Hormone replacement therapy
BMJ 2012; 344 doi: https://doi.org/10.1136/bmj.e763 (Published 16 February 2012) Cite this as: BMJ 2012;344:e763
All rapid responses
In her BMJ podcast about HRT, Martha Hickey makes it clear that she thinks the WHI and MWS results have been “unpicked” and HRT can be a safe option for some women.1 Professor Klim McPherson has described such arguments as ridiculous.2 Important trials were stopped prematurely because of increases in cancers and vascular diseases – if they had been continued the results would have been worse. So why is HRT still being promoted?
Professor Jim Thornton, a former President of the Royal College of Obstetrics and Gynaecologists, notes that Hickey and colleagues have drug company interests; the effect on mortality from all causes is in the opposite direction when only randomised trials are included; and many women get withdrawal hot flushes on stopping HRT.3
Progestogens and oestrogens can be addictive and difficult to stop.4 Former GP Margaret White wrote, “the menopause nature gave me was fine but the one that Premarin gave me was hell!” HRT is also a major cause of mental illness with an increased risk of suicide.5
It is no longer believed that HRT prevents colorectal cancer with no benefit from either estrogen-alone or estrogen plus progestogen in the WHI clinical trial and observational study after 7 to 8 years of intervention and follow-up.6 Hazard ratios (95% confidence intervals) from the WHI observational study were 0.80 (0.53-1.20) for estrogen and 1.15 (0.74-1.79) for estrogen plus progestogen. Also there was no protective effect on colorectal mortality.
The bad effects of using progestogens and oestrogens are overwhelming:-
Doubling of mortality from breast cancer 7
Doubling of mortality from ovarian cancer 8
Doubling of mortality from lung cancer 9
Doubling of deaths from suicide and suspected suicide 5
Doubling of cervical adenocarcinomas 10
4-5 fold increase in invasive cervical cancers 11
5 fold increase in endometrial cancer (oestrogens) 12
Doubling (or up to 6 times) of primary venous thrombosis 13
81% increase in myocardial infarctions (at one year) 14
44 -55% increase in ischemic strokes 15,16
Doubling (or up to 5 times) increases in migraine headaches and vascular over-reactivity 17,18
Increases in osteoporosis due to micro-thrombi in bones, mineral deficiencies, and decreases in serum bone alkaline phosphatase 19,20
HRT has been a health disaster for too long.
1. Hickey M, Elliot J, Davison SL. Hormone replacement therapy. BMJ 2012;344:e763
2 Kmietowicz Z. Articles disputing link between HRT and breast cancer are “ridiculous”. BMJ 2012; 344:e513.
3 Thornton JG. Re: Hormone replacement therapy. BMJ 18 February 2012
4 White M, Grant ECG. Addiction to oestrogen and progesterone. J Nutr Environ Med 1998; 8:117-120.
5 Price EH. Increased risk of mental illness and suicide in oral contraceptive and hormone replacement therapy in studies. J Nutr Environ Med 1998; 8:121-127.
6 Prentice RL, Pettinger M, Beresford SA, et al. Colorectal cancer in relation to postmenopausal estrogen and estrogen plus progestin in the Women's Health Initiative clinical trial and observational study. Cancer Epidemiol Biomarkers Prev 2009;18:1531-7.
7 Chlebowski RT, Anderson GL, Gass M, et al; WHI Investigators. Estrogen plus progestin and breast cancer incidence and mortality in postmenopausal women. JAMA 2010;304:1684-92.
8 Beral V, Bull D, Green J, Reeves G for the Million Women Study Collaborators. Ovarian cancer and hormone replacement therapy in the Million Women Study. Lancet 2007;369:1703-1710.
9 Chlebowski RT, Schwartz AG, Wakelee H, et al; Women's Health Initiative Investigators. Oestrogen plus progestin and lung cancer in postmenopausal women (Women's Health Initiative trial): a post-hoc analysis of a randomised controlled trial. Lancet 2009;374:1243-51.
10 J Green, A Berrington de Gonzalez, et al.. Risk factors for adenocarcinoma and squamous cell carcinoma of the cervix in women aged 20–44 years: the UK National Case–Control Study of Cervical Cancer. Br J Cancer 2003; 89: 2078–2086.
11 Zondervan KT, Carpenter LM, Painter R, Vessey MP. Oral contraceptives and cervical cancer--further findings from the Oxford Family Planning Association contraceptive study. Br J Cancer 1996;73:1291-7.
12 Persson I, Yuen J, Bergkvist L, Schairer C. Cancer incidence and mortality in women receiving estrogen and estrogen-progestin replacement therapy--long-term follow-up of a Swedish cohort. Int J Cancer. 1996;67:327-32.
13 Daly E, Vessey MP, Hawkins MM, et al. Risk of venous thromboembolism in users of hormone replacement therapy. Lancet 1996; 348:977-80.
14 Manson JE, Hsia J, Johnson KC, et al; Women's Health Initiative Investigators. Estrogen plus progestin and the risk of coronary heart disease. N Engl J Med 2003;349:523-34.
15 Hendrix SL, Wassertheil-Smoller S, Johnson KC, et al; WHI Investigators. Effects of conjugated equine estrogen on stroke in the Women's Health Initiative. Circulation 2006;113:2425-34.
16 Wassertheil-Smoller S, Hendrix SL, Limacher M, et al; WHI Investigators. Effect of estrogen plus progestin on stroke in postmenopausal women: the Women's Health Initiative: a randomized trial. JAMA 2003;289:2673-84.
17 Grant ECG. Relation between headaches from oral contraceptives and development of endometrial arterioles. BMJ 1968;3:402-05.
18 Grant ECG. The pill, hormone replacement therapy, vascular and mood over-reactivity and mineral imbalance. J Nutr Environ Med 1998;8:105-116.
19 Little K. Progestogens:thrombosis and osteoporosis. J Nutr Environ Med 1998;8:139-52.
20 McLaren-Howard J, Grant ECG, Davies S. Hormone replacement therapy and osteoporosis: bone enzymes and nutrient imbalance. J Nutr Environ Med 1998;8:129-38.
Competing interests: No competing interests
Dear Jim
Thanks for your response. No, this is not an advert for HRT. We have tried to present an evidence based approach to managing troublesome symptoms at menopause. I agree that is difficult to provide risk benefit ratios for individual women, but this is what we need to do in clinical practice. WHI largely recruited asymtomatic women, so we would not expect HRT to improve quality of life. We did include information about recurrence of hot flushes after stopping HRT.
Many women do decide to live with their hot flushes. Others are unable to function and need treatment. We have tried to provide a balanced approach to both hormonal and non-hormonal strategies, and to non-pharmacological approaches such as CBT. There is now lots of information about HRT: good, bad and ugly. This helps women to make informed decisions about use, and our article is aimed at helping this decision.
Best wishes, Martha
Competing interests: Author
Is this article an advertisement? I note the authors all have links with the HRT industry.
The claim of a dramatic reduction in hot flushes fails to mention symptom recurrence when the HRT is stopped, and that the largest trial (WHI) showed no benefit on quality of life.
The graphs appear to have been derived from, and give equal weight to, the largest randomised trial and the largest observational study. If the latter were removed and the other eight randomised trials included, the effect on all cause mortality would be in the opposite direction (odds ratio 1.06; 95% CI 0.94 -1.19) (Sanchez et al. 2005).
For the 51 year old woman with hot sweats, HRT provides short term relief. It increases the chance of some diseases, namely cardiovascular disease, strokes and breast cancer and reduces that of others, including osteoporosis, bowel cancer. The exact risk-benefit ratio varies with the woman's prior risk of each disease but the precision of the estimates is insufficient to allow individualised risk assessments.
When they learn that there is no overall improvement in quality of life, and that in the trials overall mortality was increased, most women wisely decide to live with their hot flushes.
Gabriel Sanchez R, Sanchez Gomez LM, Carmona L, Roqué i Figuls M, Bonfill Cosp X. Hormone replacement therapy for preventing cardiovascular disease in post-menopausal women. Cochrane Database of Systematic Reviews 2005, Issue 2. Art. No.: CD002229. DOI: 10.1002/14651858.CD002229.pub2.
Competing interests: My mother died of a stroke while taking HRT six months before the Women's Health Initiative trial was suspended because of the increased risk of stroke
I thought the article by Hickey et al. provided a comprehensive overview on the use of hormone replacement therapy in women with troublesome vasomotor symptoms.(1) I was surprised, however, that they failed to suggest low-dose oral progestogen as an alternative to HRT for menopausal symptoms. Medroxyprogesterone acetate (10mg) daily has been shown to be as effective as conjugated equine oestrogen (0.6mg) in controlling flushes and sweats
following surgical bilateral oopherectomy in premenopausal women.(2)
(1) Hickey M, Elliott J, Davison SL. Hormone replacement therapy. BMJ 2012;344:44-49
(2) Prior JC, Nielsen JD, Hitchcock CL, Williams LA, Vigna YM, Dean CB. Medroxyprogesterone and conjugated oestrogen are equivalent for hot flushes: a 1-year randomized double-blind trial following premenopausal ovariectomy.Clin Sci (Lond). 2007;112:517-25.
Competing interests: No competing interests
Hickey and her colleagues [1] described indications, efficacy and severe side- effects of hormone replacement therapy (HRT). Under psychiatric aspects the benefits in treating depressed postmenopausal women are discussed controversial. Results from epidemiological or clinical studies have been inconsistent. Scali J et al. [2] evaluated depressive symptoms in about 4000 postmenopausal women. Hormone therapy was not associated with a protective effect against the depressive symptoms in these elderly patients. Yalamanchili and Gallagher [3] detected in a double-blind placebo-controlled prospective study involving 489 postmenopausal older women no effect of hormone therapy and either individually or in combination with depression symptoms. Scali et al. [4] found no effect of HRT in postmenopausal women with anxiety disorders. Bromberger et al. [5] investigated the relationship between serum hormone levels and high depressive symptoms in a longitudinal study with 3302 women. It remains unclear whether alterations in hormone concentrations across the menopausal transition are linked to depressions. Other relevant studies showed that some postmenopausal women had relevant somatic and/or psychological problems. Risk groups to get a depression are women with a history of depression up to 5 times more likely during this critical time period. Studd [6] says that “Psychiatrists fail to use transdermal estradiol for postnatal depression, premenstrual depression and perimenopausal depression in spite of randomized trials demonstrating their efficacy ” and described that SSRI are associated with libido problems and the risk of osteoporosis. I think that HRT must be used carefully and individual, HRT is not beneficial for depressions or mild cognitive impairment (MCI). The long-term side-effects of HRT should observed very intensively, but screening of depressive symptoms in the menopausal transition and recognition of severe menopausal symptoms are relevant, too.
1) Hickey M, Elliot J, Davison SL. Hormone replacement therapy. BMJ 2012; 344:e763
2) Scali J, Ryan J, Carrière I, Dartigues JF, Tavernier B, Ritchie K, Ancelin ML. A prospective study of hormone therapy and depression in community-dwelling elderly women: the Three City Study.J Clin Psychiatry. 2010;71(12):1673-9
3) Yalamanchili V, Gallagher JC. Treatment with hormone therapy and calcitriol did not affect depression in older postmenopausal women: no interaction with estrogen and vitamin D receptor genotype polymorphisms.Menopause. 2011 Dec 27. [Epub ahead of print]
4) Scali J, Ryan J, Carrière I, Ritchie K, Ancelin ML.A prospective study of hormonal treatment and anxiety disorders in community-dwelling elderly women (the Esprit Study).J Affect Disord. 2009;115(1-2):274-9.
5) Bromberger JT, Schott LL, Kravitz HM, Sowers M, Avis NE, Gold EB, Randolph JF Jr, Matthews KA. Longitudinal change in reproductive hormones and depressive symptoms across the menopausal transition: results from the Study of Women's Health Across the Nation (SWAN).Arch Gen Psychiatry. 2010;67(6):598-607
6) Studd J. Why are physicians reluctant to use estrogens for anything--or do they prefer 'PROFOX'? Menopause Int. 2009;15(2):52-4
Competing interests: No competing interests
Avoiding HRT
Martha Hickey and colleagues’ attempt to resurrect Hormone Replacement Therapy (HRT), by cobbling together selected data for 50 to 59 year olds from two disparate studies, still finds significant increases in breast cancer, strokes and venous thrombotic diseases.1
In reality women aged 50 to 59 cannot have a reduced overall mortality if they take HRT because cancers, vascular diseases and mental diseases are increased in women who take hormones at any age. Mortality was increased 3 fold in women under age 30 if they had ever taken oral contraceptives in the Royal College of General Practitioners study.2
Oral contraceptives were used previously by twice as many women taking oestrogen HRT than non-oestrogen takers in the Nurses’ Health Study. At baseline women who already had cancer were excluded, as were women who had coronary artery disease at each two yearly survey. By 1993 only 9% of the nurses enrolled were still taking HRT, 43% were taking vitamins and nine out of 10 did not believe that HRT was beneficial.3
Similarly HRT gave no overall benefit in the quality of life and doubled mortality from breast and lung cancers in the WHI randomised double blind trial.4,5 The Million Women Study found HRT doubled mortality from ovarian cancer.6
Simple physiological ways of avoiding vasomotor over-reactivity and osteoporosis at the normal physiological event of the menopause include repletion of measurable essential nutrient deficiencies and avoidance of masked food allergies, smoking, alcohol use and contributing medications. 7,8
The message should be that “HRT is dead and needs to be buried”.
1 Hickey M, Elliot J, Davison SL. Hormone replacement therapy. BMJ2012;344:e763
2 Stampfer MJ, Colditz GA. Estrogen replacement therapy and coronary artery disease: a quantitative assessment of the epidemiological evidence.Prev Med 1991 ;20:47-63.
3 Chlebowski RT, Hendrix SL, Langer RD, et al. Estrogen plus progestin and breast cancer incidence and mortality in postmenopausal women. JAMA 2003;289:3243-53.
4 Chlebowski RT, Schwartz AG, Wakelee H, et al; Women's Health Initiative Investigators. Oestrogen plus progestin and lung cancer in postmenopausal women (Women's Health Initiative trial): a post-hoc analysis of a randomised controlled trial. Lancet 2009;374:1243-51.
4 Beral V, Bull D, Green J, Reeves G for the Million Women Study
Collaborators. Ovarian cancer and hormone replacement therapy in the
Million Women Study. Lancet 2007; 369: 1703-1710.
5 Hannaford PC, Iverson L, MacFarlane TV, et al. Mortality among
contraceptive pill users: cohort evidence from Royal College of General
Practitioners’ oral contraception study. BMJ 2010:340:c927.
6 Grant ECG. The pill, hormone replacement therapy, vascular and mood
over-reactivity, and mineral imbalance .J Nutr Environ Med 1998;8:105-116.
7 McLaren-Howard J, Grant ECG, Davies S. Hormone Replacement Therapy
and Osteoporosis: Bone Enzymes and Nutrient Imbalances. J Nutr Environ Med
1998; 8: 129-138
Competing interests: No competing interests
Re: Hormone replacement therapy
Please correct in abovementioned publication the statement that paroxetine and fluoxetine are CYP2D6 inducers. Instead these SSRI are inhibitors of the CYP2D6 enzyme which participates in the transformation of the prodrug tamoxifen to its active metabolite endoxifen. The combination of paroxetine with tamoxifen in patients treated for breast cancer has been shown to result in an increase risk of death of breast cancer with increasing dose of tamoxifen (1). The combination of fluoxetine with tamoxifen had not been extensively studied yet. But on grounds of this plausible interaction mechanism, the combination of paroxetine and tamoxifen should indeed be avoided since alternatives for both the SSRI and tamoxifen are available.
1 Kelley CM, Juurlink DN, Gomes T, Duong-Hua M, Prittchard KI, Austin PC, et al. Selective serotonin reuptake inhibitors and breast cancer mortality in women receiving tamoxifen: a population based cohort study. BMJ 2010;340;c693.
Competing interests: No competing interests