North American Menopause Society (NAMS) video series about important midlife health topics: Hormones and Breast Health

The North American Menopause Society (NAMS) is proud of its comprehensive video series for women on important midlife health topics. All the interviews in the series are hosted by NAM Board of Trustees Member and Immediate Past-President Dr. Marla Shapiro, a Canadian physician who led this exciting initiative. Dr. Shapiro is also the medical consultant for CTV News.

In this video of 2018 series, Dr. Shapiro discusses the very controversial topic of hormones replacement therapy (HRT) and breast cancer with Dr. Stephanie Faubion, Director, Office of Women’s Health at the Mayo Clinic, Rochester, Minnesota.

HRT remains the most effective solution for the relief of menopausal symptoms and is also effective for the prevention of osteoporosis. It is thought to be associated with increased risk of stroke and breast cancer, but the risk has not been yet quantified. Dr. Faubion talks about HRT in various clinical settings, including women who have a family history of breast cancer and those with BRCA mutations.

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Do not use HRT solely for primary prevention of chronic diseases: USPSTF final recommendation

The US Preventive Services Task Force (USPSTF) recommends against the use of HRT in asymptomatic post-menopausal women solely for preventing chronic diseases in its final statement published yesterday in JAMA.

The recommendation holds good for estrogen alone or combined with progestin and upholds the previous 2012 statement.

The USPSTF statement does acknowledge few benefits of HRT in postmenopausal women such as reducing the risk of fractures and diabetes, but the potential harms outweigh the moderate benefits cited.

Combined use of estrogen and progestin is associated with increased risk of invasive breast cancer, coronary artery disease, venous thromboembolism, stroke, dementia, gallbladder disease, and urinary incontinence.

Use of estrogen alone predisposes the women to greater risk for thromboembolism, stroke, dementia, gallbladder disease, and urinary incontinence.

The recommendations were based on evidence from  Women's Health Initiative (WHI) trials, which were stopped early because of sufficient evidence of serious adverse effects in postmenopausal women.

The USPSTF statement is accompanied by an editorial by Cora E. Lewis, MD, MSPH, from the Division of Preventive Medicine at University of Alabama at Birmingham School of Medicine, and Melissa F. Wellons, MD, MHS, from the Division of Diabetes, Endocrinology and Metabolism at Vanderbilt University Medical Center in Nashville, Tennessee says that although the WHI trial was a observational study, till date no large sufficiently powered trials exist to recommend against the WHI conclusions.

The authors further asserted that these recommendations do not apply to “women who are considering hormone therapy for the management of menopausal symptoms, such as hot flashes or vaginal dryness. It also does not apply to women who have had premature menopause (primary ovarian insufficiency) or surgical menopause.”  

Also, the route of administration considered in the study is oral or transdermal and not creams and rings because those are not generally used for primary prevention of chronic conditions.

The editorial also mentions about the “timing hypothesis” put forward by the American Association of Clinical Endocrinologists/American College of Endocrinology in its July 2017 updated guidelines on menopause.

USPSTF statement stats that there is not sufficient evidence to support the “timing hypothesis” at present. It requires very large, sufficiently powered studies to evaluate the risk/benefit ratio in this specific age group.

At present, few women are on HRT, and physicians consider HRT only for the treatment of menopausal symptoms. Relatively healthy, younger menopausal women with severe climacteric symptoms may be prescribed HRT for symptoms relief and not for chronic disease prevention.

Full Text of  USPSTF guidance
 Editorial

WHI Study: No increased all-cause mortality with menopausal hormone therapy

www.urmc.rochester.edu

Menopausal hormone therapy with conjugated equine estrogens (CEE) plus medroxyprogesterone acetate (MPA) did not increase all-cause mortality and disease specific mortality in participants of Women’s Health Study(WHI) after nearly 2 decades of follow-up says the results of new data analysis published online in JAMA.

This study is specifically important because earlier studies have never looked into disease specific and all-cause mortality of women receiving hormone therapy. Menopausal hormone therapy is debated since decades, and the interest in prescribing HT waxes and wanes as new data is published.

The researchers analyzed data from two studies:  the first study was estrogen with progestin trial and the second was estrogen only trial published in JAMA in 2002 and 2004 respectively.

The researchers conducted an extended follow-up of women included in this trial for 18 years. The combined trial included 16,608 women with a uterus while the estrogen only trial included 10,739 women with a history of hysterectomy.

In the estrogen+ progesterone group, 8506 women were randomized to receive HT and 8102 were given placebo for a median of 5.6 years. In estrogen only group, 5310 women took estrogen and 5429 were placed on placebo for a median 7.2 years.

For the current analysis, the researchers pooled the data from these 2 studies, amounting to a total of 27,347 women, with ages between 50 to 79 years and 80.6% being white. These women were followed up for 18 years. There were 7489 deaths through December 31, 2014, including 1088 during the trial and 6401 since the trials ended.

All-cause mortality did not defer between the two study arms, it was 27.1% in the hormone therapy group vs 27.6% in the placebo group (hazard ratio [HR], 0.99 [95% CI, 0.94-1.03]) in the overall pooled cohort. The figures were similar for cardiovascular and cancer mortality.

The only difference in mortality was observed for breast cancer, with estrogen+ progesterone group facing a 44% increased risk relative to placebo while estrogen was protective against breast cancer and reduced the risk by 45%. 

Both the earlier trials were stopped early when it became clear that HT did not improve the CVD outcomes as for both trials the primary outcome was prevention of chronic diseases and not to gauge the effectiveness of HT in managing menopausal symptoms.

Hence, the results of the study are especially important as they reassure the physician and patient that HT can be safely used for management of menopausal symptoms with a positive risk/benefit profile.

At the same time, it should also be noted that HT increases risk of stroke and breast cancer and decreases risk of endometrial and uterine cancer and hip fractures.

Still, the results of the study cannot be applied in every situation and for all women. Women who are at high risk for blood clots and breast cancer, the added increased risk may outweigh the benefit of alleviating menopausal symptoms individually.

The article is accompanied by an editorial by Melissa McNeil, MD, MPH, from the University of Pittsburgh in Pennsylvania which highlights the complexity of the issue. She writes, "Although the long-term data on total and cause-specific cumulative mortality of pooled data for hormone users vs nonusers is both compelling and reassuring, several questions remain. Perhaps the most challenging question involves the issue of whether there is a difference in overall mortality by age and menopausal status at the time of initiation of hormone therapy."

"This reduction in mortality...thus remains suggestive but not definitive," Dr McNeil further added. 

"Other questions that remain include the optimal duration of hormone therapy and if an even earlier initiation of hormone therapy, such as within 2 years of the menopausal transition, would provide additional benefits."

So, the takeaway from the study results is: HRT can be prescribed to treat menopausal symptoms with a positive risk-benefit profile without increasing all cause, cardiovascular and cancer mortality. It however should not be prescribed for prevention of  CVD and other chronic conditions.

The authors have disclosed no relevant financial relationship.

North American Menopause Society (NAMS) video series about important midlife health topics: Menopausal Hormone Therapy

The North American Menopause Society (NAMS) has started comprehensive video series for clinicians about important midlife health topics. All the interviews in the series are hosted by NAMS Board of Trustees Member and President Dr. Marla Shapiro, a Canadian physician, who led this exciting initiative.

This video addresses menopausal hormone therapy concerns in light of recent scientific data. Dr. Schnatz also discusses the timing hypothesis as well as multiple new routes of treatment.

Dr. Schnatz  discusses menopausal hormone therapy.

Endocrine Society issues a position statement against custom compounded Hormone therapy

The Endocrine Society cautious physicians against the use of compounded hormone for treatment of menopausal symptoms, female sexual dysfunction, and thyroid disorders in a scientific statement issued at Endo 16, the Annual Meeting at Boston from April 1-4, 2016.

The Society  supported the use of  FDA approved therapies and asserted that custom compounded Hormone formulations should only be used when the patient is allergic or does not tolerate  the FDA approved drugs and treatment is cardinal to his/her health.

“By no means do I wish to disparage the practice of pharmacists who are measuring hormones and providing them to patients,” Nanette Santoro, MD, professor and chair of reproductive endocrinology and infertility, department of obstetrics and gynecology at the University of Colorado Denver, said during a press conference discussing the recommendations. “Where we get into scientific trouble ... is as soon as something is being custom compounded, it’s being measured out and added to a variety of agents and diluters that will make it into a pill or a gel. ... How these excipients influence how these hormones get into a person, and what that hormone does, is essentially unknown.”

She also opined that one third to one quarter of all the drugs prescribed for menopausal hormone therapy are custom compounds as observed in a recent survey. She was also appalled at the large amount bioidentical and formulations available in the market that are similar to FDA approved therapies. “It is also a perversion of the intent of the practice of custom compounding,” She added.

This statement is also endorsed by a number of other societies like American College of Obstetricians and Gynecologists and the North American Menopause Society; nonetheless almost 60% of clinicians prescribe so-called bioidentical compounded menopausal hormone therapy, against recommendations from major medical societies, according to a new survey.

Custom compound hormone is a big business, with annual sales of $ 1 billion, and  are largely popular among patients as many clinicians prescribe them telling they are without any side effects. But, the reality is the side effects have never been tested. “What has happened is the absence of evidence of harm is taken as proof of safety,” Santoro said. “This is very illogical, yet it pervades the media and the popular press. You see happy people with anecdotes ... what we don’t know are how much they’re getting and what are the biological endpoints?”

Currently, the only indication for prescribing compounding therapy is in a woman who needs testosterone since there is no good commercially available drug in market added Dr Sklar, who is an assistant professor of medicine and endocrinology at Georgetown University Medical Center and George Washington University Medical Center, Washington, DC.

The endocrine society new document provides detailed review of many FDA approved hormonal products:

• No randomized, double-blind, placebo-controlled trials demonstrating efficacy of compounded bioidentical drugs in relieving menopausal symptoms exists as also no trials comparing FDA approved therapy vs. compounding formulations  could be found.
• For Menopausal Hormone therapy, non oral formulations are associated with reduced risk of venous thromboembolism and stroke.
• Micronized Progesterone is a treatment of choice opted by some physician, and is considered safe biochemically, but evidence is lacking regarding benefit on clinical front.   
• Transdermal patches, gels, and intramuscular preparations of bioidentical testosterone are available and FDA approved for use in men with hypogonadism, but no FDA approved testosterone preparation for women.
• There are currently no FDA approved preparations available for dehydroepiandrosterone (DHEA), no indication for prescribing it except in few patients with low libido. The bioidentical preparations come with all the drawbacks of dosing, absorption and safety as estrogen and progesterone.
• Vaginal formulation is currently undergoing trial for vaginal atrophy, but no FDA approved preparation is available in the market.
• Levothyroxine (LT4) is bioidentical, and is a highly effective therapy in patients with hypothyroidism. It is converted to T3 at tissue level and acts on all the target receptors in the body. Some patients may still exhibit symptoms of hypothyroidism; inspite adequate dosing and the clinician should investigate them for other causes. Compounded hormone therapy can be used in such patients with close monitoring of TSH and free T4.

The statement was published online April 1, 2016 in the Journal of Clinical Endocrinology and Metabolism.

References:

http://www.healio.com/endocrinology/hormone-therapy/news/online/%7B810eb536-ab0d-4524-8f1d-c8302774b2df%7D/custom-compounded-hormones-linked-to-risks-side-effects-in-menopausal-women

http://press.endocrine.org/doi/abs/10.1210/jc.2016-1271?journalCode=jcem

http://www.medscape.com/viewarticle/861365#vp_3