HRT: doctors demand talks with government to tackle “chaos” of shortages
BMJ 2020; 368 doi: https://doi.org/10.1136/bmj.m523 (Published 07 February 2020) Cite this as: BMJ 2020;368:m523
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Dear Editor,
Richard Fleming’s interesting suggestion that some HRT prescribing may reflect what options are available to the prescriber, rather than what is best for the symptomatic woman, (1) is reaffirmation of Ellen Grant’s safe therapeutic suggestions, which depend on case by case analysis. (1)
Baum’s irritation that anyone should question the safety of HRT prescribing is understandable, it follows from his concern for symptomatic women. (1)
Half a century of HRT, innumerable indefinite trials and the occasional meta analysis, allow the conventional prescriber considerable latitude, but leave innumerable women concerned about their safety and their symptoms, which are often severe and disabling.
The variability of menopausal symptoms, psychological and physical, cry out for an individualised remedy that can be matched to the strange, rare and peculiar symptoms that careful history taking will often identify. Profuse perspiration localised to the cubital fossae ?
Homeopaths generally enjoy the treatment of menopausal women. Their individualised treatment is usually effective, completely safe, and brief - compared to years of HRT.
How depressing that so many medical professionals are trapped in that reductionist, mechanistic mode, so elegantly described by McGilchrist.
What would happen, McGilchrist wonders, if our left cerebral hemisphere become even more dominant ?
“ Knowledge that came through experience, and the practical acquisition of embodied skill, would become suspect, appearing either a threat or simply incomprehensible. It would be re[placed by tokens or representations, formal systems to be evidenced by paper qualifications. The concepts of skill and judgement, once considered the summit of human achievement, but which come only silently with the business of living, would be discarded in favour of quantifiable and repeatable processes. “ (2)
1 https://www.bmj.com/content/368/bmj.m523/rapid-responses
2 Iain McGilchrist, The Master and his Emissary, Yale 2009, p429.
Competing interests: Peripatetic homeopath, NHS, and abroad, many decades. Never for profit.
Dear Editor
Less HRT means less breast cancer
Merethe Kumle commented that after the early terminations of the WHI HRT studies in 2002 and 2004, falls in HRT use were followed by falls in breast cancer incidences. She listed reports from Norway in 2005, New Zealand in 2006, USA and Canada in 2007, Germany, France and Norway in 2008. [1]
Bakken et al found that in Norwegian women aged 50-64 years, current HRT use doubled the risk of breast cancer whether or not they had been screened (RR 2.4 with mammography and RR 2.2 without mammography). [2]
In the UK the large percentage increases and smaller decreases in breast cancer registrations matched the increases and decreases in hormone use since 1961. [3] Graphs are in my website lectures (harmfromhormones.co.uk)
The Collaborative Group reported in 2019 that HRT use fell from 36 million to 12 million women in western countries in the past two decades. The Group found that of 108 647 postmenopausal women with breast cancer, both combined and oestrogen only HRT causally increased the risk of breast cancer and the risks increased with longer use. [4]
1 Kumle M. Declining breast cancer incidence and decreased HRT use. Lancet 2008;372:608-610.
2 Bakken K, Lund E, Eggen AE. The impact of hormone replacement therapy on the incidence of breast cancer in Norway. J Clin Oncol. 2005 May 20;23(15):3636-7.
3 Grant ECG. Reduction in mortality from breast cancer: fall in use of hormones could have reduced breast cancer mortality. BMJ 2005; 330:1024.
4 Collaborative Group on Hormonal Factors in Breast Cancer. Type and Timing of menopausal therapy and breast cancer risk individual participant meta-analysis of the worldwide epidemiological evidence. Lancet 2019;394 1159-68. :10.1016/S0140-6736(19)31474332.
Competing interests: No competing interests
Despite the lack of benefit and in the face of studies, which have shown that hormone replacement (HRT) in both men and women may produce adverse cardiovascular and oncologic health effects [1-5], clinicians continue to argue for the use of hormone replacement therapy.
There is some argument to be made for doing so when the loss of natural synthesis of hormones is the result of surgical removal of ovarian or testicular tissue – however, there is no scientific basis to support the use of synthetic or naturally occurring hormone replacement in the presence of the natural aging process.
In deed, the ability to provide a prescription or homeopathic equivalent to what is no longer being produced by the body does not mean there is a biologic advantage for doing so. The health consequences – benefits versus risks – should be considered.
In the face of shortages of a drug, the question needs to be asked – Do all the people who are being prescribed HRT truly benefit from or need HRT or are we simply prescribing it because we can? Those who make the argument that statin medications are being over prescribed should be asking the question – is HRT being over prescribed and is it this potential over prescription that is causing the shortage.
References:
1. Catakoglu AB, Kendirci M. Testosterone replacement therapy and cardiovascular events. Turk Kardiyol Dem Ars 2017;45(7):664-672.
2. Kloner RA, Carson C, Dobs A, Kopecky S, Mohler ER. Testosterone and Cardiovascular Disease. JACC 2016;67(5):545-557.
3. Fleming RM. Are there differences in breast tissue as a result of hormone replacement therapy? Can BEST imaging distinguish these differences? Integrative Cancer Therapies 2003;2:229-34.
4. Fleming RM. Do women taking hormone replacement therapy (HRT) have a higher incidence of breast cancer than women who do not? Integrative Cancer Therapies 2003;2:235-237.
5. Writing group for the women’s health initiative investigators. Risks and Benefits of Estrogen Plus Progestin in Healthy Postmenopausal Women. JAMA 2002;288(3):321-333.
Competing interests: No competing interests
Dear Editor,
The Collaborative Group on Hormonal Factors in Breast Cancer have collected an impressing data set on the association between menopausal hormone therapy (MHT) and breast cancer suggesting that the observed associations are largely causal because all studies indicate increased risk [1]. Huge data sets do not solve the problem with systematic errors.
The effect of combined progesterone and oestrogen (P+O) use in the randomized WHI trial [2] on the breast cancer risk is significantly lower than in observational studies; the relative risk after six year follow-up is 1·10 for the 6277 women without prior menopausal hormone use and 1·24 when also including 2225 women with prior hormone use [2].
If the data in the WHI trial [2] of P+O use is analyzed as done in these observational studies, the relative risk increases from 1·10 to 1·48 for women not using MHT before randomization, and from 1·24 to 1·68 if also including women who had used MHT before time of randomization [3]. The threefold increase is exclusively due to the statistical method used.
The WHI trial also reported “a substantial and statistically significant increase in the percentage of women with abnormal mammograms” starting in the first year of the trial and the authors concluded that P+O both stimulated growth and hindered breast cancer diagnoses [2]. Figure 1 in Zahl&Mæhlen [3] illustrates how cumulative risks for the intervention group initially are lower than for the control group - many diagnoses are initially delayed. After 3-4 years the incidence rates are higher (P+O is causing cancer) but also for these cancers many diagnoses are delayed.
If P+O is generating new cancers, it will take some time for cancers to grow and become clinical. Thus, it may seem reasonable to categorize women with respect to the length of MHT use at study start and assume estimated risk for long-term users is the most valid estimate. However, the delay in diagnoses is complicating the statistical regression analyses and causing bias:
Many tumors detected in the user groups would, in the absence of MHT use, have been diagnosed before the start of an observational study, causing overestimated incidence rates for those categorized as MHT users in a regression model. Furthermore, when women in the non-user group start using hormones after study start, they will have tumors masked by MHT use and diagnoses are delayed, causing underestimation of the incidence rate in the non-user group. These two sources of bias both increases the relative risk.
A shortage of HRT will not reduce the number of breast cancers as much as observational studies suggest.
References
1. Collaborative Group on Hormonal Factors in Breast Cancer. Lancet 2019; http://dx.doi.org/10.1016/S0140-6736(19)31709-X
2. Chlebowski RT, Hendrix SL, Langer RD, Stefanick ML, Gass M, Lane D, et al. Influence of estrogen plus progestin on breast cancer and mammography in healthy postmenopausal women. The women’s health initiative randomized trial. JAMA 2003; 289: 3243-3253.
3. Zahl P-H, Mæhlen J. Bias in observational studies of the association between hormone replacement therapy and breast cancer. Plos One 2015; DOI:10.1371/journal.pone.0124076.
Competing interests: No competing interests
Dear Editor
Oestrogen only HRT increases the risk of breast cancer
Michael Baum is wrong to believe that HRT has no impact on mortality; or that oestrogen replacement therapy (ERT) significantly reduces the risk of breast cancer; or that my references are out of date.
The 2019 Collaborative Group analysis, of 108 647 postmenopausal women with breast cancer, found that both combined and oestrogen only HRT not only increased the risk of breast cancer but also that the increased with longer use.1
The results of Manson and colleagues’ follow-up of the prematurely terminated WHI studies (because of unacceptable increases in cancers and vascular diseases) are relatively meaningless because cancers and vascular diseases are the main cause of mortality.2
There is confusion who had ever taken or was still taking progestogens and or oestrogens. In the original WHI combined RDBC HT study 43% of volunteers had taken OCs and 26% had taken HT for up to 10 years or longer before being randomized as HRT takers or controls. Also 10% of the placebo group took HT during the trial. Therefore, adverse effects of current progestin and oestrogen use must be underestimated. In the oestrogen-only HT study 52% of takers and 51% of controls had previously taken HT. There does not seem to be information in Manson’s latest follow-up about hormone use other than the original basal randomization groups . Mortality from breast cancer fell when HRT use reduced.3,4
Both the normal menopause and HRT withdrawal symptoms are, in my experience, often due to underlying mineral, vitamin and essential fatty acid deficiencies and to food allergies +/- excess gut fungal or bacterial fermentation, known as the " Auto -brewery syndrome", or to smoking or drinking alcohol.
It is sad that so many doctors just want to give women ever more hormones rather than investigate what is really happening.
1Collaborative Group on Hormonal Factors in Breast Cancer. Type and Timing of menopausal therapy and breast cancer risk individual participant meta-analysis of the worldwide epidemiological evidence. Lancet 2019;394 1159-68. :10.1016/S0140-6736(19)31474332.
2 Manson J E, Aron K, Aragaki MS, Rossouw JE, Anderson GL, et al. Menopausal Hormone Therapy and Long-term All-Cause and Cause-Specific Mortality The Women's Health Initiative Randomized Trials.
JAMA. 2017 Sep 12; 318(10): 927–938.
3 Grant ECG. Price EH. Reduction in mortality from breast cancer: fall in use of hormones could have reduced breast cancer mortality. BMJ 2005; 330:1024.
4 Colditz GA. Decline in breast cancer incidence due to removal of promoter: combination estrogen plus progestin. Breast Cancer Res 2007; 9:108.
Competing interests: No competing interests
Dear Editor
I was appalled by the response from Ellen Grant expressing her delight in the shortage in the supplies of HRT and totally ignoring the suffering that this will entail for those women who have been suffering from depression, hot flushes, cognitive disfunction and brittle bones. In addition she overlooks the issue of all cause mortality rather than cause specific mortality.
Her references are out of date and ignores the updates of the WHI in 2017 [1] and an even more recent review at the San Antonio Breast Cancer conference (SABCS) in December 2019. HRT has no impact on all cause mortality and Oestrogen replacement therapy (ERT) significantly reduces the risk of breast cancer. There are only two outcome measures of importance in the practice of medicine and those are length of life (LOL) and quality of life (QOL). HRT/ERT improves QOL for thousands of women with no impairment in LOL.
Michael Baum
[1] Menopausal Hormone Therapy and Long-term All-Cause and Cause-Specific Mortality
The Women's Health Initiative Randomized Trials
JoAnn E. Manson, MD, DrPH, Aaron K. Aragaki, MS, Jacques E. Rossouw, MD, Garnet L. Anderson, PhD, Ross L. Prentice, PhD, Andrea Z. LaCroix, PhD, Rowan T. Chlebowski, MD, PhD, Barbara V. Howard, PhD, Cynthia A. Thomson, PhD, Karen L. Margolis, MD, MPH, Cora E. Lewis, MD, MSPH, Marcia L. Stefanick, PhD, Rebecca D. Jackson, MD, Karen C. Johnson, MD, MPH, Lisa W. Martin, MD, Sally A. Shumaker, PhD, Mark A. Espeland, PhD, Jean Wactawski-Wende, PhD, and for the WHI.
JAMA. 2017 Sep 12; 318(10): 927–938.
Competing interests: No competing interests
Dear Editor
A shortage of HRT is good news and will save women’s lives. Less HRT – fewer breast and ovarian cancers and vascular diseases.
HRT use has fallen from 36 million to 12 million women in western countries in the past two decades following the early termination of the Women’s Health Initiative (WHI) double-blind randomized combined progestogen/oestrogen trial in 2002 and oestrogen-only HRT control trial in 2004, due to significant increases in cancers and vascular diseases with either type of HRT was followed by large falls in breast and ovarian cancer incidences and mortality.1-8
Failure to monitor and correct the biochemical perturbations (including essential nutrient deficiencies or imbalances and toxic DNA adducts) caused by exogenous hormones activating progesterone and oestrogen receptors results in numerous illnesses and steroid withdrawal symptoms such as hot flushes and depression when these hormones are stopped.9
1Collaborative Group on Hormonal Factors in Breast Cancer. Type and Timing of menopausal therapy and breast cancer risk individual participant meta-analysis of the worldwide epidemiological evidence. Lancet 2019;394 1159-68. :10.1016/S0140-6736(19)31474332.
2 IARC. Combined estrogen-progestogen contraceptives and combined
estrogen-progestogen menopausal therapy. IARC Monographs on the Evaluation of Carcinogenic Risks to Humans 2007; Volume 91.
3 Rossouw JE, Anderson GL, Prentice RL. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women's Health Initiative randomized controlled trial. JAMA 2002;288:321-33.
4 The Women's Health Initiative Randomized Controlled Trial. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy. JAMA 2004;291: 1701-1712.
5 Grant ECG. Price EH. Reduction in mortality from breast cancer: fall in use of hormones could have reduced breast cancer mortality. BMJ 2005; 330:1024.
6 Colditz GA. Decline in breast cancer incidence due to removal of promoter: combination estrogen plus progestin. Breast Cancer Res 2007; 9:108.
7 Ravdin M, Cronin KA, Howlander N, Berg CD, Chlebowski RT, Feuer EJ, Edwards BK, Berry DA. The Decrease in Breast Cancer Incidence in 2003 in the United States. NEJM 2007;356:6.
8 Grant EC. Oral Contraceptive Progestin and Estrogen Use and Increases in Breast, Ovarian, and Endometrial Cancers. JAMA Oncol. 2018 Sep 13. doi: 10.1001/jamaoncol.2018.4146.
9 Grant ECG. The pill, hormone replacement therapy, vascular and mood over-reactivity and mineral imbalance. J Nutr Environ Med 1998 8:789-91. DOI:10.1080/13590849862131
Competing interests: No competing interests
Re: HRT: doctors demand talks with government to tackle “chaos” of shortages
Dear Editor
Estrogens-only of HRT do not cause breast cancer
There is incontestable evidence that combined (estrogen plus progestogen) hormone replacement therapy (HRT) can cause breast cancer. Plausibly the best evidence for this comes from the WHI studies1.2, both of which were the same randomized placebo-controlled study, whose reports were reported at different time points. The randomized placebo controlled design allows direct inference of causality. The same study design by the same group of authors has provided convincing evidence that estrogen-only HRT (or unopposed estrogen - ERT) does not cause breast cancer, both in the initial report3 and in a subsequent report of the follow up of the women 16 years later4. We therefore take an opposite view to that expressed by Ellen Grant on estrogen-only HRT, whose views appear to be primarily informed by observational collaborative studies5. It is a fundamental truism that if the wrong epidemiological tools are used, the wrong result will be arrived at. Thus prospective studies cannot and should not be mixed with retrospective studies, and the correct measures of outcome should be applied. The Relative risk and Hazard ratios are reserved for randomized controlled studies, and are proportions of those with disease or no disease after exposure within the whole exposed group, and compared to the same groups within the non-exposed group in randomized controlled studies. But a prospective cohort study can only measure and report on the number of new cases (the incidence) after an exposure (HRT).
The collaborative study5 that Grant relies on is methodologically deficient from many aspects, including:
1. Firstly, a confusion which will affect the results occurs in this reference when an analysis of outcome in prospective cohort studies which always start from exposure (HRT) to outcome (incidence of breast cancer), is mixed with retrospective studies, albeit one case, which can start with exposure to disease (measuring the odds ratio of disease) or which can start with disease to exposure (measuring the odds ratio of exposure).
2. Secondly, this study can only really use the incidence risk or incidence ratio to be interpretable or valid as a prospective cohort study.
3. Thirdly, in the interpretation of the results, the collaborative group expressed the incidences of breast cancer although they measured the Risk ratios. They are incompatible currencies or measures of effect.
Teleologic considerations would also lead us to believe that unopposed estrogen in HRT could not be a cause of breast cancer. Without estrogens, the breast simply does not/cannot develop, as evidenced by the absence of breasts in girls with pure Turners syndrome when ovarian failure occurs before puberty. In the long run, if estrogens caused breast cancer, most women with normal XX chromosomes should develop breast cancer because of the large amounts of circulating estrogens they are exposed to during the reproductive phase of their lives, either from natural menstrual cycles or the oral contraceptive pill or from high gravidity with prolonged periods of Estriol during any one pregnancy However the risk is not increased during these phases..
Issues of biologic plausibility also support our view. Estrogens cause glandular enlargement of the breasts so they look filled on estrogen treatment or empty when in the menopause if estrogens are not given. However it is the progesterone that causes mitotic breast changes, likely for breast feeding. This mitotic activity stops when ovulation stops, but resumes with progestogen supplementation in HRT at the peri-menopause or menopause. Indeed, Manyonda et al 20196 showed that on review of the evidence about HRT and breast cancer, progesterone seems to be the causative factor. An abnormality of this mitosis might be the logical reason for the increased incidence of breast cancer with HRT versus the absence of increase in breast cancers with unopposed estrogen in the peri-menopause or menopause.
In addition, there is clear evidence that while breast cancer is rare in pre-pubertal girls with none to minimal estrogens, with only one case in the world literature (Ahmed, 2013)7, the incidences of breast cancer in women in the UK and USA, quoted per 100,000 women as 1.5-63.1 in the UK and 1.0-65.0 in the US between the age of 20 and 39 years when women are likely to be menstruating or using the pill or pregnant, with massive amounts of circulating cyclical or constant estrogen of pregnancy; 123.9-283.5/100,000 women in the UK and 131.0-217.0 in the US between the age of 40-54 years, the perimenopausal years; and 227.6-478.3/100,000 women in the UK and 263.0-391.0/100,000 women in the US between the age of 55 and 89 years, the menopausal years8,9. These incidences in the Western world confirm that the absence of estrogen as women grow older is associated with increased breast cancer incidences.
We conclude that ERT does not increase the risk of breast cancer, but could reduce it. It might even be tempting to suggest that estrogen could be protective against breast cancer: the WHI report from 2004 showed a 23% non-significant reduction in the risk of breast cancer [HR 0.77; 95% CI: 0.59–1.01] after 6.1 average follow-up; but after 16.1 years, there was a 23% significant reduction in Hazards ratio (HR 0.77, 95%CI 0.65-0.92. p=0.005) and a significant reduction in breast mortality (44% reduction) compared to placebo4 – how else should this data be interpreted other than that it shows “protection”?
References
1. Chlebowski RT, Hendrix SL, Langer RD et al. Influence of estrogen plus progestin on breast cancer and mammography in healthy postmenopausal women: the Women’s Health Initiative Randomized Trial. JAMA 2003; 289: 3243–3253.
2. Chlebowski, RT., Kuller, LH., Prentice RL., et al for the WHI Investigators. 2009. Breast cancer after use of estrogen plus progestin in postmenopausal women. New England Journal of Medicine, 6 (360) 573–587.
3. Anderson, Garnet L Limacher, Marian Assaf, Annlouise R et al. Women’s Health Initiative Steering Committee. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women’s Health Initiative randomized controlled trial. JAMA 2004, 291:1701–1712.
4. Chlebowski RT, Anderson GL, Aragaki AK, et al. Long-term follow-up shows estrogen alone and estrogen plus progestin have opposite effects on breast cancer incidence in postmenopausal women. Presented at: the 2019 San Antonio Breast Cancer Symposium; December 10-14, 2019; San Antonio, Tx. Abstract GS5-00.
5. Collaborative Group on Hormonal Factors in Breast Cancer. Type and timing of menopausal hormone therapy and breast cancer risk: individual participant meta-analysis of the worldwide epidemiological evidence. Lancet 2019 Sep 28; 394: 1159–1168.
6. Manyonda I, Talaulika VS, Pirhadi R, Onwude J. Progestogens are the problem in hormone replacement therapy: Time to reappraise their use. Post Reproductive Health, 2019, 1–6.
7. Ahmed ST Singh SK, Mukherjee T and Banerjee M. Breast carcinoma in a prepubertal girl. BMJ Case Rep. Published online: doi:10.1136/bcr-2013-203251
8. Age Distribution of Breast Cancer in the UK. https://www.cancerresearchuk.org/health-professional/cancer-statistics/s....
9. Age Distribution of Breast Cancer in the USA. Breast Cancer Incidence per 100,000 women, United States, 1986. http://www.nap.edu/catalog/1814.html.
Competing interests: No competing interests