-only MHT was not increased (HR=1.00; 95% CI: 0.66–1.54).
British study finds combined HRT nearly triples risk of breast cancer, the guardian, 23 August 2016.
Lack of updating MHT status through follow-up and inclusion of women with inferred menopausal age is likely to result in substantial underestimation of the excess relative risks for oestrogen plus progestogen MHT use in studies with long follow-up, limited updating of exposures, and changing or short durations of use.
Endocrine disrupting chemicals and disease susceptibility
The ability of EDCs to alter reproductive function and health in females has been clearly demonstrated by the consequences of DES use in pregnant women. The daughters of women given DES while pregnant were shown to have rare cervicovaginal cancers, decreased fertility and increases in rates of ectopic pregnancy , and early menopause. Many of these disorders have been replicated in laboratory animals treated with DES during gestation. As Newbold points out, the lessons learned from 40 years of DES research in humans and animals are that the female fetus is susceptible to environmentally induced reproductive abnormalities,that gonadal organogenesis is sensitive to synthetic hormones and hormone mimics during critical exposure windows, and that reproductive disease may not appear until decades after exposures.
Endocrine disrupting chemicals and disease susceptibility, Journal of Steroid Biochemistry & Molecular Biology, doi:10.1016/j.jsbmb.2011.08.007, 6 August 2011.
Proper development of ovarian follicles in the fetus is dependent on estrogen exposure during critical periods of development. For instance, mice treated with DES on postnatal day 1–5 develop multioocytic follicles as adults. Therefore,maintaining a homeostatic balance of local and systemic hormones during follicle development is necessary for normal follicle development and germ cell quality. Perturbations in hormone signaling resulting from chemical exposures during developmental periods could contribute to ovarian disorders and declining conception rates in human populations.And while the mechanisms by which EDCs alter follicle development are not fully understood, there is evidence that these chemicals are contributing to increased rates of aneuploidy, polycyctic ovary syndrome (PCOS), premature ovarian failure (POF), and altered cyclicity and fecundity. For example, studies have shown that prenatal exposure to BPA causes irregular cycles in mice, which is likely due to hypothalamic alterations in the circuitry that controls luteinizing hormone (LH) secretion and ovulation. In humans, altered cyclicity has been reported in individuals exposed to organochlorine pesticides. Indeed, cycle irregularities have been noted in women whose mothers were exposed in utero to DES.
Uterine fibroids (leiomyomas) are the most common tumor of the female reproductive system, occurring in 25–50% of all women. The risk of the development of uterine fibroids increases with age during premenopausal years, but tumors typically regress with the onset of menopause. Obesity, age at menarche and unopposed estrogen signaling have been shown to increase the risks for fibroids. The best characterized animal model for the study of uterine fibroids is the Eker rat. A mutation of the tuberous sclerosis complex 2 (Tsc2) tumor suppressor gene causes females to develop spontaneous uterine fibroids at a high frequency. Studies using this model have shown that exposure to EDCs increases the incidence of fibroids in these animals. Developmental exposure to DES causes rats that are genetically predisposed to uterine tumors to develop even more tumors of a larger size, but fails to induce tumors in wild-type rats. Importantly, DES exposure imparts a hormonal imprint on the developing uterus that causes an increase in estrogen-responsive gene expression. The potential for DES to cause uterine fibroids in humans is less clear. Two studies on DES daughters came to different conclusions. In a study of 2570 women born during the period DES was prescribed, no association was found between prenatal exposure and uterine fibroids. Another study of 1188 women found a significant relationship between DES exposure and uterine fibroids. On analysis of these studies, Baird and Newbold concluded that there was a definitive increase in uterine fibroids in DES daughters and the discrepancies between the studies was due to the differences and sensitivities of the methods used to detect the tumors.
In summary, both animal and human studies suggest a role of EDCs in altering female reproductive development. Data from animal experiments show that EDC exposure during critical periods of development, both prenatal and neonatal, can induces functional changes that appear later in life. There are data gaps in understanding the mechanisms by which EDCs carry out their action, but it is clear that to reduce the risk of reproductive disorders we must take action to reduce exposure to these chemicals.
There are things women can do to reduce breast cancer risk
Researchers estimate that close to 30% of all breast cancers in the U.S. could be prevented if women maintained a healthy weight, do not use hormone therapy for menopause, and cut back on drinking and smoking. That conclusion held true even for women who were at a high risk for breast cancer due to family history and genetics.
Breast Cancer Risk From Modifiable and Nonmodifiable Risk Factors Among White Women in the United States, JAMA Oncology, May 26, 2016.
An improved model for risk stratification can be useful for guiding public health strategies of breast cancer prevention.
To evaluate combined risk stratification utility of common low penetrant single nucleotide polymorphisms (SNPs) and epidemiologic risk factors.
Design, Setting, and Participants
Using a total of 17 171 cases and 19 862 controls sampled from the Breast and Prostate Cancer Cohort Consortium (BPC3) and 5879 women participating in the 2010 National Health Interview Survey, a model for predicting absolute risk of breast cancer was developed combining information on individual level data on epidemiologic risk factors and 24 genotyped SNPs from prospective cohort studies, published estimate of odds ratios for 68 additional SNPs, population incidence rate from the National Cancer Institute-Surveillance, Epidemiology, and End Results Program cancer registry and data on risk factor distribution from nationally representative health survey. The model is used to project the distribution of absolute risk for the population of white women in the United States after adjustment for competing cause of mortality.
Single nucleotide polymorphisms, family history, anthropometric factors, menstrual and/or reproductive factors, and lifestyle factors.
Main Outcomes and Measures
Degree of stratification of absolute risk owing to
and some components of menstrual and/or reproductive history
and modifiable factors:
body mass index [BMI; calculated as weight in kilograms divided by height in meters squared],
menopausal hormone therapy [MHT],
The average absolute risk for a 30-year-old white woman in the United States developing invasive breast cancer by age 80 years is 11.3%. A model that includes all risk factors provided a range of average absolute risk from 4.4% to 23.5% for women in the bottom and top deciles of the risk distribution, respectively. For women who were at the lowest and highest deciles of nonmodifiable risks, the 5th and 95th percentile range of the risk distribution associated with 4 modifiable factors was 2.9% to 5.0% and 15.5% to 25.0%, respectively. For women in the highest decile of risk owing to nonmodifiable factors, those who had low BMI, did not drink or smoke, and did not use MHT had risks comparable to an average woman in the general population.
Here Are The Things Women Can Do to Avoid Breast Cancer, time, May 26, 2016.
Conclusions and Relevance
This model for absolute risk of breast cancer including SNPs can provide stratification for the population of white women in the United States. The model can also identify subsets of the population at an elevated risk that would benefit most from risk-reduction strategies based on altering modifiable factors. The effectiveness of this model for individual risk communication needs further investigation.
Female Estrogen-Related Factors and Incidence of Basal Cell Carcinoma in a Nationwide US Cohort
2015 Study Abstract
UV radiation exposure is the primary risk factor for basal cell carcinoma (BCC), the most common human malignancy. Although the photosensitizing properties of estrogens have been recognized for decades, few studies have examined the relationship between reproductive factors or exogenous estrogen use and BCC.
Using data from the US Radiologic Technologists Study, a large, nationwide, prospective cohort, we assessed the relationship between reproductive factors, exogenous estrogen use, and first primary BCC while accounting for sun exposure, personal sun sensitivity, and lifestyle factors for geographically dispersed women exposed to a wide range of ambient UV radiation.
Elevated risk of BCC was associated with late age at natural menopause (hazard ratio [HR] for ≥ 55 years v 50 to 54 years, 1.50; 95% CI, 1.04 to 2.17) and any use of menopausal hormone therapy (MHT; HR, 1.16; 95% CI, 1.03 to 1.30; P for trend for duration = .001). BCC risk was most increased among women reporting natural menopause who used MHT for 10 or more years versus women who never used MHT (HR, 1.97; 95% CI, 1.35 to 2.87). Risk of BCC was not associated with age at menarche, parity, age at first birth, infertility, use of diethylstilbestrol by participant’s mother, age at hysterectomy, or use of oral contraceptives.
These analyses confirm a previous finding of increased risk of BCC associated with MHT. Novel findings of increased BCC risk associated with MHT in women experiencing natural menopause and for late age at natural menopause warrant further investigation. Users of MHT may constitute an additional high-risk group in need of more frequent skin cancer screening.
Sources and more information
Female Estrogen-Related Factors and Incidence of Basal Cell Carcinoma in a Nationwide US Cohort, American Society of Clinical Oncology, doi: 10.1200/JCO.2015.62.0625, November 2, 2015.
Age at menopause, hormone therapy linked to BCC risk, medicalxpress., November 3, 2015.
Washington, DC – The Clinical Practice Guideline (CPG), entitled “Treatment of Symptoms of the Menopause: An Endocrine Society Clinical Practice Guideline” was published online and will appear in the November 2015 print issue of the Journal of Clinical Endocrinology and Metabolism (JCEM), a publication of the Endocrine Society.
Menopause is the life stage that takes place when a woman’s ovaries dramatically decrease production of the hormones estrogen and progesterone, and her menstrual periods stop. The average age of an American woman experiencing menopause is around 51 years old.
During menopause, many women experience symptoms such as hot flashes, night sweats, sleep disturbances, mood changes, joint pain, recurrent urinary tract infections, and difficult or painful sexual intercourse. These symptoms can start in the years before a woman’s final menstrual period and last for more than a decade.
Women now have a broader range of treatment options for menopausal symptoms than ever before, but many clinicians are reluctant to pursue them. A 2012 Endocrine Society survey found that 72 percent of women currently experiencing menopause symptoms had not received any treatment for them.
Hormone therapy—at one time the most popular treatment for menopausal symptoms— has been under intense scrutiny since 2002, when a large government study called the Women’s Health Initiative (WHI) reported that hormone therapy – specifically the combination of conjugated equine estrogens and medroxyprogesterone acetate (Prempro) – increased the risk for blood clots, stroke, breast cancer and heart attacks in postmenopausal women aged 50 to 79 years at study onset. But additional research conducted in the ensuing years indicated the level of risk depends on the individual woman’s health history, age and other factors. Experts have formed a consensus that the benefits of menopausal hormone therapy exceed the risks for most healthy women seeking relief of menopausal symptoms.
“There is no need for a woman to suffer from years of debilitating menopausal symptoms, as a number of therapies, both hormonal and non-hormonal are now available,” said Cynthia A. Stuenkel, MD, the chair of the task force that authored the guideline and an endocrinologist specializing in menopause at the University of California, San Diego. “Every woman should be full partners with her health care providers in choosing whether treatment is right for her and what treatment option best suits her needs. The decision should be based on available evidence regarding the treatment’s safety and effectiveness, as well as her individual risk profile and personal preferences.”
In the CPG – see full PDF – the Endocrine Society recommends that women with a uterus who decide to undergo menopausal hormone therapy with estrogen and progestogen be informed about risks and benefits, including the possible increased risk of breast cancer during and after discontinuing treatment. Health care providers should advise all women, including those taking menopausal hormone therapy, to follow guidelines for breast cancer screening.
Other recommendations from the CPG include:
Transdermal estrogen therapy by patch, gel or spray is recommended for women who request menopausal hormone therapy and have an increased risk of venous thromboembolism – a disease that includes deep vein thrombosis.
Progestogen treatment prevents uterine cancer in women taking estrogen for hot flash relief. For women who have undergone a hysterectomy, it is not necessary.
If a woman on menopausal hormone therapy experiences persistent unscheduled vaginal bleeding, she should be evaluated to rule out endometrial cancer or hyperplasia.
Medications called selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), gabapentin or pregabalin are recommended for women who want medication to manage moderate to severe hot flashes, but either prefer not to take hormone therapy or have significant risk factors that make hormone therapy inadvisable.
Low-dose vaginal estrogen therapy is recommended to treat women for genitourinary symptoms of menopause, such as burning and irritation of the genitalia, dryness, discomfort or pain with intercourse; and urinary urgency or recurrent infections. This treatment should only be used in women without a history of estrogen-dependent cancers.
The Hormone Health Network, the Endocrine Society’s public education arm, developed an interactive digital resource called the Menopause MapTM for women to explore the stages of menopause and learn about symptoms they may experience. The Menopause MapTMrelated resources are available. The Hormone Health Network also offers a digital toolkit for health care providers.
Other members of the Endocrine Society task force that developed this CPG include: Susan R. Davis of Monash University in Melbourne, Australia; Anne Gompel of the Université Paris Descartes in Paris, France; Mary Ann Lumsden of the University of Glasgow School of Medicine in Glasgow, Scotland; M. Hassan Murad of the Mayo Clinical in Rochester, MN; JoAnn V. Pinkerton of the University of Virginia in Charlottesville, VA; and Richard J. Santen of the University of Virginia Health System in Charlottesville, VA.This CPG was co-sponsored by the Australasian Menopause Society, British Menopause Society, European Society of Endocrinology and the International Menopause Society.
The Society established the CPG Program to provide endocrinologists and other clinicians with evidence-based recommendations in the diagnosis and treatment of endocrine-related conditions. Each CPG is created by a task force of topic-related experts in the field. Task forces rely on scientific reviews of the literature in the development of CPG recommendations as well as feedback from co-sponsoring societies, members of the Endocrine Society and expert reviewers. The Endocrine Society does not solicit or accept corporate support for its CPGs. All CPGs are supported entirely by Society funds. A list of CPGs can be found here.