Association between hormone replacement therapy and subsequent stroke: a meta-analysis
BMJ 2005; 330 doi: https://doi.org/10.1136/bmj.38331.655347.8F (Published 10 February 2005) Cite this as: BMJ 2005;330:342All rapid responses
Rapid responses are electronic comments to the editor. They enable our users to debate issues raised in articles published on bmj.com. A rapid response is first posted online. If you need the URL (web address) of an individual response, simply click on the response headline and copy the URL from the browser window. A proportion of responses will, after editing, be published online and in the print journal as letters, which are indexed in PubMed. Rapid responses are not indexed in PubMed and they are not journal articles. The BMJ reserves the right to remove responses which are being wilfully misrepresented as published articles or when it is brought to our attention that a response spreads misinformation.
From March 2022, the word limit for rapid responses will be 600 words not including references and author details. We will no longer post responses that exceed this limit.
The word limit for letters selected from posted responses remains 300 words.
Professor Ebrahim and colleagues confirm that HRT has been used mostly by higher social class women. Hormone prescribing has been a major part of the private practice of gynaecologists since the 1960s.
Observational studies have underestimated relative risks of HRT-induced increases in mortality precisely because comparisons were made with mortality risks of women in the general population. Women in lower socio-economic classes have an increased risk of premature death. They are also more likely to smoke, which has a synergistic adverse effect with HRT. By the mid 1970s, because the absolute numbers of thrombosis cases increases with age, women over age 35 were advised not to use hormones.
In my responses above I have referred to some of the reasons for HRT-induced increases in cancers, vascular and mental illnesses and immune dysfunction. Ebrahim and colleagues could study the publications on blood vessel and clotting changes, interferences with amine metabolism, especially lowering zinc and raising copper levels, B vitamin deficiencies and variations the activities of catechol-o-methyl-transferase and monoamine oxidase enzymes.
In 1987 the UK HRT study, the authors acknowledged a “healthy volunteer” effect as “high risk” women, those deemed to have contraindications to HRT (perhaps because of illnesses due to past use of contraceptive hormones), would be less likely than others to be prescribed HRT.1 The authors considered that the selected nature of the populations might account for the low mortality ratios and low cardio-vascular morbidity in their study and those of Stampfer, Bush and Wilson. Also by study design, women with short or intermittent use (e.g. those with immediate adverse vascular and mental effects) were excluded from enrolment and therefore from mortality follow-up. Among 4544 women, enrolled at ages 45 -54 who had used HRT continuously for at least 12 months and were followed up for an average of 67 months, the relative risk of mortality from suicide or suspected suicide was 2.53 (95% C I 1.26- 4.54). Nevertheless, and regardless of the obvious reasons observational studies were underestimating HRT-induced mortality, “HRT halves mortality” became the rallying cry of hormone-promoters.
Belief in misleading epidemiological evidence is ingrained. Meir Stamper and others at an HRT meeting in Milan in 1999 agreed that, in spite of lack of proof, the evidence was sufficiently strong to claim that HRT lowered the risk of coronary heart disease. I objected, saying that this claim to be published in the consensus statement of the meeting,2 was ignoring long established basic scientific facts.
Even the alarming results from randomised double blind trials, which led to early terminations of large international trials, still underestimate the true scale of Pill and HRT disasters because few women now have never taken hormone and most control women are previous hormone users.
From 1961 to 2005 I have been consulted by women of any age or socio-economic background who have had severe and frightening side-effects with one or two pills. Very wisely, these sensitive women often recognise warning symptoms even if their doctors don’t, and they choose not to return to clinics where the offending hormones were prescribed.
1 Hunt K, Vessey M, McPherson K, Coleman M. Long-term surveillance of mortality and cancer incidence in women receiving hormone replacement therapy. Br J Obstet Gynae 1987: 94: 620-635.
2 Clinical Synthesis panel on HRT. Hormone replacement therapy. Editorial. J Epidemiol Biostat 1999; 4: 123-128.
Competing interests: None declared
Competing interests: No competing interests
Bath and Gray consider that the reasons for the discrepancy between the observational studies and randomised trials of the effects of hormone replacement therapy are unclear.[1] Two explanations are relevant: first, that women who took part in the trials are different from those included in observational studies; and second, that the observational findings were confounded. Both selection effects and confounding deserve greater recognition by clinicians as they can produce powerful distorting effects.
In a cohort of British women aged 60 to 79 years, we have shown that adverse socioeconomic indicators from across the life course were associated with use of HRT. Indicators of socioeconomic deprivation in childhood were associated with reduced odds of using HRT, and these associations were independent of adult socio-economic position, behavioural and physiological risk factors.[2] Since adverse social circumstances in childhood show a particularly strong association with risk of stroke in adulthood [3] these findings indicate that typical adjustments for confounders in most observational studies would still result in residual confounding of sufficient amount to produce spurious findings, despite influential assertions to the contrary.[4]
As long ago as 1986, it was shown in observational studies that HRT was apparently equally protective against accidental and violent deaths as it was against death resulting from cardiovascular disease.[5] The lack of any biologically plausible link between HRT and external causes of death should have highlighted the likely role of residual confounding in explaining associations with either outcome.
1. Bath P, Gray LJ. Association between hormone replacement therapy and subsequent stroke: a meta-analysis. BMJ 2005;330:342
2. Lawlor DA, Davey Smith G, Ebrahim S. Socioeconomic position and hormone replacement therapy use: explaining the discrepancy in evidence from observational and randomised controlled trials. American Journal of Public Health 2004; 94: 2149-2154
3. Davey Smith G, Hart C, Blane D, Hole D. Adverse socioeconomic conditions in childhood and cause specific adult mortality: prospective observational study. BMJ 1998;316:1631-1635.
4. Stampfer MJ, Colditz GA. Estrogen replacement therapy and coronary heart disease: a quantitative assessment of the epidemiologic evidence. Prev Med. 1991;20:47–63
5. Petitti DB, Perlman JA, Sidney S. Postmenopausal estrogen use and heart disease. N Engl J Med. 1986; 315:131–132
Competing interests: None declared
Competing interests: No competing interests
Victor Palmer quotes from my Rapid Response above his which was not written by the MWS author Emily Banks. Hormone promoters have long described hard scientific evidence as “scare stories”. Increases in thrombosis risks of 4-8 times are not slight for a major cause of death.
What exactly are the proven benefits of HRT? Perhaps a male journalist can tell me what I have failed to confirm pathologically, immunologically or biochemically in any woman patient taking hormones for any reason over the last 45 years.
In Chlebowski’s WHI paper estrogen plus progestin increased total (245 /185 cases; hazard ratio [HR], 1.24; weighted P<.001) and invasive (199 vs 150 cases; HR, 1.24; weighted P =.003) breast cancers compared with placebo.1 The invasive breast cancers diagnosed in the estrogen plus progestin group were similar in histology and grade but were larger (P =.04) and were at more advanced stage (regional/metastatic 25.4% vs 16.0%, respectively; P =.04) compared with those diagnosed in the placebo group. After 1 year, the percentage of women with abnormal mammograms was substantially greater in the estrogen plus progestin group (716 [9.4%] of 7656) compared with placebo group (398 [5.4%] of 7310; P<.001). This pattern which continued for the study duration. In the WHI studies nearly all the women in the placebo group had previously used hormones and some restarted HRT (?addicted) during the study, which would underestimate HRT- induced increases in cancers, vascular diseases and fractures.
Progesterones also cause thrombosis although progesterone and oestrogen combinations cause most adverse vascular changes, as I first described in the 1960s. The warnings over increased thrombosis risk with newer progesterones led to falls in HRT use and there is evidence of a corresponding fall in breast cancer mortality.2
Oral contraceptive use 20 years earlier doubles the numbers of breast cancers with cyclin D1 overexpression.3 There is also evidence of cumulative effect of oral contraceptive use followed by HRT. When joint effects of longer term use of both agents were considered, subjects who reported use of oral contraceptives for 10 or more years and hormone replacement for 3 or more years had a relative risk of 3.2 (95% CI 1.4- 7.4) compared with nonusers of either preparation.4
By the 1990s the greatest increases in breast cancer incidences since the 1960s were in women who were likely to have taken oral contraceptives when younger and were currently taking HRT. The changes in breast cancer incidences, mostly huge increases, match the changes, mostly huge increases, in hormone use since 1962.
1 Chlebowski RT, Hendrix SL, Langer RD et al, for the WHI Investigators. Influence of estrogen plus progestin on breast cancer and mammography in healthy postmenopausal women: The Women’s Health Initiative randomised trial. JAMA 2003; 289: 3243-53.
2 Grant ECG. Fall in HRT use would have reduced breast cancer mortality http://bmj.com/cgi/eletters/330/7485/220#94525, 27 Jan 2005
3 Terry MB, Gammon MD, Schoenberg JB, Brinton LA, et al. Oral contraceptive use and cyclin D1 overexpression in breast cancer among young women. Cancer Epidemiol Biomarkers Prev. 2002 ; 11: 1100-3.
4 Brinton LA, Brogan DR, Coates RJ, et al. Breast cancer risk among women under 55 years of age by joint effects of usage of oral contraceptives and hormone replacement therapy.Menopause. 1998 ; 5: 145- 51.
Competing interests: None declared
Competing interests: No competing interests
Two months after publication of the Bath and Gray meta-analysis, perhaps it is time to reflect on what the paper itself and the responses to it add to our knowledge of the hazards and possible benefits of HRT. The answer must surely be very little: the slightly increased thrombotic tendency of any type of oestrogen therapy has been recognised for some years and is the reason why women with any history of, or predisposing factors for, thromboembolism are contra-indicated for either HRT or oral contraceptive therapy.
Nevertheless these results have been seized upon once again by the anti-HRT brigades who are so concerned that women should be "fully informed" that they are quite happy to feed the tabloid press with scare stories (HRT doubles the risk of breast cancer AND strokes) with never a mention of relative risk, or of the proven benefits of HRT. As Mrs Edge's response demonstrates, women who are indeed FULLY informed are well able to make their own decisions and have only scorn for those who distort the facts in pursuit of their own agenda. (Dr Banks informed me in a reply to my rapid response to the MWS Personal Characteristics paper (1) that both the WHI and MWS had to be terminated due to the increased risk of breast cancer. I do not understand why a study of mammographic records would need to be terminated whatever its findings. Still, we should not let the facts get in the way of a good story!)
However as the first respondent, Dr Burman, notes despite its title Prof Bath's meta-analysis includes few studies that fall under the heading of physiological sex hormone therapy. Most are secondary intervention studies that assess the effects of hormonal therapy on a variety of conditions: UTI, RA, IHD, MI and a range of thrombo-embolic conditions, including secondary prevention of stroke! The classification of the patients in the two legs of the WHI (which together make up almost 60% of the Bath meta-analsis)as "healthy" is a matter of some debate.
Let us suppose for a moment that Prof Bath's study had shown a small but significant decrease in strokes - and had been sponsored by a pharmaceutical company. How would the anti-HRT lobby have responded? Might I Suggest that the would have "rubbished" it by noting that:
-three of the analysed studies are almost 40 years old
-one of the studies is exclusively in men, two others include,respectively, 63% and 75% men
-the treaments are completely untypical of current HRT, at least in Europe ( over 80% of patients received equine oestrogens and in 50% this was in combination with MPA: the current British National Formulary lists 18 products suitable for women with a uterus, of these there is one CEO/MPA combination,one other product contains MPA and one contains CEO).
- the mean age of the subjects is mid-60s, much older than actual candidates for "real" HRT (in 4 of the analysed studies mean age was >70 and in one >80).
A final point: in her rapid response above, Dr Banks suggests that women cannot choose therapy for a short term because breast cancer risk increases much more rapidly than previously thought. She goes on to say that: "Both the WHI and the MWS confirmed increases in breast cancer within the first 12 months of current use of HRT including doubling of abnormal mammograms. In the MWS, up to a year's (sic) of most HRT formulations increased breast cancer risks by 45%-63%. Any current use doubled the risk of breast cancer and increased the risk of breast cancer being fatal by at least 22%."
However the MWS also showed a great reduction in risk one year after discontinuation of HRT and a return to baseline within 5 years.
The latest market data I have seen reports that HRT use peaked at 90 million prescriptions in the USA in 2002, falling,as a result of scare stories, to less than 60 million prescriptions in 2003 and continuing to fall in 2003. The situation in Europe paralleled that in the USA. I look forward to seeing evidence of this in a significant decrease in the incidence of, and mortality from, breast cancer when 2004 statistics become available.
(1)Rapid responses to: Influence of personal characteristics...........in the Million Woman Study:cohort study. Banks E, Reeves G, Beral V et al. BMJ 2004;329:477
Competing interests: None declared
Competing interests: No competing interests
How on earth can women “choose therapy for a short term if they wish and understand what they stand to gain or lose” when leading international experts are surprised that, “Breast cancer risk increases with shorter use than previous evidence suggested”?1
Both the WHI and the MWS confirmed increases in breast cancer within the first 12 months of current use of HRT including doubling of abnormal mammograms.2 In the MWS, up to a year’s of most HRT formulations increased breast cancer risks by 45% - 63%. Any current use doubled the risk of breast cancer and increased the risk of breast cancer being fatal by at least a 22%.
The HABITS (hormonal replacement therapy after breast cancer-is it safe?) trial was terminated after 2 years because 28 patients, mostly current HRT users, had new breast-cancer events, compared with 5 non users.3 What else causes more than 5 times more cancer in such a short time?
The WHI combined HRT study confirmed no clinically meaningful effect on health-related quality of life.4 Both combined and oestrogen-only HRT studies were terminated early because of unacceptable increases in potentially fatal diseases including breast cancer, vascular diseases and dementia.
“Terrible hot flashes” are a sign of vascular over-reactivity, usually due to increased reactions to common foods and chemicals, unmasked by falling hormone levels, even from very high concentrations as in tachyphylaxsis. Like migraine, which is also increased in HRT users, hot flushes can be easily and safely prevented by correction of immune system defects due to nutritional deficiencies, along with low allergy diets, and avoiding smoking and alcohol. 5,6
Flawed epidemiological studies, like the Salpeter et al meta- analysis, have helped HRT promotions to continue.7-9 Women do not need to be fooled any longer by the false claims that the menopause is a disease entity.
1 Beral V, Banks E, Reeves G, Bull D, on behalf of the Million Women Study Collaborators. Breast cancer and hormone-replacement therapy: the Million Women Study. Lancet 2003; 362: 1331.
2 Chlebowski RT, Hendrix SL, Langer RD et al, for the WHI Investigators. Influence of estrogen plus progestin on breast cancer and mammography in healthy postmenopausal women: The Women’s Health Initiative randomised trial. JAMA 2003; 289: 3243-53.
3 Holmberg L, Anderson H; et al. HABITS steering and data monitoring committees. HABITS (hormonal replacement therapy after breast cancer--is it safe?), a randomised comparison: trial stopped. Lancet 2004; 363: 453- 5.
4 Hays J, Ockene JK, Brunner RL, et al. Effects of estrogen plus progestin on health-related quality of life. N Engl J Med. 2003; 348: 1839 -54.
5 Grant ECG. Grant ECG. Food allergies and migraine. Lancet 1979; 1: 966-69.
6 Grant ECG. Food allergy and migraine. Lancet 1979; 2: 358-59.
7 Grant ECG. Epidemiologists’ long-term underestimation of harm from hormones http://bmj.com/cgi/eletters/329/7456/2#65645, 3 Jul 2004
8 Grant ECG. Pill and HRT Epidemiologists http://bmj.com/cgi/eletters/329/7463/467#72387, 27 Aug 2004
9 Grant ECG. Re: Meta analyses and misleading claims about HRT mortality. http://bmj.com/cgi/eletters/329/7474/1093#85813, 17 Nov 2004
Competing interests: None declared
Competing interests: No competing interests
Women take HRT to function better in their day to day lives so that their sleep, mood and other basic health building blocks are better. The WHI trial and other articles such as this one do well to warn women of possible effects, however I would make the criticsm that the context is rarely explained in brief headlines, leaving our patients anxious and confused. And all this on top of terrible hot flashes. Also important to note that not all cultures have "menopause" as a concept like the "western biomedical' model. This is one area of life where we might be better to leave more medical research aside and promote healthy living for our patients. Let them choose therapy for a short term if they wish and understand what they stand to gain or lose. And by the way, why was one of the studies exclusively with male patients.... did I misread or does there seem to be something a bit funny about that. Thanks.
Competing interests: None declared
Competing interests: No competing interests
Two years ago (2003) as a 53-year-old slim fit businesswoman who had experienced an early menopause, I found myself during an HRT review at the receiving end of the HERS trial “Women had died”! Women who use HRT are advised to be informed. Even at that time there were conflicting opinions. This led me to read research, my computer now holds over 20Gb on the subject which has included reading the full version of the Million Women Study (MWS) the day after release and the recent Royal College of Gynaecologists (RCOG) book.
The morning of 7th January I was alerted to an HRT item on GMTV (Bath & Gray paper - 1). A Doctor commenting on the latest paper informed viewers-- it was drawn from a wide range of studies, it could not be criticised in the way some experts had criticised the American studies, ie. many of the women obese and much older than women using HRT in the UK.
Later that day I read the paper, I was astonished to find:
· 59.32% Drawn from the 2 WHI HRT arms; not immediately obvious as one of the WHI arms is referred to as “Wasserheil et Al” (2)(3)
· 16.21% the HERS trial this appears as “Simon et Al” women mean age 68, BMI mean 29 CEO/MPA with pre-existing cardio-vascular disease (4)
· 11.31% Viscoli – 1Mg oral Oestradiol – women mean age 71 HRT following stroke (5)
· 6.24% Veterans Co-operative – all men, age unknown – with cerebrovascular disease – 1966 large men, large dose?
93% of this meta-analysis has been drawn from these 5 studies, 3 of these papers are unquestionably secondary prevention.
The WHI has received critical comment by many menopause specialists questioning its presentation as a Primary Prevention “healthy” study. Quoting from American Association of Reproductive Medicine (ASRM) “Drawing from several WHI reports, the doctors calculated that WHI participants in the 50-59 year-old age group were an average of 12 years past menopause. They also noted that there were only 574 moderately to severely symptomatic women in the 50 to 54 year-old age group, half of them receiving hormone therapy, half placebos. Based on the small number of women studied in this age group, it is not possible to conclude that, for those women in the menopausal transition, hormone therapy has no cardioprotective effect” (6).
Recruitment was spread from 50-79 yrs which must have led to some women being into their 80s when the trial was terminated early. The level of obesity 36% BMI>30, even higher on the Oestrogen only arm. To a layperson this appears extraordinary. 34% of participants’ were hypertensive on medication and an even a higher percentage on the Oestrogen only arm fell into this category. The UK public are bombarded with information advising them that obesity and hypertension lead to strokes, heart attacks, DVT and also breast cancer. Many women believe obesity and hypertension are a contra-indication for use of HRT. Most women on HRT receive regular BP checks.
The Bath/Gray meta-analysis is dominated by an
· 86.07% usage of Conjugated Equine Oestrogens (CEO) used with Medroxyprogesterone acetate (MPA) when uterus present. Numbers on trials total 32941 (including some men). This is one of the earliest HRTs, which appears to be considered by some Doctors in the UK to be less desirable.
· 13.93% - trialed Oestradiol and some variations (numbers 3771)
· The four transdermal trials contributed no stroke events
The Authors correctly conclude that HRT cannot be recommended for Secondary prevention of stroke (note – the authors suggest possible reasons for results - high doses and method of delivery). Is this meta- analysis a fair analysis of Primary Prevention treatments for younger women commencing Oestradiol at the time of the menopausal transition?
HRT in the UK is prescribed for menopausal symptoms and prevention of osteoporosis. Is it prescribed as a prevention treatment for stroke to women considered to be at increased risk?
After reading the paper, the day of release, I emailed the author and did receive an immediate interesting response from Professor Bath. His final comments, “future research will address whether alternative doses or forms of oestrogen, or delivery (transdermal) are better”.
Over the last two years after reading many papers, I came across the IMS position statement (7) and was grateful to find it was in line with my thinking. Hopefully further research will commence using HRT not HT as used on the WHI and HERS trials etc using other more modern treatments.
I also have come across a paper (8) "Looking for the Pony in the HERS Trial" offering more or less the opposite view to the IMS.
On balance unless the premise that there is deterioration to the heart and bones beyond menopause caused by lowering levels of Oestrogen is fundamentally flawed - it seems reasonable to hypothesise that replicating these hormones that have been reduced might be beneficial. This begs the question can this be done effectively and safely?
There is evidence to suggest HRT commenced at the menopause is beneficial (9)(10) and may not produce the same results as the WHI. Many women in there 40s and 50s are working hard in a competitive world to fulfil career commitments etc. so why should women be frightened off HRT by what appears to be an amplification of the risks that may lead to their using unproven treatments.
Ms Nina Edge
1. Bath PMW. Gray LG. Association between hormone replacement therapy and subsequent stroke: a meta-analysis BMJ 2005;330:342 (12 February), doi:10.1136/bmj.38331.655347.8F (published 7 January 2005)
2. Writing group for the Women's Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women. JAMA 2002; 288: 321-333.
3. The Women's Health Initiative Steering Committee. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy. JAMA 2004;291:1701-12.
4. Simon JA, Hsia J, Cauley JA, Richards CL, Harris F, Fong J, et al. Postmenopausal hormone replacement therapy and risk of stroke. The heart and estrogen-progestin replacement study (HERS). Circulation 2001;103:638- 42.
5. Viscoli CM, Brass LM, Kernan WN, Sarrel PM, Suissa S, Horwitz RI. A clinical trial of estrogen-replacement therapy after ischemic stroke. N Engl J Med 2001;345:1243-9.
6. ASRM Bulletin Volume 6, Number 32 June 23, 2004 Highlights from Fertility & Sterility Volume 81, Number 6, June 2004
7. International Menopause Society statement 2004 http://www.imsociety.org
8. Barrett-Connor, E. (2002). Looking for the Pony in the HERS data. Circulation 105:902-903
9. Salpeter SR, Walsh JM, Greyber E, Ormiston TM, Salpeter EE. Mortality associated with hormone replacement therapy in younger and older women: a meta-analysis. J Gen Intern Med 2004;19:791-804.
10. Lobo RA. Evaluation of cardiovascular event rates with hormone therapy in healthy, early postmenopausal women: results from two large clinical trials. Arch Intern Med 2004;64:482–4
Competing interests: None declared
Competing interests: No competing interests
Zinc deficiency impairs endogenous sex hormone productions, increases side-effects form OCs and HRT, impairs adrenal steroid hormone metabolism and also interferes with thyroid function.
“Zinc deficiency and thyroid function” brings up 26 citations in PubMed.
Arthur and Beckett’s review from the Rowan Research Institute at Aberdeen states that normal thyroid status is dependent on the presence of many trace elements for both the synthesis and metabolism of thyroid hormones. Iodine is most important as a component of the hormones, thyroxine and 3,3',5-tri-iodothyronine (T3) and iodine deficiency may affect approximately one billion people throughout the world. Selenium is essential for normal thyroid hormone metabolism being involved with selenium-containing iodothyronine de-iodinases that control the synthesis and degradation of the biologically active thyroid hormone, T3. The roles of iron, zinc and copper in the thyroid are less well defined but sub- or supraoptimal dietary intakes of all these elements can adversely affect thyroid hormone metabolism.
Zimmermann and Kohrle write that coexisting deficiencies of iodine, iron, selenium, and zinc can impair thyroid function.2
Children who were zinc deficient in their sweat had normal range serum zinc levels, therefore seem to have more stable serum zinc homeostasis than adults.3 However, Bucci et al found that plasma zinc levels are commonly detected below the normal range in subjects with trisomy 21 (Down syndrome). Zinc deficiency also impairs immune response and growth rate but hypothyroidism is the most common endocrinological deficit. After months of zinc supplementation, TSH significantly decreased in treated hypozincemic children (4.48 versus 2.96 mUI/mL) and was no longer different to normozincemic children.4
Nishiyama et al found disabled patients with elevated levels of serum T3 showed an enhanced reaction of serum thyrotropin (TSH) after TRH injection. Nine of 13 patients had mild to moderate zinc deficiency evaluated by body zinc clearance and increased urinary zinc excretion. After oral supplementation of zinc sulphate for 12 months, levels of serum free T3 and T3 normalized, serum T3 decreased, and the TRH-induced TSH reaction normalized.5
As with HRT, progesterone and DHEA supplements, there is a huge internet promotion of thyroid extracts which are claimed to “treat” every imaginable symptom. Abnormal hormone levels signal the need for investigations of basic causes such as zinc, copper, magnesium, selenium, glutathione or iodine deficiencies.
1 Arthur JR, Beckett GJ. Thyroid function. Br Med Bull. 1999; 55: 658 -68.
2 Zimmermann MB, Kohrle J. The impact of iron and selenium deficiencies on iodine and thyroid metabolism: biochemistry and relevance to public health. Thyroid. 2002; 12: 867-78.
3 Grant ECG, Howard JM, Davies S,Chasty H,Hornsby B, Galbraith J. Zinc deficiency in children with dyslexia: concentrations of zinc and other minerals in sweat and hair. BMJ 1989;296:607-9.
4 Bucci I, Napolitano G, Giuliani C, et al. Zinc sulfate supplementation improves thyroid function in hypozincemic Down children. Biol Trace Elem Res. 1999; 67: 257-68.
5 Nishiyama S, Futagoishi-Suginohara Y, Matsukura M, et al. Zinc supplementation alters thyroid hormone metabolism in disabled patients with zinc deficiency. J Am Col Nutr. 1994; 13: 62-7.
Competing interests: None declared
Competing interests: No competing interests
The re-emergence of the old chestnut, that adverse effects of HRT (progesterones and oestrogens) depends on the age since the menopause, betrays a lack of understanding of how hormones act. I observed adverse changes in endometrial blood vessels, which matched increases in headaches, migraines and strokes, in previously healthy young women who volunteered to take these hormones as oral contraceptives in the early 1960s.1
What is the age of the menopause? Post-Pill amenorrhoea and anovulation at age 20 because of starting OCs at age 15? Hysterectomy and bilateral oophorectomy at age 30 because of OC-induced wide-spread endometriosis? Women with ovarian failure at age 40, due to years of tobacco smoking and Pill taking and who take further hormones as HRT, already have higher risks of vascular diseases.
In the WHI combined HRT study concluded that excess risk of all stroke was apparent in all age groups, in all categories of baseline stroke risk, and in women with and without hypertension, prior history of cardiovascular disease, use of hormones, statins, or aspirin.2 The intention-to-treat hazard ratio (HR) for ischemic stroke was 1.44 (95% CI, 1.09-1.90) which is statistically significant.
As OCs and HRT cause hypertension, which is, or should be, a contra- indication to further hormone use. Only one in 5 strokes were therefore haemorrhagic. Small numbers in subgroups make statistically significant results less likely. The WHI studies underestimate risks because most women randomised to take either combined or oestrogen-only HRT, or placebos, had previously used these hormones as HRT or for contraception.
Also in 1965 OCs were reported to cause cerebral insufficiency.3 In 1967 neurologists noticed that OCs also caused subarachnoid haemorrhages and in 1981 the RCGP OC study reported an increased risk of mortality of 4.0 (1.3-12.9) from this condition.4,5 The increased mortality risks were estimated to be 2.9 (1.3-6.4) for all cerebrovascular diseases and 5.6 (2.0-16.6) for all non-rheumatic heart disease and hypertension.
How many times does the wheel have to be reinvented ?
1 Grant ECG. Relation between headaches from oral contraceptives and development of endometrial arterioles. Lancet 1965; 1: 1143-4.
2 Wassertheil-Smoller S et al. Effects of Estrogen plus progestin in postmenopausal women. A women's health initiative randomized trial. JAMA 2003;289:2673-81.
3 Illis L, Kocen RS, McDonald WI, Mondkar VP. Oral contraceptives and cerebral arterial occlusion. BMJ 1965; 2: 1164-66.
4 Bickerstaff ER, Holmes JM. Cerebral arterial insufficiency and oral contraceptives. Cerebral arterial insufficiency and oral contraceptives. BMJ 1967; 1: 726.
5 Royal College of General Practitioners’ Oral Contraception Study. Further analyses of mortality in oral contraceptive users. Lancet 1981; i: 541-546.
Competing interests: None declared
Competing interests: No competing interests
Re: Remember the most important reason
Thank you Christine Singh for your common sense comment. As a post- menopausal woman suffering the most horrendous symptoms I can live with the miniscule real increase in any of the risks associated with HRT because it quite simply gives me back a life.
Competing interests: None declared
Competing interests: No competing interests