16 September 2019:
Andrew M. Kaunitz, MD and JoAnn E. Manson, MD, DrPH
NEJM Journal Watch
No; benefits will outweigh risks for many menopausal patients who, through discussion of research findings and shared decision making, can make informed choices about HT use.
Hormone therapy (HT) is the most effective treatment for bothersome menopausal vasomotor symptoms. However, after initial publication of findings from the Women's Health Initiative (WHI) randomized clinical trial in 2002, which found that estrogen-progestin therapy (EPT) increased risk for cardiovascular events and breast cancer among women aged 50 to 79 at enrollment (NEJM Journal Watch Womens Health Nov 2013 and JAMA 2013 Oct 2; 310:1353), use of HT plummeted in the U.S. and globally. Subsequently, the estrogen-alone trial in women with hysterectomy showed that conjugated estrogens (for a median of 7 years) did not increase breast cancer risk. Both regimens raised risk for stroke and venous thromboembolism but lowered risk for fractures and diabetes. Thus, HT has a complex risk-benefit pattern, with studies suggesting more-favorable profiles in younger than older women.
Although observational studies over the past several decades have linked HT to increased breast cancer risk, the specific associations with HT formulation, route of delivery, and duration have been poorly studied. In a recent meta-analysis (Lancet Aug 29 2019 [e-pub]), investigators used individual participant data from 58 observational studies reported between 1992 and 2018 to quantify the strength of the relation and the roles of these factors in the HT−breast cancer connection.
All systemic HT formulations (including those using oral conjugated equine estrogens or estradiol or transdermal estradiol) were associated with excess risk for breast cancer. Use of EPT was associated with a greater risk for breast cancer than was estrogen-only therapy (ET). Type of progestogen did not appear to affect these associations. Vaginal estrogen was not associated with increased risk. Assuming the reported associations are causal, the authors estimated the absolute risk for breast cancer up to age 70. For never-users of HT and women who initiated EPT at age 50 and continued for 5 years, risks were 6.3% and 8.3%, respectively; the two percentage-point difference indicates one additional breast cancer case per 50 treated women. At 10 years of HT use, risks were approximately twice that at 5 years.
Experts rip into HRT-cancer study
From The Medical Republic - 9 September 2019
A large study in The Lancet has thrown shade on hormone replacement therapy again by linking it to breast cancer, but experts say the data reflect old prescribing habits and that the benefits of HRT outweigh the risks for many women.
The study was conducted by a group of UK epidemiologists, called The Collaborative Group on Hormonal Factors in Breast Cancer, that have been collecting worldwide data on HRT (also now known as Menopausal Hormone Therapy or MHT) for decades.
Their latest meta-analysis pooled data from 58 observational studies, including about 600,000 women.
The study found that all types of HRT were associated with an excess risk of breast cancer, except topical vaginal oestrogen.
The risk was higher in post-menopausal women who used HRT for longer periods of time, and in women who used HRT more regularly.
Oestrogen-progestogen carried a higher risk of breast cancer than oestrogen-only therapy, and the risk increased over time.
After five to 14 years on oestrogen-progestogen, the risk of breast cancer had doubled compared with never-users.
If these relationships were found to be causal, around one million cases of breast cancer could be linked to HRT use since 1990, the authors estimated.
But these conclusions have been soundly refuted by Australian experts.
It had been known for some time that HRT slightly elevated the risk of breast cancer, but this study was probably overexaggerating the risks, Professor Susan Davis, the president of the International Menopause Society and an endocrinologist based in Melbourne, said.
The paper in The Lancet was based on observational research, which could not control for unknown confounders and could therefore be misleading, she said.
The risks of breast cancer reported by the Women’s Health Initiative (WHI) were probably closer to the truth, Professor Davis said.
The WHI was a randomised trial of 27,000 US women in the 1990s, which revealed that oestrogen plus progesterone increased invasive breast cancer risk by 24% compared with placebo over six to seven years.
However, both studies used older HRT preparations that clinicians no longer prescribed, which limited their relevance to current patients, she said.
“Today, we use non-oral oestrogen, which we can prescribe as a patch or a gel, so we can use much, much lower doses.
“And we prefer to prescribe it with progesterone, which is not the synthetic progestogen. That may have very different effects. We really don’t know but … there are some data to suggest that these are much safer.”
The Lancet paper only addressed breast cancer risk, but “HRT is never unidimensional”, Professor Davis said. “You might have a small increased risk of breast cancer maybe [from using HRT] but you also might have a profoundly reduced risk of fracture.”
HRT was also known to reduce the risk of cardiovascular disease and diabetes, so clinicians needed to carefully weigh the costs and benefits for the individual patient, Professor Davis said.
Update on vaginal laser therapy
9 November 2018:
Earlier this week, Professor Chris Maher a urogynaecologist from the University of Queensland and Dr Melissa Buttini, a gynaecologist at the Wesley Hospital in Brisbane raised some serious questions about vaginal laser treatment of genitourinary syndrome of the menopause (GSM).
The Therapeutics Goods Administration (TGA) approved CO2 laser therapy for a number of body soft tissues, however was not listed specifically for treatment of GSM. There is no Medicare Benefits Schedule item number for CO2 laser therapy and so the extent of its use cannot be measured. We do know however that advertisements for CO2 laser therapy treatment for symptoms of GSM are extensive.
In July this year, the Food and Drug Administration (FDA) in the US issued a warning about the use of CO2 laser therapy for ‘vaginal rejuvenation’ and stated “These products have serious risks and don’t have adequate evidence to support their use for these purposes. We are deeply concerned women are being harmed.”
AMS President Clinical Associate Professor Amanda Vincent was interviewed for the Australian Doctor in response to the MJA article and noted “There are safety concerns and significant costs involved - the recommendation is for 3 treatments in a 12-month period with each treatment costing $500-$1000.”
Maher and Buttini question the abstract and conclusion of the first randomised control trial undertaken by Cruz et al reported in January this year. While Cruz et al suggest that vaginal laser therapy has a place in the treatment of GSM, further investigation of the methods and results paint a different story. Patients in the vaginal oestrogen intervention reported better outcomes compared with patients in the laser/sham cream arm who reported a significant worsening of pain.
In MJA InSight, Maher warns “What really causes some anxiety for me is we have been through all this within the past 10 years with transvaginal meshes, we’re still going through it.” Clearly further evidence is required from rigorous clinical trials before we can recommend vaginal laser as a therapy for GSM. In the interim, vaginal/topical oestrogen is the gold standard treatment for GSM as it is safe and efficacious. The only group of women who can’t use that are those with breast cancer or breast cancer survivors.
The AMS looks forward to hearing the results of a double-blinded, randomised, placebo-controlled trial of the efficacy of the MonaLisa Touch procedure for the treatment of postmenopausal vulvovaginal symptoms currently being undertaken by Professor Jason Abbott at the Royal Hospital for Women in Randwick.
FDA Approves New Oral Hormone Therapy Treatment For Menopause Symptoms
The U.S. Food and Drug Administration approved TherapeuticsMD’s oral hormone therapy for menopause symptoms such as hot flashes, sleep disturbances and night sweats, the company reported late October 2019.
The therapy, Bijuva, is an oral softgel capsule containing a combination of artificial hormones chemically identical to human female sex hormones, estradiol and progesterone.
Bijuva is expected to be available in the United States in the second quarter of 2019. The treatment carries a boxed warning.
Obesity and vitamin D deficiency may indicate greater risk for breast cancer
Vitamin D is already well known for its benefits in building healthy bones. A new study supports the idea that it also may reduce cancer risk as well as breast cancer mortality, especially in women with a lower body mass index.
Breast cancer remains the most common cancer in women worldwide and is the leading cause of death from cancer in women. Reproductive risk factors such as early onset of puberty, late menopause, later age at first pregnancy, never having been pregnant, obesity, and a family history have all been shown to be associated with breast cancer development. The role of vitamin D concentration in the development of breast cancer, however, continues to be debated.
This study involving more than 600 Brazilian women suggests that vitamin D may reduce cancer risk by inhibiting cell proliferation. Study results appear in the article "Low pretreatment serum concentration of vitamin D at breast cancer diagnosis in postmenopausal women."
Researchers involved in the study concluded that postmenopausal women had an increased risk of vitamin D deficiency at the time of their breast cancer diagnoses, associated with higher rates of obesity, than women of the same age group without cancer. Similar studies also have previously demonstrated a relationship between vitamin D and breast cancer mortality. Women in the highest quartile of vitamin D concentrations, in fact, had a 50% lower death rate from breast cancer than those in the lower quartile, suggesting that vitamin D levels should be restored to a normal range in all women with breast cancer.
"Although published literature is inconsistent about the benefits of vitamin D levels and breast cancer, this study and others suggest that higher levels of vitamin D in the body are associated with lowered breast cancer risk," says Dr. JoAnn Pinkerton, executive director of NAMS. "Vitamin D may play a role in controlling breast cancer cells or stopping them from growing. Vitamin D comes from direct sunlight exposure, vitamin D3 supplements, or foods rich in vitamin D."
Risk of early menopause and exercise
The amount of physical activity that women undertake is not linked to their risk of early menopause, according to the largest study ever to investigate this question.
Until now, there have been conflicting findings about the relation between physical activity and menopause, with some studies suggesting that women who are very physically active may be at lower risk of a menopause before the age of 45, while others have found evidence of the opposite effect.
However, the study that is published in Human Reproduction , one of the world's leading reproductive medicine journals, has analysed data from 107,275 women, who were followed prospectively from the time they joined the Nurses' Health Study II in 1989 until 2011, and found no association between physical activity at any age and early natural menopause.
Dr Elizabeth Bertone-Johnson, Professor of Epidemiology at the University of Massachusetts, USA, who directed the research, said: "Our study provides considerable information in helping us understand the relationship between activity and timing of menopause; this is because of its size, its focus on early menopause specifically, and because of its prospective design, which limited the likelihood of bias and allowed us to look at physical activity at different time periods.
"Several previous well-designed studies have found suggestions that more physical activity is associated with older age at menopause, but even in those studies the size of the effect was very small. Our results, in conjunction with other studies, provides substantial evidence that physical activity is not importantly associated with early menopause."
Female US registered nurses aged 25-42 were enrolled in the Nurses' Health Study II in 1989 and they completed questionnaires about lifestyles and medical conditions every two years thereafter. They were asked about the time they spent in recreational physical activities such as walking, running, cycling, racquet sports, swimming laps, aerobic activities, yoga, weight training and high intensity activities such as lawn mowing. The researchers also collected information on factors such as race, ethnicity, age, education, height, the age when the women had their first periods, whether or not they had been pregnant and how often, use of oral contraceptives and hormone therapy, whether or not they smoked, weight and body mass index (BMI), diet and use of dietary supplements.
In order to assess the frequency, duration and intensity of the activities, the researchers multiplied the hours per week of each activity by its metabolic equivalent (MET) score to create total MET hours per week. One MET equals one kilogram calorie per kilogram per hour (kcal/kg/h), which is the amount of energy expended by sitting quietly for an hour.
During the 20 years of follow-up, 2786 women experienced natural menopause before the age of 45. The researchers found no significant difference in the risk of early menopause between, for instance, women reporting less than three MET hours a week of physical activity and women reporting 42 or more hours a week (the equivalent to four or more hours of running or eight or more hours of brisk walking per week). The amount of physical activity that the women reported in their teenage years was also unrelated to the risk of early menopause.
Chemotherapy may lead to early menopause in young women with lung cancer
A study suggests chemotherapy may cause acute amenorrhea leading to early menopause in women with lung cancer. The study is the first to comment on amenorrhea rates in women younger than 50, concluding that women with lung cancer who desire future fertility should be educated about risks and options before starting treatment.
According to the Mayo Clinic, although the rate of lung cancer diagnoses in men has decreased by 32% since 1975, it has risen 94% percent in women and now has surpassed breast cancer as the leading cause of cancer death in US women. Although lung cancer is more common in older adults, women are diagnosed at a younger age compared with men, and approximately 5,000 premenopausal US women are diagnosed with lung cancer annually. Extensive research of women receiving treatment for breast cancer has found that between 40% and 80% have premature menopause. However, early menopause rates after lung cancer treatments are understudied.
Unique to the premenopausal survivor population is the concern that systemic chemotherapy may cause acute amenorrhea and menopause, leading not only to hot flashes, vaginal dryness, and bone loss but also the possibility of loss of fertility. Premenopausal women with lung cancer may want children and should consult their healthcare providers about options for embryo and oocyte cryopreservation, the gold standard for fertility preservation.
The study included 182 premenopausal women (average age at diagnosis, 43 years). The Mayo Clinic Epidemiology and Genetics of Lung Cancer Research Program surveyed women between 1999 and 2016 at diagnosis and annually thereafter about their menstrual status. Types of lung cancer treatments were recorded, and frequencies of self-reported menopause at each survey were calculated.
The results of the study appear in the article "Amenorrhea after lung cancer treatment." Although the study is small, for the 85 women who received chemotherapy, 64% self-reported that they were menopausal within a year of diagnosis. Only 15% of the 94 patients who did not receive systemic therapy within a year of diagnosis experienced self-reported menopause. Three patients received targeted therapy alone, two of whom remained premenopausal at the final survey completed a median of 3 years after diagnosis. The results suggest that chemotherapy for patients with lung cancer increases the risk of the early loss of menses in survivors.
"Although more definitive research is needed, premenopausal women who need chemotherapy for lung cancer appear to have a similar risk of amenorrhea, early menopause, and loss of fertility as premenopausal women receiving chemotherapy for breast cancer and lymphoma," according to Dr. JoAnn Pinkerton, executive director of NAMS. "I agree that premenopausal patients with lung cancer need to be educated about the risk for chemotherapy-related amenorrhea, menopause issues (hot flashes, vaginal dryness, and bone loss), and the potential loss of fertility before chemotherapy is initiated."
New guidelines for the evaluation and treatment of perimenopausal depression
New "Guidelines for the Evaluation and Treatment of Perimenopausal Depression: Summary and Recommendations have been co-published in Journal of Women's Health and Menopause: The Journal of The North American Menopause Society. The Guidelines are published online here in Journal of Women's Health, a peer-reviewed publication from Mary Ann Liebert, Inc., publishers, and are available to download free until October 5, 2018.
The North American Menopause Society (NAMS) expert panel was convened by NAMS and the Women and Mood Disorders Task Force of the National Network of Depression Centers (NNDC) to conduct a systematic review of the existing literature, and develop clinical guidelines for the evaluation and treatment of depression during the perimenopause.
Panel co-chairs Pauline M. Maki, PhD, University of Illinois at Chicago and Susan G. Kornstein, MD (Editor-in-Chief of Journal of Women's Health), Virginia Commonwealth University Institute for Women's Health, Richmond, VA, developed the recommendations with panel members on behalf of the Board of Trustees for NAMS and the Women and Mood Disorders Task Force of the NNDC. The panel focused on five key areas: epidemiology of depressive symptoms and depressive disorders; the clinical presentation of depression; the therapeutic effects of antidepressant medications; the effects of hormone therapy; and the efficacy of other therapies, such as psychotherapy, exercise, and natural health products.
"There has been a need for expert consensus, as well as clear clinical guidance regarding how to evaluate and treat depression in women during the perimenopause," states Dr. Kornstein. "These new clinical recommendations address this gap, and offer much-needed information and guidance to healthcare practitioners so that they can provide optimal care and treatment for midlife women."
The guidelines address 5 areas: epidemiology; clinical presentation; therapeutic effects of antidepressants; effects of hormone therapy; and efficacy of other therapies.
Among the recommendations:
- When selecting antidepressants during perimenopause, a woman’s prior history of antidepressant use should be considered.
- Cooccurring sleep disturbances and night sweats should be considered as part of treatment for menopause-related depression.
- While estrogen-based therapies may help improve clinical response to antidepressants, their use in older women should be considered with caution.
Estrogen may protect against depression after heart attack
Estrogen may protect against heart failure-related depression by preventing the production of inflammation-causing chemicals in the brain. The study is published ahead of print in the American Journal of Physiology - Heart and Circulatory Physiology.
Research suggests that people with heart failure--including those who survive heart attacks--are two to three times more likely to suffer from depression than the general population. The reason for heart failure-related depression is thought to be increased inflammation in the brain. Previous studies have also found that post-menopausal women with heart disease have a greater risk of depression than younger women and men of all ages.
Researchers from the University of Ottawa Heart Institute and Brain and Mind Institute in Canada studied a rat model of heart failure after heart attack. Adult female rats without ovaries--mimicking menopause--were compared to adult males and adult females with ovaries. Half of the "menopausal" rats received estrogen supplements while the other half did not. Sex-matched rats without heart failure served as controls. The animals were given several standardized tests to assess depression-like behavior, learning, memory and the ability to experience pleasure. The researchers also took blood samples to measure inflammation levels in the brain (neuroinflammation).
The male rats, but not the female rats, with heart failure showed signs of depression and brain inflammation compared to their controls. In contrast, the menopausal females displayed higher rates of depression-like behavior than all of the males studied. However, the group receiving estrogen showed no depression--their levels were on par with the control females with ovaries--and no increase in inflammation in brain areas involved in mood and pleasure.
"Our findings demonstrate that sex and estrogens influence neuroinflammation and depression-like behavior in rats with [heart failure] post [heart attack]," the researchers wrote. "Understanding the mechanisms contributing to these sex-specific and estrogen-dependent responses may contribute to new therapies that may be sex-specific."
Vaginal Laser Therapy
Statement from FDA Commissioner Scott Gottlieb, M.D., on efforts to safeguard women’s health from deceptive health claims and significant risks related to devices marketed for use in medical procedures for “vaginal rejuvenation”
Our most fundamental obligation to the American public is providing patients with access to safe and effective medical products to meet their health care needs as well as protecting them from harmful products and deceptive medical claims. A large part of our work focuses on efforts to bring forth innovative, new products. But we’re equally dedicated to monitoring the landscape to ensure products are delivering on their intended benefits and to ensure that if new health risks arise, we take appropriate action.
Delivering on this complementary mission is a key aim of our Medical Device Safety Action Plan. The plan outlines how the FDA will encourage innovation to improve safety, detect safety risks earlier and keep doctors and patients better informed. Our plan would establish a robust medical device patient safety net in the U.S. We are taking steps to streamline and modernize how we implement post-market actions to address device safety issues to make our response to risks more timely and effective.
Advancing the health of women is a priority for the FDA. As part of our action plan, we’re working to improve evidence generation about the safety and effectiveness of health technologies in clinical areas that are unique to women. And as part of these efforts, we also watch for, and take action against, bad actors who unfortunately take advantage of unsuspecting consumers by marketing unapproved, deceptive products that may pose safety risks and violate the trust of American consumers.
That’s what we’re doing today.
We’ve recently become aware of a growing number of manufacturers marketing “vaginal rejuvenation” devices to women and claiming these procedures will treat conditions and symptoms related to menopause, urinary incontinence or sexual function. The procedures use lasers and other energy-based devices to destroy or reshape vaginal tissue. These products have serious risks and don’t have adequate evidence to support their use for these purposes. We are deeply concerned women are being harmed.