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.

Endometrial cancer management guidelines updated: assorting the uncertainties! -----2

The first joint European Society for Medical Oncology (ESMO), European SocieTy for Radiotherapy & Oncology (ESTRO) and European Society of Gynaecological Oncology (ESGO) consensus conference on endometrial cancer was held on 11–13 December 2014 in Milan, Italy.

These guidelines were published in an article by Colombo N et al in January issue of Annals of Oncology. 

These guidelines were developed based on 12 questions identified by the expert panel. 

The first question was addressed in part 1: Which surveillance should be used for asymptomatic women?

The second question is: What work-up and management scheme should be undertaken for fertility-preserving therapy in patients with atypical hyperplasia (AH)/endometrial intraepithelial neoplasia (EIN) and grade 1 endometrioid endometrial cancer (EEC)?

 

It’s rare that young women of childbearing age will be diagnosed with EC, with only 4% of all patients being younger than 40 years of age. 

Younger women also have a better prognosis, being at early and low grade stage of disease when diagnosed. The standard approach in women of childbearing age is hysterectomy and bilateral salpingo-oophorectomy with or without lymphadenectomy. This procedure has a very good survival ( 93% at 5 years) but results in permanent loss of reproductive capacity. 

The conservative management consist of medical therapy with progestins (oral or local) for premalignant and grade 1 EC.

Recommendation 2.1: Patients with AH/EIN or grade 1 EEC requesting fertility-preserving therapy must be referred to specialised centres. Level of evidence: V, Strength of recommendation: A

Recommendation 2.2: In these patients, D&C with or without hysteroscopy must be performed .Level of evidence: IV, Strength of recommendation: A 

Recommendation 2.3: AH/EIN or grade 1 EEC must be confirmed/diagnosed by a specialist gynaecopathologist .Level of evidence: IV,Strength of recommendation: A

Recommendation 2.4: Pelvic MRI should be performed to exclude overt myometrial invasion and adnexal involvement. Expert ultrasound can be considered as an alternative.Level of evidence: III, Strength of recommendation: B

Recommendation 2.5: Patients must be informed that fertility-sparing treatment is a non-standard treatment and the pros and cons must be discussed. Patients should be willing to accept close follow-up and be informed of the need for future hysterectomy.Level of evidence: V,Strength of recommendation: A

Recommendation 2.6: For patients undergoing fertility-preserving therapy, MPA (400–600 mg/day) or MA (160–320 mg/day) is the recommended treatment. However, treatment with LNG-IUD with or without GnRH analogues can also be considered.Level of evidence: IV,Strength of recommendation: B

Recommendation 2.7: In order to assess response, D&C, hysteroscopy and imaging at 6 months must be performed. If no response is achieved after 6 months, standard surgical treatment should be performed. Level of evidence: IV,Strength of recommendation: B

Recommendation 2.8: In case of complete response, conception must be encouraged and referral to a fertility clinic is recommended.Level of evidence: IV, Strength of recommendation: B

Recommendation 2.9: Maintenance treatment should be considered in responders who wish to delay pregnancy.Level of evidence: IV,Strength of recommendation: B

Recommendation 2.10: Patients not undergoing hysterectomy should be re-evaluated clinically every 6 months.Level of evidence: IV,Strength of recommendation: B

Recommendation 2.11: After completion of childbearing, a hysterectomy and salpingo-oophorectomy should be recommended. The preservation of the ovaries can be considered depending on age and genetic risk factors. Level of evidence: IV, Strength of recommendation: B 

Pregnancy is protective for endometrial cancer and the pooled pregnancy rate in a recent metaanalysis was 28%, which reached 39% when assisted reproductive technology was used.
  

To be continued…..

References:

Colombo N,Creutzberg CL, Amant F et al. ESMO-ESGO-ESTRO consensus conference on endometrial cancer: diagnosis, treatment and follow-up. Ann Oncol 2016; 27: 16–41.