Category Archives: Medical Treatments with Cancer Risks

NCHR Comments on Risks and Benefits of Menopause Hormone Therapy

Medical Treatments with Cancer Risks, Policy, Testimony & Briefings, Uncategorized

The National Center for Health Research (NCHR) appreciates the opportunity to provide comments in response to the FDA’s request for public input on the risks and benefits of menopause hormone therapy (MHT), following the July 17, 2025, Expert Panel meeting and the opening of docket FDA-2025-N-2589.

NCHR is a nonprofit think tank committed to bridging the gap between scientific evidence and public policy to protect the health and safety of patients and consumers. Our work focuses on ensuring that medical and consumer products are evaluated based on rigorous, independent evidence, with particular attention to how benefits and risks may differ across patient populations, including women and men at different life stages.

We commend the FDA for seeking broad stakeholder input to update the labeling of hormone therapy products for menopause to reflect current scientific understanding. Given the widespread use of menopausal hormone therapy (MHT) for symptom relief, it is vital that labeling clearly communicates nuanced risks and benefits so that women and their healthcare providers can make informed, evidence-based decisions.

Local (Vaginal) Hormones vs Systemic

Randomized controlled trials including the REJOICE trial of a vaginal estradiol soft-gel capsule, the MsFLASH Vaginal Estradiol Trial, and a phase III trial of DHEA (dehydroepiandrosterone-  Prasterone) along with systematic reviews demonstrate that low-dose vaginal estrogen and DHEA provide symptomatic relief of dyspareunia, dryness, and recurrent UTIs without increasing serum estradiol above placebo and systematic reviews demonstrate that low-dose vaginal estrogen and DHEA provide symptomatic relief of dyspareunia, dryness, and recurrent UTIs without increasing serum estradiol above placebo levels [1–3]. DHEA is a precursor steroid that can be converted intracellularly into estrogens and androgens in vaginal tissue, improving vaginal epithelium thickness, elasticity, and lubrication without raising systemic estradiol levels [4-6].

The Nurses’ Health Study followed postmenopausal women for up to 18 years, during which a subset reported vaginal estrogen use at one or more time points. Analyses compared ever-users versus never-users over that follow-up period and found no increased risk of myocardial infarction, stroke, venous thromboembolism, breast cancer, endometrial cancer, or other invasive cancers [7]. This study did not determine whether there were differences in risks for women who used vaginal estrogen for a longer vs. shorter period of time during those 18 years. 

The Women’s Health Initiative Observational Study (WHI-OS) had a median follow-up of 7.2 years. Within that timeframe, Crandall et al. reported that women who used vaginal estrogen for a median of 2 years did not show higher risks of breast, endometrial, or cardiovascular events compared with non-users [8]. While 2–7 years of use and follow-up are informative, longer use and longer follow-up would provide greater reassurance about safety, since cancer usually is more likely to develop after longer-term exposures and longer latency periods.

Pharmacokinetic studies further support these findings, showing serum estradiol levels remain within postmenopausal ranges during treatment [9].

There are several studies of the impact of vaginal estrogen on breast cancer survivors who took endocrine therapy to reduce the recurrence of breast cancer. It is important to emphasize that women with estrogen receptor–positive breast cancer, which is the most common type, are typically prescribed 5–10 years of adjuvant endocrine therapy (tamoxifen or aromatase inhibitors) specifically to block estrogen [11-14]. Prescribing additional estrogen, even at local low doses, may undermine the benefits of their cancer hormonal treatment [12].

The evidence for vaginal estrogen for women taking endocrine therapy for cancer is mixed and limited by lack of stratification evaluating frequency of use or comparing long-term and short-term use:

  • Streff et al. studied women on aromatase inhibitors using Estring and found a statistically significant but modest increase in serum estradiol (from undetectable to ~10–20 pmol/L in some women), suggesting partial reversal of estrogen suppression and warranting individualized decision-making [10].
  • Cold et al., in a large Danish cohort, reported that vaginal estrogen was associated with increased recurrence risk when combined with aromatase inhibitors, but not when used concurrently with tamoxifen [15].
  • McVicker et al., a UK population-based study of more than 49,000 cancer survivors, reported no reduction in survival among vaginal estrogen ever-users compared with never-users. However, this study did not stratify by ER status or by concurrent use of tamoxifen or aromatase inhibitors, making it difficult to draw useful conclusions about the possible risks [11].

Taken together, these findings underscore the need for better research evaluating different levels of exposure to low-dose vaginal estrogen, and for careful oncologist–patient consultation before initiating vaginal hormones in women with ER-positive disease, particularly those receiving adjuvant endocrine therapy.

Black Box Warning 

The current Black Box warning on low-dose vaginal estrogen extrapolates systemic WHI trial data from women who were aged 50–79 years at enrollment (mean age ~63), many of whom initiated therapy more than 10 years after menopause and had higher baseline cardiometabolic risk, to local therapies with minimal absorption [16]. Although research evidence from WHI-OS and the Nurses’ Health Study are limited by not evaluating the impact of long-term low-dose vaginal hormone use, as noted above, the results are frequently reported as showing no increased risk of breast cancer, endometrial cancer, cardiovascular disease, or VTE among users of low-dose vaginal estrogen versus non-users. Similarly, a systematic review of randomized trials (most lasting 12 months or less) and observational studies of low-dose vaginal estrogens found very low rates of endometrial hyperplasia and cancer [6]. Serum estradiol levels generally remained within postmenopausal ranges during treatment [9], although small increases were observed in some aromatase-inhibitor–treated survivors using a vaginal ring [10]. 

Patients deserve labels on low-dose vaginal estrogen that accurately reflect the best research data.  Although long-term clinical trials are not available, the evidence to date indicates a safer product than the current label implies.  Women who want to use low-dose vaginal estrogen to treat GSM symptoms, recurrent UTIs, progression to urosepsis, and atrophic changes,  should be aware of the known benefits as well as the limited number of years those results are based on [17, 18]. Recent research indicates that vaginal estrogen is an effective non-antibiotic strategy to prevent recurrent UTIs, which could lower antibiotic use that results in  antimicrobial resistance [19].

Systemic Hormone Therapy for Menopause 

Despite controversies about Systemic MHT, there are two areas of widespread agreement:

Temporary Benefit for Osteoporosis: MHT prevents fractures only while therapy is continued; benefits wane or disappear after discontinuation [10].
Endometrial Cancer: Systemic estrogen without progestin increases endometrial cancer risk; progestins mitigate this [10].

Impact on Dementia and Cardiovascular Health. In contrast, claims that systemic MHT prevents dementia or cardiovascular disease are not supported by the most recent, well-designed trials. The Women’s Health Initiative Memory Study (WHIMS) was a randomized, double-blind, placebo-controlled ancillary trial of the WHI that enrolled postmenopausal women aged 65 and older [20]. It found that women randomized to combined estrogen plus progestin had a statistically significant doubled risk of probable dementia compared with placebo, where ‘probable dementia’ was defined by DSM-IV clinical criteria after abnormal screening on the Modified Mini-Mental State Examination (3MS). WHI also showed no reduction in coronary heart disease (CHD) and instead reported a statistically significant increased risks of stroke and venous thromboembolism (VTE) [21]. Statements at the FDA Expert Panel describing MHT as “very safe” and protective against dementia and heart disease rely on studies with major methodological weaknesses, and have findings contradicted by more recent, better designed studies. High-quality evidence from RCTs and meta-analyses, including a 2015 Cochrane review [22], confirms systemic MHT does not prevent CHD or dementia. Therefore, labeling should explicitly state those risks as well as: ‘Not indicated for prevention of dementia, cognitive decline, coronary heart disease, or stroke.’

Examples of the flaws of the studies quoted in support of claims of preventing dementia or cardiovascular disease include the following:

Paganini-Hill and Henderson (1996): This case-control study used death certificates to ascertain Alzheimer’s disease and retrospective exposure assessment, with minimal adjustment for confounders and high potential for selection and survival bias. Findings were later contradicted by WHIMS randomized controlled trial results [20,23].

Simpkins (2012): This is a narrative review of rodent and mechanistic studies. It therefore cannot establish clinical benefit for dementia prevention in postmenopausal women [24].

Saleh (2023; EPAD): This cross-sectional analysis of the European Prevention of Alzheimer’s Dementia (EPAD) cohort focused on APOE4 carriers, which is a group at higher genetic risk for dementia. Among these women, only 29 were using HRT, while the remainder of the APOE4 carriers were not. The small study was non-randomized, was subject to healthy user bias and residual confounding, and relied on surrogate outcomes such as cognition and imaging markers rather than incident dementia. Therefore, no causal inference is appropriate [25].

Bagger (2005): This was a post-hoc subgroup analysis of the Danish Osteoporosis Prevention Study (DOPS). Although the parent trial enrolled over 2,000 women, only 333 underwent cognitive testing, creating a small sample to be analyzed. Results suggested cognitive benefit with early HRT initiation, but the analysis was underpowered, involved multiple comparisons with wide confidence intervals, and was potentially influenced by conflicts of interest. The findings were not replicated in later, larger randomized trials such as WHIMS  [26].

Barrett Connor (1991) and Nurses’ Health Study (2000): These observational cohorts adjusted for some confounding variables but remained subject to  substantial healthy user bias, since hormone therapy users were generally healthier, of higher socioeconomic status, and had better access to care. These studies were also limited by confounding by indication and time related biases. The apparent cardioprotective signals were refuted by WHI randomized findings [22, 27-28].

Breast Cancer Risks.

Breast cancer risk with MHT is complex. WHI showed combined estrogen + progestin increases incidence, while estrogen-only may reduce risk in women who had a  prior hysterectomy [21, 29]. Duration and timing are key: Brien et al. pooled analysis found that more than 2 years of estrogen + progestin was linked to increased ER-negative and triple-negative cancers in younger women [30]. Zhang et al. found that women with dense breasts using MHT were more likely to develop interval cancers, which are more aggressive and often ER-negative [31].

Recommendations for Boxed Warnings

The FDA has precedent for formulation-specific warnings (e.g., lidocaine topical vs systemic) and we recommend that for MHT as well. We recommend retaining boxed warnings for all estrogen-containing products, but they should differ for systemic and local therapies.

Low-dose Vaginal Estrogen

Boxed warnings for low-dose vaginal products should not be based on systemic MHT but instead should state that long-term RCTs are lacking, and that unknown risks remain regarding prolonged use and long-term follow-up. The boxed warning should say that relatively short-term studies have not demonstrated excess cardiovascular or cancer risk. This labeling should emphasize caution for ER+ breast cancer survivors whether or not they are currently taking hormonal therapy for breast cancer.

Systemic Hormone Therapy for Menopause

FDA should retain the current boxed warning for systemic hormonal therapy for menopause, with a notation that there is specific information included in the regular narrative section on warnings and contraindications.  

Systemic Therapy is Not Preventive. Labeling for systemic MHT should include an explicit statement that it is not indicated for prevention of dementia, cognitive decline, coronary heart disease, or stroke. It should specify that it reduces osteoporosis temporarily, while the woman is using MHT only. The label should cite WHI and WHIMS as the highest-quality data.

Breast Cancer Risks: Nuanced and Subtype-Specific. The label should be updated to reflect the following:

  • Increased incidence with combined estrogen-progestin (WHI).
  • Reduced or neutral risk with estrogen-only in women with prior hysterectomy.
  • Increased risk of ER-negative and triple-negative cancers after more than 2 years of combined use in younger women [30].
  • Higher likelihood of interval cancers in women with dense breasts using MHT [31].
  • Advise tailored screening and shared decision-making for these higher-risk women.

The warning section should also indicate the following:

  • Postmenopausal bleeding warrants evaluation for endometrial pathology.
  • Breast cancer survivors should consult with their oncologists before using MHT.

Evidence Gaps and Future Research

The label should acknowledge the absence of high-quality RCTs stratified by dose, route, formulation, and duration.

In conclusion, we recommend the following FDA Actions

  1. Revise boxed warnings to distinguish systemic from local therapies [1-3,7-8, 15-16, 32].
  2. Add an explicit “Not preventive” statement that systemic MHT is not indicated for dementia, cognitive decline, CHD, or stroke [20-21,23-28,33].
  3. Update breast cancer sections with regimen- and subtype-specific risks, including young-onset and dense breast findings [15,29,31].
  4. Add guidance for breast cancer patients and survivors: Avoid vaginal estrogen during cancer hormonal therapy unless benefits outweigh risks; consider alternatives such as DHEA or ospemifene [8-11].
  5. Revise Medication Guides to differentiate between systemic vs local therapies, summarizing benefits, risks, and unknowns.
  6. Provide guidance to industry to conduct RCTs to clarify comparative safety by dose, route, formulation, and duration.

Thank you for the opportunity to share our views. We urge the FDA to hold Advisory Committee meetings prior to revising the labeling, and that the Committee members represent a diversity of views based on scientific and statistical expertise free of conflicts of interest associated with pharmaceutical funding or medical practice. Women deserve accurate, evidence-based labeling that distinguishes risk profiles of different MHT products and promotes informed, patient-centered decision-making free of bias.  We welcome the opportunity to work with the FDA on this important issue, and can be reached at info@center4research.org. 

References

  1. Constantine, G. D., Simon, J. A., Pickar, J. H., Archer, D. F., Kushner, H., Bernick, B., … & Mirkin, S. (2017). The REJOICE trial: a phase 3 randomized, controlled trial evaluating the safety and efficacy of a novel vaginal estradiol soft-gel capsule for symptomatic vulvar and vaginal atrophy. Menopause, 24(4), 409-416.
  2. Mitchell, C. M., Reed, S. D., Diem, S., Larson, J. C., Newton, K. M., Ensrud, K. E., … & Guthrie, K. A. (2018). Efficacy of vaginal estradiol or vaginal moisturizer vs placebo for treating postmenopausal vulvovaginal symptoms: a randomized clinical trial. JAMA internal medicine, 178(5), 681-690.
  3. Labrie, F., Archer, D., Bouchard, C., Fortier, M., Cusan, L., Gomez, J. L., … & Balser, J. (2009). Intravaginal dehydroepiandrosterone (Prasterone), a physiological and highly efficient treatment of vaginal atrophy. Menopause, 16(5), 907-922.
  4. Labrie F, Archer DF, Koltun W, Vachon A, Young D, Frenette L, Moyneur É. Efficacy of intravaginal DHEA (prasterone) on moderate to severe dyspareunia and vaginal dryness in postmenopausal women. Menopause. 2018;25(11):1339–1353.
  5. Panjari M, Davis SR. Vaginal DHEA to treat menopause-related atrophy: a review of the evidence. Maturitas. 2011;70(1):22–25.
  6. Constantine GD, Graham S, Lapane K, Ohleth K, Bernick B, Liu J, Mirkin S. Endometrial safety of low-dose vaginal estrogens in menopausal women: a systematic evidence review. Menopause. 2019;26(7):800–807.
  7. Bhupathiraju, S. N., Grodstein, F., Stampfer, M. J., Willett, W. C., Crandall, C. J., Shifren, J. L., & Manson, J. E. (2019). Vaginal estrogen use and chronic disease risk in the Nurses’ Health Study. Menopause, 26(6), 603-610.
  8. Crandall CJ, Hovey KM, Andrews CA, Chlebowski RT, Stefanick ML, Lane DS, Shifren JL, Chen C, Kaunitz AM, Cauley JA, Manson JE. Breast cancer, endometrial cancer, and cardiovascular events in participants who used vaginal estrogen in the Women’s Health Initiative Observational Study. Menopause. 2018;25(1):11–20.
  9. Dimitrakakis, C., Zhou, J., & Bondy, C. A. (2002). Androgens and mammary growth and neoplasia. Fertility and Sterility, 77, 26-33.
  10. Streff, A., Chu-Pilli, M., Stopeck, A., & Chalasani, P. (2021). Changes in serum estradiol levels with Estring in postmenopausal women with breast cancer treated with aromatase inhibitors. Supportive Care in Cancer, 29(1), 187-191.
  11. McVicker, L., Labeit, A. M., Coupland, C. A., Hicks, B., Hughes, C., McMenamin, Ú., … & Cardwell, C. R. (2024). Vaginal estrogen therapy use and survival in females with breast cancer. JAMA oncology, 10(1), 103-108.
  12. Davies, C., Pan, H., Godwin, J., Gray, R., Arriagada, R., Raina, V., … & Peto, R. (2013). Long-term effects of continuing adjuvant tamoxifen to 10 years versus stopping at 5 years after diagnosis of oestrogen receptor-positive breast cancer: ATLAS, a randomised trial. The Lancet, 381(9869), 805-816.
  13. Early Breast Cancer Trialists’ Collaborative Group (EBCTCG). Aromatase inhibitors versus tamoxifen in early breast cancer: patient-level meta-analysis of the randomized trials. Lancet. 2015;386(10001):1341–1352.
  14. Burstein, H. J., Temin, S., Anderson, H., Buchholz, T. A., Davidson, N. E., Gelmon, K. E., … & Griggs, J. J. (2014). Adjuvant endocrine therapy for women with hormone receptor–positive breast cancer: American Society of Clinical Oncology clinical practice guideline focused update. Journal of clinical oncology, 32(21), 2255-2269.
  15. Cold, S., Cold, F., Jensen, M. B., Cronin-Fenton, D., Christiansen, P., & Ejlertsen, B. (2022). Systemic or Vaginal Hormone Therapy After Early Breast Cancer: A Danish Observational Cohort Study. Journal of the National Cancer Institute, 114(10), 1347–1354. https://doi.org/10.1093/jnci/djac112
  16. Constantine, G. D., Graham, S., Lapane, K., Ohleth, K., Bernick, B., Liu, J., & Mirkin, S. (2019). Endometrial safety of low-dose vaginal estrogens in menopausal women: a systematic evidence review. Menopause, 26(7), 800-807.
  17. Tan-Kim, J., Shah, N. M., Do, D., & Menefee, S. A. (2023). Efficacy of vaginal estrogen for recurrent urinary tract infection prevention in hypoestrogenic women. American journal of obstetrics and gynecology, 229(2), 143.e1–143.e9. https://doi.org/10.1016/j.ajog.2023.05.002
  18. https://www.auanet.org/about-us/media-center/press-center/american-urological-association-releases-new-guideline-on-genitourinary-syndrome-of-menopause
    Accessed on September 22-24, 2025
  19. Danan, E. R., Sowerby, C., Ullman, K. E., Ensrud, K., Forte, M. L., Zerzan, N., Anthony, M., Kalinowski, C., Abdi, H. I., Friedman, J. K., Landsteiner, A., Greer, N., Nardos, R., Fok, C., Dahm, P., Butler, M., Wilt, T. J., & Diem, S. (2024). Hormonal Treatments and Vaginal Moisturizers for Genitourinary Syndrome of Menopause : A Systematic Review. Annals of internal medicine, 177(10), 1400–1414. https://doi.org/10.7326/ANNALS-24-00610
  20. Shumaker, S. A., Legault, C., Rapp, S. R., Thal, L., Wallace, R. B., Ockene, J. K., … & WHIMS Investigators. (2003). Estrogen plus progestin and the incidence of dementia and mild cognitive impairment in postmenopausal women: the Women’s Health Initiative Memory Study: a randomized controlled trial. Jama, 289(20), 2651-2662.
  21. Rossouw, J. E., Anderson, G. L., Prentice, R. L., LaCroix, A. Z., Kooperberg, C., Stefanick, M. L., … & Ockene, J. (2002). Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women’s Health Initiative randomized controlled trial. Jama, 288(3), 321-333.
  22. Boardman, H., Hartley, L., Eisinga, A., Main, C., & Figuls, M. R. I. (2016). Cochrane corner: oral hormone therapy and cardiovascular outcomes in post-menopausal women. Heart, 102(1), 9-11.
  23. Paganini-Hill, A., & Henderson, V. W. (1996). Estrogen replacement therapy and risk of Alzheimer disease. Archives of internal medicine, 156(19), 2213-2217.
  24. Simpkins, J. W., Singh, M., Brock, C., & Etgen, A. M. (2012). Neuroprotection and estrogen receptors. Neuroendocrinology, 96(2), 119-130.
  25. Saleh, R. N. M., Hornberger, M., Ritchie, C. W., & Minihane, A. M. (2023). Hormone replacement therapy is associated with improved cognition and larger brain volumes in at-risk APOE4 women: results from the European Prevention of Alzheimer’s Disease (EPAD) cohort. Alzheimer’s research & therapy, 15(1), 10. https://doi.org/10.1186/s13195-022-01121-5
  26. Bagger, Y. Z., Tankó, L. B., Alexandersen, P., Qin, G., Christiansen, C., & PERF Study Group. (2005). Early postmenopausal hormone therapy may prevent cognitive impairment later in life. Menopause, 12(1), 12-17.
  27. Barrett-Connor, Elizabeth, and Trudy L. Bush. “Estrogen and coronary heart disease in women.” Jama 265, no. 14 (1991): 1861-1867.
  28. Grodstein, F., Manson, J. E., Colditz, G. A., Willett, W. C., Speizer, F. E., & Stampfer, M. J. (2000). A prospective, observational study of postmenopausal hormone therapy and primary prevention of cardiovascular disease. Annals of internal medicine, 133(12), 933-941.
  29. Chlebowski, R. T., Anderson, G. L., Gass, M., Lane, D. S., Aragaki, A. K., Kuller, L. H., … & WHI Investigators. (2010). Estrogen plus progestin and breast cancer incidence and mortality in postmenopausal women. Jama, 304(15), 1684-1692.
  30. O’Brien, K. M., House, M. G., Goldberg, M., Jones, M. E., Weinberg, C. R., de Gonzalez, A. B., Bertrand, K. A., Blot, W. J., DeHart, J. C., Couch, F. J., Garcia-Closas, M., Giles, G. G., Kirsh, V. A., Kitahara, C. M., Koh, W. P., Park, H. L., Milne, R. L., Palmer, J. R., Patel, A. V., Rohan, T. E., … Sandler, D. P. (2025). Hormone therapy use and young-onset breast cancer: a pooled analysis of prospective cohorts included in the Premenopausal Breast Cancer Collaborative Group. The Lancet. Oncology, 26(7), 911–923. https://doi.org/10.1016/S1470-2045(25)00211-6
  31. Zhang, Y., Rodriguez, J., Mao, X., Grassmann, F., Tapia, J., Eriksson, M., … & Czene, K. (2025). Incidence and risk factors of interval and screen-detected breast cancer. JAMA oncology, 11(5), 519-527.
  32. Hickey, T. E., Selth, L. A., Chia, K. M., Laven-Law, G., Milioli, H. H., Roden, D., … & Tilley, W. D. (2021). The androgen receptor is a tumor suppressor in estrogen receptor–positive breast cancer. Nature medicine, 27(2), 310-320.
  33. MedPage Today. FDA panel on MHT. 2025 Jul 17. Available from: https://www.medpagetoday.com/obgyn/menopause/117467
    Accessed on September 22-24,2025. 

Compounded Bioidentical Hormone Therapy

Breast Cancer, Medical Treatments with Cancer Risks, , , ,

Keris KrennHrubec, Meg Seymour, & Diana Zuckerman, PhD

To avoid the risks of conventional hormone therapy, more and more women are seeking alternatives. But how safe are compounded bioidentical hormones?

When women enter menopause, their bodies produce less estrogen and progesterone. This can cause hot flashes, night sweats, insomnia and other symptoms. Hormone therapy can supplement those hormones, but it increases the risk of breast cancer and other serious diseases. What are your options if the symptoms of menopause are difficult to cope with?

In 2002, a major research study reported that FDA-approved hormone therapy can increase a woman’s risk of heart disease, breast cancer, and stroke. (For more information, please visit: Hormone Therapy and Menopause). As a result, women started to look for alternatives to conventional hormone therapy. Custom-compounded bioidentical hormone therapy (CBHT) has been marketed as more natural and safer, but does the scientific evidence support those claims?

Natural and Safe?

Many of the hormones used in conventional hormone therapy are derived from animal products. Bioidentical hormones, on the other hand, are from plants and are more similar (although not necessarily identical) to the hormones that naturally occur in the human body. However, the term “bioidentical” is misleading and has no scientific value. Bioidenticals are created in laboratories through at least 15 chemical reactions, and they are not identical to hormones produced by human bodies.[1,2] To date, no studies have shown that bioidenticals are safer than conventional hormone therapy and experts used to assume they have similar benefits and risks for patients.[3,4]

The FDA asked the National Academies of Sciences, Engineering and Medicine to form a committee that would assess whether cBHT is an adequate substitute for the traditional therapies that are FDA-approved. In 2020, the committee issued a report that there was not sufficient data to say that cBHT is a safe and effective treatment for menopause. Although some people have reported anecdotal claims that cBHT is safe and effective, these anecdotes are not scientific data.[5] 

The Pros and Cons of Compounding

Some bioidentical hormones (such as small particles of progesterone and estradiol) have been approved by the FDA,[1] but most are not. Instead, they are prescribed as a compound with ingredients that are mixed and blended by pharmacies to “create a customized medication for an individual patient”.[6,7] Since compounding is used to make individualized medication, it is not approved by the FDA. Compounding of some medications is necessary for some patients, such as patients who are allergic to one component of an approved drug or who need a particular dosage that differs from the FDA-approved medicine. However, since it is not monitored the way an FDA-approved drug is, compounded drugs are not proven to be safe or effective.[7]

Women who are considering compounded bioidentical hormones often start by getting their individual hormone levels checked through saliva or serum tests. This may create the impression that the bioidentical drugs will be customized for each patient, but research has not shown that these hormonal tests are meaningful or can ensure a safe or effective product.[1,3]

Risks Through Compounding

In addition to not being approved by the FDA as safe or effective, compounded drugs have an additional risk of being contaminated [3] or having an inaccurate dosage.[6] Either can be dangerous. Since compounded drugs are not FDA-approved, they also lack warnings on labels about possible side effects, including serious ones.[1,8] Several of the ingredients that are commonly used in bioidentical hormones – such as testosterone – have not been approved by the FDA for use for postmenopausal women.[3]

Despite these concerns, many women have been prescribed bioidentical hormones for menopause. That’s why the FDA announced in 2018 that they will expand research on compounded bioidentical hormone therapy.[9]

How Do I Know If My Hormone Therapy Has Been Compounded?

Compounded bioidentical drugs are legal if they are in response to a doctor’s prescription.[7] It is unlawful for a pharmacy to simply give you modified drugs without consent. However, even if it is legal, that doesn’t mean it will be safe or effective. If you have any questions or concerns about your hormone therapy, you should talk to your doctor or pharmacist.[10]

You can recognize FDA-approved hormone therapy by the use of brand names such as Premarin, Vagifem and Estrace. The bioidenticals micronized progesterone (brand name Prometrium) and estradiol (brand name Vivelle) have also been approved by the FDA. If your medication has been compounded, you will see terms such as estrone, estradiol, testosterone or progesterone instead of brand names. You are probably receiving CBHT if you have been asked for a saliva or serum test to establish an individualized treatment course.[1,2]

Traditional hormone therapy can be effective for menopausal symptoms, but can increase the risk of cancer and other serious diseases. Bioidentical hormones may have the same risks. You can find more information on the FDA-approved hormone therapies here.

 

All articles are reviewed and approved by Dr. Diana Zuckerman and other senior staff.

  1. American College of Obstetricians. (2012). Compounded bioidentical menopausal hormone therapy. Fertility and Sterility, 98(2), 308-312. (reaffirmed in 2018)
  2. Gass, M. L., Stuenkel, C. A., Utian, W. H., LaCroix, A., Liu, J. H., & Shifren, J. L. (2015). Use of compounded hormone therapy in the United States: report of the North American Menopause Society Survey. Menopause, 22(12), 1276-1285.
  3. Pinkerton, J. V., & Pickar, J. H. (2016). Update on medical and regulatory issues pertaining to compounded and FDA-approved drugs, including hormone therapy. Menopause (New York, NY), 23(2), 215.
  4. National Institute on Aging. (June 2017). Hot Flashes: What Can I Do? Retrieved from: https://www.nia.nih.gov/health/hot-flashes-what-can-i-do#risks
  5. The National Academies of Sciences, Engineering and Medicine (July 2020). Report: The Clinical Utility of Compounded Bioidentical Hormone Therapy (cBHT) A Review of Safety, Effectiveness, and Use. Retrieved from: https://www.nap.edu/resource/25791/cBHT%20Consensus%20Study%20Report%20Highlights.pdf
  6. FDA (June 2018). Report: Limited FDA Survey of Compounded Drug Products. Retrieved from: https://www.fda.gov/drugs/human-drug-compounding/report-limited-fda-survey-compounded-drug-products
  7. FDA (June 2018). Compounding and the FDA: Questions and Answers. Retrieved from: https://www.fda.gov/drugs/human-drug-compounding/compounding-and-fda-questions-and-answers.
  8. FDA (June 2018). Compounding Oversight. Retrieved from: https://www.fda.gov/drugs/human-drug-compounding/compounding-oversight
  9. FDA (September 2018). FDA announces new and expanded compounding research projects. Retrieved from: https://www.fda.gov/drugs/drug-safety-and-availability/fda-announces-new-and-expanded-compounding-research-projects
  10. FDA (February 2018). Menopause: Medicines to Help You. Retrieved from: https://www.fda.gov/consumers/free-publications-women/menopause-medicines-help-you

Allergan Recalls Textured Breast Implants Globally Due to Cancer Links

In the News, Medical Treatments with Cancer Risks, News Stories & Editorials, We're In the News

Sasha Chavkin, IJIC: July 24, 2019.

Allergan will recall its Biocell textured breast implants worldwide after United States health authorities requested that it remove them from the market due to their association with a rare cancer of the immune system.

The announcement, which reflects the most sweeping recognition to date of the serious health risks associated with breast implants, comes after the U.S. Food and Drug Administration obtained new data showing that Allergan implants were linked to most known cases of the cancer, breast implant-associated anaplastic large cell lymphoma (BIA-ALCL).

“Once the evidence indicated that a specific manufacturer’s product appeared to be directly linked to significant patient harm, including death, the FDA took action to alert the firm to new evidence indicating a recall is warranted to protect women’s health,” said FDA Principal Deputy Commissioner Amy Abernethy, in a statement issued by the agency.

The company said the recalled implants, both saline and silicone, would no longer be distributed or sold in any market where they are currently available.

[…]

President of the National Center for Health Research Diana Zuckerman, who has called for stricter oversight of breast implants, said Allergan’s recall was a step in the right direction but did not eliminate the risks of BIA-ALCL.

“When women decide to get breast implants for reconstruction after mastectomy or for breast augmentation, they should not be putting their lives at risk for lymphoma,” Zuckerman said.

“This recall will reduce that risk but it won’t eliminate it, because the FDA has stated that not all women with BIA-ALCL had these specific types of implants.”

In its press conference, the FDA said that it was considering additional measures to protect patient safety.

The agency said it would soon announce updated labeling standards for breast implants, and that these might include a black box safety warning, which is reserved for products that pose the most serious health risks.

The FDA also said it might require a patient checklist, a document that briefly states the key health risks from breast implants which patients would sign before undergoing surgery. The agency is not recommending that women who currently have Allergan Biocell implants get their implants removed, unless they experience signs or symptoms of BIA-ALCL.

Read the full story here.

Allergan Recalls Textured Breast Implants Linked to Rare Cancer

In the News, Medical Treatments with Cancer Risks, News Stories & Editorials, We're In the News

Laurie McGinley, Washington Post: July 24, 2019.

Allergan announced a worldwide recall of textured breast implants Wednesday after the Food and Drug Administration found a sharp increase in a rare cancer and deaths linked to the products and asked the company to pull them off the U.S. market.

The Dublin-based company said it is recalling Biocell textured breast implants and tissue expanders from all markets in which they are sold. The devices had already been banned or recalled in several countries.

The FDA said the new data shows that 573 cases worldwide have linked the rare cancer to the implants since the agency began tracking the issue in 2011. The vast majority of those cases involve Allergan products. Thirty-three women have died of what’s known as breast implant-associated anaplastic large cell lymphoma, a cancer of the immune system. Of those fatalities, authorities identified the implant manufacturer in 13 cases — and it was Allergan in all but one.

In February, the last time the FDA had updated its numbers on implant-associated illness, it reported 457 cases and nine deaths worldwide.

The agency said Wednesday that the latest data indicates the risk of such disease is six times greater with Allergan Biocell textured implants than with other types of textured implants sold in the United States.

The FDA’s new stance against the Biocell product is a reversal of its posture a few months ago, when it said there was insufficient evidence to try to remove the devices from the market.

Jeffrey Shuren, director of the FDA’s Center for Devices and Radiological Health, said on a news call the agency changed its position partly after seeing the sharp increase in reported deaths.

Allergan pulled the products off the European market last year. Canada banned them in May after finding an increased risk of cancer.

[…]

Diana Zuckerman, president of the National Center for Health Research, a nonprofit organization, welcomed the FDA’s decision to press Allergan to recall the implants. “We are very glad they have done it,” she said. “I think they could have done it months ago and I hope a lot of women have not been getting these implants in the meantime.”

The FDA said that in most cases, the rare lymphoma linked to the implants is found in scar tissue and fluid near the devices, but that sometimes it can spread throughout the body. The condition can be life-threatening if it isn’t diagnosed and treated promptly, the agency said. Most patients are treated successfully by surgery to remove the implant and scar tissue but some may require chemotherapy or radiation.

Scientists are not sure why certain textured implants might be linked to the rare cancer. “We don’t know what it is that might increase the risk,” said Binita Ashar, director of the FDA’s office of surgical and infection control devices.

The agency said its data on the rising incidence of illnesses and deaths related to the implants came from medical device reports and searches of medical literature.

See the full article here.

Allergan Recalls Textured Breast Implant Tied to Rare Cancer

In the News, Medical Treatments with Cancer Risks, News Stories & Editorials, We're In the News

Matthew Perrone, AP for ABC Action News; July 24, 2019

WASHINGTON (AP) — Breast implant maker Allergan Inc. issued a worldwide recall Wednesday for textured models because of a link to a rare form of cancer.

The U.S. Food and Drug Administration said it called for the removal after new information showed Allergan’s Biocell breast implants with a textured surface account for a disproportionate share of rare lymphoma cases. The move follows similar action in France, Australia and Canada.

The FDA is not recommending women with the implants have them removed if they are not experiencing problems.

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 Photo by: Matt McGlashen 

WASHINGTON (AP) — Breast implant maker Allergan Inc. issued a worldwide recall Wednesday for textured models because of a link to a rare form of cancer.

The U.S. Food and Drug Administration said it called for the removal after new information showed Allergan’s Biocell breast implants with a textured surface account for a disproportionate share of rare lymphoma cases. The move follows similar action in France, Australia and Canada.

The FDA is not recommending women with the implants have them removed if they are not experiencing problems.

[…]

The FDA said the latest figures show more than 80 percent of the 570 confirmed cases of the lymphoma worldwide have been linked to Allergan implants. The updated figures reflect 116 new cases of the cancer since the FDA last released figures earlier this year.

The new numbers still reflect a rare disease considering an estimated 10 million women globally have breast implants.

There is no firm agreement on the exact frequency of the disease, known as breast implant-associated anaplastic large cell lymphoma. Published estimates ranging from 1 in 3,000 patients to 1 in 30,000 patients.

Diana Zuckerman, a researcher who has studied breast implant safety, called the removal of the devices inevitable.

“Either the company would voluntarily decide to withdraw them from the market to protect from lawsuits, or the FDA would persuade Allergan to do so,” Zuckerman said in an email.

Read the full story here.

Radiation Therapy for Ductal Carcinoma In Situ (DCIS)

Breast Cancer, Breast Cancer, General Treatment Issues, Medical Treatments with Cancer Risks

Diana Zuckerman, PhD, Cancer Prevention and Treatment Fund.

In recent years, ductal carcinoma in situ (DCIS) has become one of the most commonly diagnosed breast conditions. It is often referred to as “stage zero breast cancer” or a “pre-cancer.” It is a non-invasive breast condition that is usually diagnosed on a mammogram when it is so small that it has not formed a lump. In DCIS, some of the cells lining the ducts (the parts of the breast that secrete milk) have developed abnormally, but the abnormality has not spread to other breast cells.

DCIS is not painful or dangerous, but it sometimes develops into breast cancer in the future if it is not treated. If it develops into breast cancer, it can spread.  If that happens, it is called invasive breast cancer. The goal of treating invasive cancer is to prevent it from spreading to the lungs, bones, brain, or other parts of the body, where it can be fatal. Since DCIS is not an invasive cancer, it is even less of a threat than Stage 1 or Stage 2 breast cancer, which are the earliest types of invasive cancer.1  For more information, see our free DCIS booklet, and our other articles on DCIS.

Most women with DCIS will never develop invasive cancer whether they are treated or not.  Unfortunately, it is impossible to predict which women with DCIS will develop cancer and which ones won’t. That’s why treatment is recommended. A woman with DCIS does not need all the same treatments as a woman diagnosed with invasive breast cancer, but surgery is almost always recommended, as is hormonal therapy (such as tamoxifen) if the DCIS is estrogen-receptor positive. Most DCIS patients will choose a lumpectomy (which removes the DCIS but does not remove the entire breast), and radiation therapy is usually recommended for those women to destroy any stray abnormal cells in the same breast.1  However recommendations for radiation therapy are changing.

Is Radiation Necessary?

Doctors usually recommend radiation therapy for lumpectomy patients, but since it is inconvenient and has some side effects, many women prefer to avoid it.  In fact, some DCIS patients decide to have a mastectomy because they do not want to undergo radiation.  However, mastectomy is a much more radical surgery and is very rarely a good idea for DCIS patients. That’s because almost all women with DCIS live long lives, and undergoing radiation does not affect whether DCIS patients live a long life or not.

Instead, the main advantage of radiation for DCIS is to prevent recurrence of DCIS in the breast where the DCIS was removed. A study of more than 1,700 women with DCIS who underwent a lumpectomy evaluated different treatment options.4  The women were randomly assigned either to radiation, tamoxifen, radiation plus tamoxifen, or no treatment after surgery.  Undergoing radiation had a very small benefit for women in general, and has little impact on your chances of living a cancer-free life.

In women treated with radiation, about 10% developed DCIS or breast cancer within the next 10 years after surgery, and it made no difference whether these women took tamoxifen or not. And while the vast majority of women were alive 10 years later, their chances of survival were no different whether they were treated with radiation, tamoxifen, both, or neither.4  

For women who did not have radiation therapy, tamoxifen reduced the chances of developing DCIS within 10 years in the same breast by about 3% and the chances of developing DCIS in the other breast by about 1%. Tamoxifen did not significantly decrease the chances of developing invasive breast cancer in the same breast, and only reduced the chances of developing invasive cancer in the opposite breast by about 1%.4

So why do doctors so strongly recommend radiation and hormone therapy for DCIS?  Doctors tend to focus on reducing “relative risk” rather than actual risk. So, if a  treatment decreases the chances of recurrence by about 50% that sounds impressive — but 50% of a 16% chance is 8%, for example, and that isn’t much of a difference. And 50% of a 6% chance of recurrence is even less meaningful.  Most important, it doesn’t affect survival so women can skip radiation now and choose it later if they have a recurrence. In contrast, if a woman has radiation after a lumpectomy and later has a recurrence anyway, she can’t undergo radiation again.

When is radiation most important for DCIS?  It is more likely to benefit younger women (especially women diagnosed before age 40), women with more serious types of DCIS (a high grade DCIS called comedo), and women with a family history of breast cancer.

The Van Nuys Prognostic Index incorporates four independent factors that predict local tumor recurrence (tumor sizes, margin width, pathology grade and necrosis, and patient age). Experts recommend that women with DCIS with a low score (4–6) on this Index should undergo a lumpectomy alone without radiotherapy since the chances of recurrence are low, and there is no evidence that radiation would reduce the chances of dying from breast cancer. 5

What is the benefit of hormone therapy for women also undergoing radiation therapy?

Tamoxifen blocks the effects of estrogen on breast cells, which can stop the growth of cancer cells that are sensitive to estrogen. A study of more than 1,800 pre-menopausal and post-menopausal women with DCIS evaluated the benefits of tamoxifen for women who had lumpectomy and radiation treatment. These women were randomly assigned to take tamoxifen for 5 years or a placebo (sugar pill). The study found that after 5 years, women who took tamoxifen were about 5% less likely to develop either DCIS or cancer in the same breast, cancer in the opposite breast, or distant cancer spread.  The difference was 8 of women taking tamoxifen compared to 13% of women taking placebo. However, the vast majority of women survived and they did not live any longer whether they took tamoxifen or not.1

For postmenopausal women, aromatase inhibitors may be used instead of tamoxifen. Aromatase inhibitors block the body’s ability to make estrogen. A study of more than 3,000 post-menopausal women with DCIS evaluated the benefits of hormone treatment for women who had lumpectomy and radiation treatment. These women were randomly assigned to take tamoxifen or anastrozole for 5 years. The study found that after 5 years, compared to women taking tamoxifen, the women taking anastrozole were 2% less likely to develop either DCIS or cancer in the same breast, cancer in the opposite breast, or distant cancer spread.  The difference was about 8% of women taking tamoxifen compared to 6% taking anastrozole.  As in the previous study, the vast majority of women survived and those taking anastrozole did not live any longer than women taking tamoxifen.2

That was a very small benefit for anastrozole compared to tamoxifen, and another study of post-menopausal women with DCIS found no difference between the two hormone treatments.3

Bottom Line:  Radiation and hormone therapy both have benefits for most women who undergo lumpectomy, because they decrease the chances of DCIS returning after surgery.  However, the benefits are quite modest and neither of these treatments affect how long women live, because almost all women diagnosed with DCIS are still alive 20 years later.

References:

  1. National Cancer Institute. Breast Cancer Treatment PDQ. (Feb. 2018). Available online: https://www.cancer.gov/types/breast/hp/breast-treatment-pdq#link/_1576_toc
  2. Margolese, Richard G et al. Anastrozole versus tamoxifen in postmenopausal women with ductal carcinoma in situ undergoing lumpectomy plus radiotherapy (NSABP B-35): a randomised, double-blind, phase 3 clinical trial.The Lancet. 2016;387(10021): 849 – 856.
  3. Forbes, John F et al. Anastrozole versus tamoxifen for the prevention of locoregional and contralateral breast cancer in postmenopausal women with locally excised ductal carcinoma in situ (IBIS-II DCIS): a double-blind, randomised controlled trial. The Lancet.2016;387(10021): 866 – 873.
  4. Cuzick, Jack et al. Effect of tamoxifen and radiotherapy in women with locally excised ductal carcinoma in situ: long-term results from the UK/ANZ DCIS trial. The Lancet Oncology. 2011; 12(1): 21 – 29
  5. Wong JS, Kaelin CM, Troyan SL, et al. Prospective study of wide excision alone for ductal carcinoma in situ of the breast. J Clin Oncol. 2006;24:1031–1036.

Hormone Therapy and Menopause

Breast Cancer, Medical Treatments with Cancer Risks, ,
Anna E. Mazzucco, PhD, Elizabeth Santoro, RN, MPH, Maushami DeSoto, PhD, and Jae Hong Lee, MD, MPH

Do women need to “replace” hormones as they age? Millions of women struggle with the decision about hormones during and after menopause: should I go on, should I stay on, or should I go off?

For decades, women were told that hormone therapy was like a fountain of youth that would protect them against many of the diseases and symptoms of aging that increase after menopause. Since estrogen alone was known to increase the risk of uterine cancer, doctors usually prescribed a combination of estrogen and progestin, unless a woman had a hysterectomy and therefore was at no risk of uterine cancer.

In addition to its proven effectiveness for decreasing hot flashes, night sweats, and vaginal dryness, in the 1980’s and 1990’s hormone therapy was thought to decrease osteoporosis, prevent heart disease, improve memory and concentration, reduce wrinkles, and improve mood. Women were encouraged to start hormone therapy before menopause started and to continue to take it for years, if not decades, in order to improve their health and their quality of life.

However, the research evidence is now clear: the risks of hormones outweigh the benefits for the vast majority of women.

What the Research Says

In December 2017, the experts at the U.S. Preventive Services Task Force issued a clear recommendation:  post-menopausal women should NOT take hormones to prevent chronic health conditions, such as increasing bone strength to avoid fractures. The reason is that the risks of these hormones outweigh the benefits.1

This recommendation is just the latest evidence that taking hormones to “replace” those that are reduced in menopause if often bad for your health. Previous evidence came from the Women’s Health Initiative (WHI), sponsored by the National Institutes of Health (NIH), which included more than 27,000 women in three different trials to study the effect of hormones on women’s bodies.2,3,4 The 3 trials were: 1) the Estrogen Plus Progestin Trial, 2) the Women’s Health Initiative Memory Study, and 3) the Estrogen-alone Trial.

The researchers found that women taking a combination of estrogen and progesterone hormones were more likely to develop breast cancer, stroke, and blood clots, and at least as likely to develop heart disease, compared to women taking placebo. Those on estrogen alone were at an increased risk for strokes and at a significantly increased risk for deep vein, thrombosis.† The Memory Study revealed that women taking a combination of estrogen plus progesterone were twice as likely to develop Alzheimer’s Disease and other forms of dementia compared to women on placebo.

All the three trials were stopped early for ethical reasons when it became clear that women taking hormones were more likely to be harmed than helped. While there are some short-term benefits to taking hormones, the researchers concluded that for most women, the risks of hormone therapy outweigh the benefits.

Following release of these findings, use of hormone therapy in the U.S. dropped significantly.  Since then, several large studies have pointed out that breast cancer incidence also dropped a few years after the decline in hormone use for menopause.5,6 This unexpected and unprecedented drop in breast cancer incidence suggests that HRT has a more dramatic impact on breast cancer risk than previously thought.7 In 2021, a meta-analysis of more than 4,000 women in 4 different studies of women previously being treated for breast cancer, found that those who subsequently took hormone therapy (combined estrogen plus progesterone) were much more likely to have a recurrence of cancer than breast cancer survivors who took a placebo.8 The women who had estrogen receptor positive breast cancer prior to hormone therapy were 80% more likely to have a recurrence than women taking placebo, which was a statistically significant difference that did not occur by chance. The women who had estrogen receptor negative breast cancer were 19% more likely to have a recurrence than the women taking placebo, which was a small difference that might have occurred by chance.

In 2009, a study found that hormone therapy increased the risk of dying of lung cancer among women who smoked or previously smoked, compared to smokers or former smokers who did not take hormone therapy. For more information click here.

In 2010 the University of California at San Francisco did a study of nearly 700,000 women. The researchers found that taking hormones may actually promote the growth of tumors in the breast which increases the incidence of invasive cancer and the risk of ductal carcinoma in situ (DCIS), a form of non-invasive pre-cancer. You can read more about that study by clicking here.

Experts who promote the use of HRT have criticized the WHI for enrolling women after menopause rather than just before or in the earliest stages.  So, it is important to note that in 2014, a study of 727 women in early menopause showed that hormone therapy did not prevent atherosclerosis (artery thickening), as had been claimed previously.  Following women on HRT for 4 years, the researchers from the Kronos Longevity Research Institute, a pro-HRT research institute, and other institutions, found no difference in artery thickening between the women who took HRT and those who didn’t.9 In 2015, the same group published an article admitting that hormone therapy also had no impact on “cognitive decline,” despite claims that it would prevent Alzheimer’s and memory loss.10 Although the authors focused on a small improvement in mood related to using hormone pills for 4 years (but not found with hormone creams), they downplayed the more important finding: no impact on depression as measured by the valid and reliable Beck Depression Inventory.

What are the Risks and Benefits of Hormone Therapy?

To emphasize that lost hormones don’t necessarily need to be replaced, the term “hormone replacement therapy” has been changed to “hormone therapy.” Experts now advise women to use hormone therapy only for severe symptoms of menopause that reduce the quality of life, such as severe hot flashes, night sweats, insomnia, and vaginal dryness. Women are urged to take hormones at the lowest dose that is effective and for the shortest possible period of time. However, even short-term use (less than one year) increases some risks; for example, the increase in heart disease comes primarily from the first year of hormone use.

Hormone therapy may be recommended in severe cases of vulvar and vaginal atrophy‡ as well as for treating severe postmenopausal osteoporosis when non-estrogen medications or other strategies are unsuccessful or impossible. A decision to use any combination of estrogen and progestin should be discussed with a physician who is expert on the topic, and specific criteria for the indication, dose, and duration of these hormones must be met prior to their prescription and administration.

Risks:

Compared to women taking placebo, within 5 years the women who received estrogen plus progestin experienced:

— 41% more strokes

— 29% more heart attacks

— twice as many blood clots

— 22% more heart disease of all types

— 26% more breast cancer

— 37% fewer cases of colorectal cancer

— one-third fewer hip fractures

— 24% fewer bone fractures of any type

— no difference in the overall death rate

It’s important to note that only 2.5% of the women in the study experienced health problems. So, while the percentage increase in some diseases was rather large, the risk for most patients remained relatively small. That does not mean these risks are not important however.

To provide a better sense of the additional risks that come with combination hormone therapy, the study data can be summarized more simply. Compared to a group of 10,000 women taking placebo, 10,000 women taking combination hormone therapy will experience:

— 7 more heart attacks

— 8 more strokes

— 8 more cases of breast cancer

— 18 more blood clots

— 6 fewer cases of colorectal cancer

— 5 fewer hip fractures

Research Evidence

The Women’s Health Initiative was a major 15-year research program to address the most common causes of death, disability and poor quality of life in post-menopausal women – cardiovascular disease, cancer, and osteoporosis. The WHI was launched in 1991 and consisted of a set of clinical trials and an observational study. The clinical trials were designed to test the effects of post-menopausal hormone therapy, diet modification, and calcium and vitamin D supplements on heart disease, fractures, and breast and colorectal cancer.

The hormone trial had two studies: the estrogen-plus-progestin study of women with a uterus and the estrogen-alone study of women without a uterus. (Women with a uterus were given progestin in combination with estrogen, a practice known to prevent endometrial cancer.) In both hormone therapy studies, women were randomly assigned to either the hormone medication being studied or to placebo. Those studies ended several years ago, and the women are now participating in a follow-up phase, which will last until 2010.

Estrogen plus Progestin Trial (stopped in July 2002)

Compared with women in the placebo those on estrogen plus progestin had:

  • Increased risk of heart attack
  • Increased risk of stroke
  • Increased risk of blood clots
  • Increased risk of breast cancer
  • Reduced risk of colorectal cancer
  • Fewer fractures
  • No protection against mild cognitive impairment and increased risk of dementia (study included only women 65 and older)
  • Increased risk of dying of lung cancer

Women’s Health Initiative Memory Study (stopped in May 2003)

  • Women taking hormones had twice the risk for developing dementia
  • Hormones provided no protection against mild cognitive impairment/memory loss

Estrogen-alone Trial (stopped in February 2004)

  • Estrogen increased risk for stroke
  • Estrogen decreased risk for hip fracture
  • No positive or negative effect on breast cancer

Compared to placebo women on estrogen alone had:

  • Increased risk of stroke
  • Increased risk of blood clots
  • Uncertain effect for breast cancer
  • No difference in risk for colorectal cancer
  • No difference in risk for heart attack
  • Reduced risk of fracture

Links to Research summaries of the Women’s Health Initiative studies  –

Estrogen Plus Progestin Trial: 2002

The Women’s Health Initiative Memory Study: 2005

The Estrogen-alone Trial: 2004

_______________________________________________

† Deep vein thrombosis refers to a blood clot deep inside the veins, usually in the legs.

‡ Symptoms include thinning and inflammation of the vaginal walls and changes in the vulva.

All articles are reviewed and approved by Dr. Diana Zuckerman and other senior staff.

The National Center for Health Research is a nonprofit, nonpartisan research, education and advocacy organization that analyzes and explains the latest medical research and speaks out on policies and programs. We do not accept funding from pharmaceutical companies or medical device manufacturers. Find out how you can support us here.

References:

  1. Jin J. Hormone therapy for primary prevention of chronic conditions in postmenopausal women. JAMA. 2017;318(22):2265-.
  2. Writing Group for the Women’s Health Initiative Investigators, Writing Group for the Women’s Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women’s Health Initiative randomized controlled trial. JAMA. 2002;288(3):321-33.
  3. Craig MC, Maki PM, Murphy DG. The Women’s Health Initiative Memory Study: findings and implications for treatment. The Lancet Neurology. 2005;4(3):190-4.
  4. Anderson GL, Limacher M, Assaf AR, Bassford T, Beresford SA, Black H, Bonds D, Brunner R, Brzyski R, Caan B, Chlebowski R. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women’s Health Initiative randomized controlled trial. JAMA. 2004;291(14):1701-12.
  5. Ravdin PM, Cronin KA, Howlader N, Berg CD, Chlebowski RT, Feuer EJ, Edwards BK, Berry DA. The decrease in breast-cancer incidence in 2003 in the United States. New England Journal of Medicine. 2007;356(16):1670-4.
  6. Katalinic A, Rawal R. Decline in breast cancer incidence after decrease in utilisation of hormone replacement therapy. Breast Cancer Research and Treatment. 2008;107(3):427-30.
  7. Colditz GA. Decline in breast cancer incidence due to removal of promoter: combination estrogen plus progestin. Breast Cancer Research. 2007;9(4):1-3.
  8. Poggio F, Del Mastro L, Bruzzone M, Ceppi M, Razeti MG, Fregatti P, Ruelle T, Pronzato P, Massarotti C, Franzoi MA, Lambertini M. Safety of systemic hormone replacement therapy in breast cancer survivors: a systematic review and meta-analysis. Breast Cancer Research and Treatment. 2021:1-7.
  9. Harman SM, Black DM, Naftolin F, Brinton EA, Budoff MJ, Cedars MI, Hopkins PN, Lobo RA, Manson JE, Merriam GR, Miller VM. Arterial imaging outcomes and cardiovascular risk factors in recently menopausal women: a randomized trial. Annals of Internal Medicine. 2014;161(4):249-60.
  10. Gleason CE, Dowling NM, Wharton W, Manson JE, Miller VM, Atwood CS, Brinton EA, Cedars MI, Lobo RA, Merriam GR, Neal-Perry G. Effects of hormone therapy on cognition and mood in recently postmenopausal women: findings from the randomized, controlled KEEPS–cognitive and affective study. PLoS Medicine. 2015;12(6):e1001833.

 

A Shocking Diagnosis: Breast Implants “Gave Me Cancer”

Medical Treatments with Cancer Risks, News Stories & Editorials, news-you-can-use
Denise Grady, The New York Times: May 14, 2017

Raylene Hollrah was 33, with a young daughter, when she learned she had breast cancer. She made a difficult decision, one she hoped would save her life: She had her breasts removed, underwent grueling chemotherapy and then had reconstructive surgery.

In 2013, six years after her first diagnosis, cancer struck again — not breast cancer, but a rare malignancy of the immune system — caused by the implants used to rebuild her chest.

“My whole world came crumbling down again,” said Ms. Hollrah, now 43, who owns an insurance agency in Hermann, Mo. “I had spent the past six years going to the oncologist every three months trying to keep cancer away, and here was something I had put in my body to try to help me feel more like a woman, and it gave me cancer. I thought, ‘I’m not going to see my kids grow up.’”

Her disease — breast implant-associated anaplastic large-cell lymphoma — is a mysterious cancer that has affected a tiny proportion of the more than 10 million women worldwide who have received implants. Nearly all the cases have been linked to implants with a textured or slightly roughened surface, rather than a smooth covering. Texturing may cause inflammation that leads to cancer. If detected early, the lymphoma is often curable.

The Food and Drug Administration first reported a link between implants and the disease in 2011, and information was added to the products’ labeling. But the added warnings are deeply embedded in a dense list of complications, and no implants have been recalled. The F.D.A. advises women only “to follow their doctor’s recommended actions for monitoring their breast implants,” a spokeswoman said in an email this month.

 Until recently, many doctors had never heard of the disease, and little was known about the women who suddenly received the shocking diagnosis of cancer brought on by implants.

An F.D.A. update in March that linked nine deaths to the implants has helped raise awareness. The agency had received 359 reports of implant-associated lymphoma from around the world, although the actual tally of cases is unknown because the F.D.A.’s monitoring system relies on voluntary reports from doctors or patients. The number is expected to rise as more doctors and pathologists recognize the connection between the implants and the disease.

Women who have had the lymphoma say that the attention is long overdue, that too few women have been informed of the risk and that those with symptoms often face delays and mistakes in diagnosis, and difficulties in receiving proper care. Some have become severely ill.

Implants have become increasingly popular. From 2000 to 2016, the number of breast augmentations in the United States rose 37 percent, and reconstructions after mastectomy rose 39 percent. Annually, nearly 400,000 women in the United States get breast implants, about 300,000 for cosmetic enlargement and about 100,000 for reconstruction after cancer, according to the American Society of Plastic Surgeons. Allergan and Mentor are the major manufacturers. Worldwide, an estimated 1.4 million women got implants in 2015.

As late as 2015, only about 30 percent of plastic surgeons were routinely discussing the cancer with patients, according to Dr. Mark W. Clemens II, a plastic surgeon and an expert on the disease at the University of Texas MD Anderson Cancer Center in Houston.

“I’d like to think that since then we’ve made progress on that,” Dr. Clemens said.

Late last year, an alliance of cancer centers, the National Comprehensive Cancer Network, issued treatment guidelines. Experts agree that the essential first step is to remove the implant and the entire capsule of scar tissue around it. Otherwise, the disease is likely to recur, and the prognosis to worsen.

Not all women have been able to get the recommended treatment. Kimra Rogers, 50, a nursing assistant in Caldwell, Idaho, learned last May that she had lymphoma, from textured implants she had for more than 10 years. But instead of removing the implants and capsules immediately, her doctor prescribed six rounds of chemotherapy and 25 rounds of radiation. A year later, she still has the implants.

“Unfortunately, my doctor didn’t know the first line of defense,” Ms. Rogers said.

She learned about the importance of having the implants removed only from other women in a Facebook group for those with the disease.

Her health insurer, Blue Cross Blue Shield of Montana, covered the chemotherapy and radiation but has refused to pay for removal of the implants, and told her that her appeal rights were “exhausted.” In a statement sent to The New York Times, a spokesman said, “Cosmetic breast implants are a contract exclusion, as are any services related to complications of the cosmetic breast implants, including implant removal and reconstruction.”

Physicians dispute that reasoning, saying the surgery is needed to treat cancer. Her lawyer, Graham Newman, from Columbia, S.C., said he was planning a lawsuit against the implant makers, and had about 20 other clients with breast-implant lymphoma from Australia, Canada, England and the United States.

Ms. Rogers has been unable to work for a year. If she has to pay to have the implants removed, it will mean taking out a $12,000 loan.

“But it’s worth my life,” she said.

Insurers generally cover implants after a mastectomy, but not for cosmetic enlargement, which costs $7,500 or more. Repeat operations for complications are also common, and usually cost more than the original surgery.

Diagnosis and Treatment

Most of the cancers have developed from two to 28 years after implant surgery, with a median of eight. A vast majority occurred with textured implants.

Most implants in the United States are smooth. But for some, including those with teardrop shapes that would look odd if they rotated, texturing is preferable, because tissue can grow into the rough surface and help anchor the implant.

Researchers estimate that in Europe and the United States, one in 30,000 women with textured implants will develop the disease. But in Australia the estimate is higher: one in 10,000 to one in 1,000. No one knows why there is such a discrepancy.

What’s inside the implant — silicone or saline — seems to make no difference: Case numbers have been similar for the two types. The reason for the implants — cosmetic breast enlargement or reconstruction after a mastectomy — makes no difference, either.

Symptoms of the lymphoma usually include painful swelling and fluid buildup around the implant. Sometimes there are lumps in the breast or armpit.

To make a diagnosis, doctors drain fluid from the breast and test it for a substance called CD30, which indicates lymphoma.

The disease is usually treatable and not often fatal. Removing the implant and the entire capsule of scar tissue around it often eliminates the lymphoma. But if the cancer has spread, women need chemotherapy and sometimes radiation.

“In the cases where we have seen bad outcomes, it was usually because they were not treated or there was a major delay in treatment, on the level of years,” Dr. Clemens said. Doctors at MD Anderson have treated 38 cases and have a laboratory dedicated to studying the disease.

About 85 percent of cases can be cured with surgery alone, he said. But he added that in the past, before doctors understood how well surgery worked, many women were given chemotherapy that they probably did not need.

Case reports on the F.D.A. website vary from sketchy to somewhat detailed and rarely include long-term follow-up. Some describe initial diagnoses that were apparently mistaken, including infection and other types of cancer. In some cases, symptoms lasted or recurred for years before the right diagnosis was made.

What exactly causes the disease is not known. One theory is that bacteria may cling to textured implants and form a coating called a biofilm that stirs up the immune system and causes persistent inflammation, which may eventually lead to lymphoma. The idea is medically plausible, because other types of lymphoma stem from certain chronic infections. Professional societies for plastic surgeons recommend special techniques to avoid contamination in the operating room when implants are inserted.

“It could also just be the immune system response to some component of the texturing,” Dr. Clemens said. The rough surface may be irritating or abrasive. Allergan implants seem to be associated with more cases than other types, possibly because they are more deeply textured and have more surface area for bacteria to stick to, he said. Allergan uses a “lost-salt” method that involves rolling an implant in salt to create texture and then washing the salt away. Other makers use a sponge to imprint texturing onto the implant surface.

Allergan is studying bacterial biofilms, and immune and inflammatory responses to breast implants, a spokesman said in an email. He said the company took the disease seriously and was working with professional societies to distribute educational materials about it.

Another possible cause is that some women have a genetic trait that somehow, in the presence of implants, predisposes them to lymphoma. Dr. Clemens said researchers were genetically sequencing 50 patients to look for mutations that might contribute to the disease.

Dr. Clemens was a paid consultant for Allergan from 2013 to 2015, but not for breast implants, and no longer consults for any company, he said.

A spokeswoman for Mentor said the company was monitoring reports about the lymphoma, and stood behind the safety of its implants.

[…]

Read the full article here.

Hormone replacement therapy and breast cancer

Breast Cancer, Medical Treatments with Cancer Risks
By Elizabeth Santoro, RN, MPH, Maushami DeSoto, PhD, and Jae Hong Lee, MD, MPH

Do women need to “replace” hormones as they age? Millions of women struggle with the decision about hormones during and after menopause: should I go on, should I stay on, or should I go off?

For decades, women were told that hormone therapy was like a fountain of youth that would protect them against many of the diseases and symptoms of aging that increase after menopause. Since estrogen alone was known to increase the risk of uterine cancer, doctors usually prescribed a combination of estrogen and progestin, unless a woman had a hysterectomy and therefore was at no risk of uterine cancer.

In addition to its proven effectiveness for decreasing hot flashes, night sweats, and vaginal dryness, in the 1980’s and 1990’s hormone therapy was thought to decrease osteoporosis, prevent heart disease, improve memory and concentration, reduce wrinkles, and improve mood. Women were encouraged to start hormone therapy before menopause started and to continue to take it for years, if not decades, in order to improve their health and their quality of life.

However, the research evidence is now clear: the risks of hormones outweigh the benefits for the vast majority of women.

What the research says

Research shows that, “replacing” the hormones women lose as they age is not only unnecessary, but it can bad for your health. The Women’s Health Initiative (WHI), sponsored by the National Institutes of Health (NIH), enrolled over 27,000 women in three different trials to study the effect of hormones on women’s bodies. The 3 trials were: 1) the Estrogen Plus Progestin Trial, 2) the Women’s Health Initiative Memory Study, and 3) the Estrogen-alone Trial.

The researchers found that women taking a combination of estrogen and progesterone hormones were more likely to develop breast cancer, stroke, and blood clots, and at least as likely to develop heart disease, compared to women taking placebo. Those on estrogen alone were at an increased risk for strokes and at a significantly increased risk for deep vein, thrombosis.† The memory Study revealed that women taking a combination of estrogen plus progesterone were twice as likely to develop Alzheimer’s Disease and other forms of dementia compared to women on placebo.

All the three trials were stopped early for ethical reasons when it became clear that women taking hormones were more likely to be harmed than helped. While there are some short-term benefits to taking hormones, the researchers concluded that for most women, the risks of hormone therapy outweigh the benefits.

Following release of these findings, use of hormone therapy in the U.S. dropped significantly.  Since then, several large studies have pointed out that breast cancer incidence also dropped a few years after the decline in HRT use. 1, 2  This unexpected and unprecedented drop in breast cancer incidence suggests that HRT has a more dramatic impact on breast cancer risk than previously thought. 3  In 2009, a study found that hormone therapy increased the risk of dying of lung cancer among women who smoked or previously smoked, compared to smokers or former smokers who did not take hormone therapy. For more information click here.

In 2010 the University of California at San Francisco did a study of nearly 700,000 women. The researchers found that taking hormones may actually promote the growth of tumors in the breast which increases the incidents of invasive cancer and the risk of ductal carcinoma in situ (DCIS), a form of non-invasive pre-cancer. You can read more about that study by clicking here.

Experts who promote the use of HRT have criticized the WHI for enrolling women after menopause rather than just before or in the earliest stages.  So, it is important to note that in 2014, a study of 727 women in early menopause showed that hormone therapy did not prevent atherosclerosis (artery thickening), as had been claimed previously.  Following women on HRT for 4 years, the researchers from the Kronos Longevity Research Institute, a pro-HRT research institute, and other institutions, found no difference in artery thickening between the women who took HRT and those who didn’t. 4   In 2015, the same group published an article admitting that hormone therapy also had no impact on “cognitive decline,” despite claims that it would prevent Alzheimer’s and memory loss. 5  Although the authors focused on a small improvement in mood related to using hormone pills for 4 years (but not found with hormone creams), they downplayed the more important finding: no impact on depression as measured by the valid and reliable Beck Depression Inventory.

What are the risks and benefits of hormone therapy?

To emphasize that lost hormones don’t necessarily need to be replaced, the term “hormone replacement therapy” has been changed to “hormone therapy.” Experts now advise women to use hormone therapy only for severe symptoms of menopause that reduce the quality of life, such as severe hot flashes, night sweats, insomnia, and vaginal dryness. Women are urged to take hormones at the lowest dose that is effective and for the shortest possible period of time. However, even short-term use (less than one year) increases some risks; for example, the increase in heart disease comes primarily from the first year of hormone use.

Hormone therapy may be recommended in severe cases of vulvar and vaginal atrophy‡ as well as for treating severe postmenopausal osteoporosis when non-estrogen medications or other strategies are unsuccessful or impossible. A decision to use any combination of estrogen and progestin should be discussed with a physician who is expert on the topic, and specific criteria for the indication, dose, and duration of these hormones must be met prior to their prescription and administration.

To learn more about the debate about hormone therapy for menopause, click here.

Risks:

Compared to women taking placebo, within 5 years the women who received estrogen plus progestin experienced:
— 41% more strokes
— 29% more heart attacks
— twice as many blood clots
— 22% more heart disease of all types
— 26% more breast cancer
— 37% fewer cases of colorectal cancer
— one-third fewer hip fractures
— 24% fewer bone fractures of any type
— no difference in the overall death rate

It’s important to note that only 2.5% of the women in the study experienced health problems. So, while the percentage increase in some diseases was rather large, the risk for most patients remained relatively small. That does not mean these risks are not important however.

To provide a better sense of the additional risks that come with combination hormone therapy, the study data can be summarized more simply. Compared to a group of 10,000 women taking placebo, 10,000 women taking combination hormone therapy will experience:
— 7 more heart attacks
— 8 more strokes
— 8 more cases of breast cancer
— 18 more blood clots
— 6 fewer cases of colorectal cancer
— 5 fewer hip fractures

Research evidence

The Women’s Health Initiative was a major 15-year research program to address the most common causes of death, disability and poor quality of life in post-menopausal women – cardiovascular disease, cancer, and osteoporosis. The WHI was launched in 1991 and consisted of a set of clinical trials and an observational study. The clinical trials were designed to test the effects of post-menopausal hormone therapy, diet modification, and calcium and vitamin D supplements on heart disease, fractures, and breast and colorectal cancer.

The hormone trial had two studies: the estrogen-plus-progestin study of women with a uterus and the estrogen-alone study of women without a uterus. (Women with a uterus were given progestin in combination with estrogen, a practice known to prevent endometrial cancer.) In both hormone therapy studies, women were randomly assigned to either the hormone medication being studied or to placebo. Those studies ended several years ago, and the women are now participating in a follow-up phase, which will last until 2010.

Estrogen plus progestin trial (stopped in July 2002)

Compared with women in the placebo those on estrogen plus progestin had:

  • Increased risk of heart attack
  • Increased risk of stroke
  • Increased risk of blood clots>
  • Increased risk of breast cancer
  • Reduced risk of colorectal cancer
  • Fewer fractures
  • No protection against mild cognitive impairment and increased risk of dementia (study included only women 65 and older)
  • Increased risk of dying of lung cancer

Women’s Health Initiative memory study (stopped in May 2003)

  • Women taking hormones had twice the risk for developing dementia
  • Hormones provided no protection against mild cognitive impairment/memory loss

Estrogen-alone trial (stopped in February 2004)

  • Estrogen increased risk for stroke
  • Estrogen decreased risk for hip fracture
  • No positive or negative effect on breast cancer

Compared to placebo women on estrogen alone had:

  • Increased risk of stroke
  • Increased risk of blood clots
  • Uncertain effect for breast cancer
  • No difference in risk for colorectal cancer
  • No difference in risk for heart attack
  • Reduced risk of fracture

Links to Research Information

Estrogen Plus Progestin Trial: July 2002
The Women’s Health Initiative Memory Study: May 2003
The Estrogen-alone Trial: February 2004

_______________________________________________

† Deep vein thrombosis refers to a blood clot deep inside the veins, usually in the legs.
‡ Symptoms include thinning and inflammation of the vaginal walls and changes in the vulva.

Does abortion cause breast cancer?

Breast Cancer, Medical Treatments with Cancer Risks

No. Although there has been a great deal of controversy on this topic, scientists have agreed that abortion does not cause breast cancer.

The world’s leading experts, including epidemiologists, clinical researchers, and basic scientists, have discussed the scientific data on reproductive events in a woman’s life that could affect her risk of developing breast cancer. They evaluated the research that has been done on this topic and concluded that abortion and miscarriage do not increase a woman’s risk of breast cancer.

Breast cancer is related to reproductive experiences such as age of puberty and age of motherhood, and for years anti-abortion activists have cited research showing a link between abortion and breast cancer. That research has been quoted by some politicians as evidence that should be provided to women to discourage abortions. A workshop was held in 2003 (during the Bush Administration) at the National Cancer Institute (NCI) as a result of this controversy, and despite political pressures it concluded that the research linking breast cancer and abortion is flawed and not as credible as research indicating that there is no link between breast cancer and either abortion or miscarriage.

A medical journal article published in 20156 evaluated 15 studies on this issue, which included 31,816 women with breast cancer from seven studies in the U.S., seven studies in Europe, and one in China, conducted between 1986 and 2013. The scientists only evaluated studies which used the most reliable research design (what is known as a “prospective study”) and concluded that the evidence does not show a link between cancer and abortion.

The fact that abortion does not increase the risk of breast cancer is also supported by, among others, the World Health Organization (WHO), the National Cancer Institute and the American Cancer Society, as well as many women’s health advocacy organizations, including the National Breast Cancer Coalition, the National Women’s Health Network and Our Bodies Ourselves.

For more information on the NCI workshop and early reproductive events and breast cancer, please see: http://cancer.gov/cancerinfo/ere.