By Jerome Burne
So, women who take HRT to help with symptoms of the menopause have a three times greater risk of developing breast cancer, according to a paper in the British Journal of Cancer1)Michael E Jones, Minouk J Schoemaker at al Menopausal hormone therapy and breast cancer: what is the true size of the increased risk? British Journal of Cancer (2016) 115, 607–615 published a couple of weeks ago. That’s certainly alarming news if you are approaching or going through menopause but it should really not come as a great surprise. The issue of HRT and cancer has been rumbling away for over a decade.
What’s depressing but familiar is that there is another option that might well avoid the risk. But instead of being properly investigated it has been side-lined and dismissed. Alarm bells about the cancer link – as well as one with heart disease – have been ringing since 2002 when they both showed up, to general surprise, in a big randomised controlled trial (RCT) of HRT called the Women’s Health Initiative (WHI)2) Evan Simpson & Richard J Santen, Celebrating 75 years of oestradiol (T1–T20), Journal of Molecular Endocrinology V.55 (2015) .
The alternative is a more natural form of HRT – using what are called bio-identical (BI) hormones. At least eight years ago good evidence was being published suggesting that BI was as effective and possibly safer. For all too familiar financial reasons none of the studies were RCTs but they certainly suggested this was an area worth following up.
Instead the official line became that BI had nothing to offer a proper science based approach. A typical example was published in the Cleveland Clinic Journal of Medicine in 2011. ‘The use of bio-identical hormones is based on misconceptions and unfounded claims that they are more natural and safe than approved hormone therapy.’3) Pattimakiel L1 et al, Bioidentical hormone therapy: clarifying the misconceptions. Cleve Clin J Med. 2011 Dec;78(12):829-36
Replace like with like if you want the same results
So why should BI be taken seriously? Some doctors and patients still aren’t aware that when you get HRT you are not being given hormones that are exactly the same as those which your body has been making. In some cases their molecules have been slightly tinkered with in the lab; others come from a source that makes them different. The important result is that because they are no longer something found in nature, they can be patented. This makes it worth running large expensive RCTs on them.
Bio-identical hormones are also made in the lab but rather than being made deliberately slightly different, they are deliberately made to be exactly the same. This is why they are said to be more natural; it’s also why they can’t be patented.
Replacing like with like is far more likely to produce the same effect. This is especially true in the case of hormones; minor molecular differences – such as between oestrogen and testosterone – can result in very different effects. Look up the ‘chemical diagrams’ of these two hormones on line and see how similar they are.
Then check out the diagrams of the natural and synthetic versions of the hormone progesterone. A “tweaked” version – known as progestin or progestogen – is normally combined with oestrogen in standard HRT. Since the difference between the two is at least as great as that between oestrogen and testosterone, it’s reasonable to suspect their effects could be just as different. There are now good reasons to think they are.
The HRT combo first found to raise the cancer risk
The women in the WHI trial got two non-bioidentical hormones in their HRT. The oestrogen was derived from mares’ urine and so contains oestrogens not otherwise found in humans; it’s known as conjugated equine oestrogen (CEE). The progestin, there are a number of variations, was one called medroxyprogesterone acetate (MPA). The combination increased the relative risk of heart problems by 26% and of cancer by 25% 4) Evan Simpson & Richard J Santen, Celebrating 75 years of oestradiol (T1–T20), Journal of Molecular Endocrinology V.55 (2015) .
There has been much re-analysis of those findings and starting younger seems to carry less risk but the original non-identical combo is still widely used. What also hasn’t changed is the relentlessly hostile attitude to bioidenticals. A paper in 2007 described the term as a “pseudoscientific neologism”, the FDA has asserted that there is no difference in the side-effects of progesterone and progestin and in April of this year the Endocrine Society of America issued a ‘scientific statement’ stating that: ‘evidence demonstrating a benefit of micronized progesterone (the most widely available form) on clinical outcomes is lacking.’
All of these charges are demonstrably untrue and the latest finding that the cancer risk is greater than previously thought makes the failure to investigate bioidenticals in any serious way even more unforgivable. Summarising the benefits from a number of BI RCTs, for instance, is rarely useful because there aren’t many and they are usually small. Money is hard to find for thorough trials of this and other unpatentable treatments such as omega 3 oils or vitamins
Benefits for progesterone – not for synthetic version
The Cochrane Library did such a summary of trials recently on the effectiveness of BI for hot flushes.5) Ana Marcia IS Gaudard et al, Bioidentical hormones for women with vasomotor symptoms. The Cochrane Library; 1 August 2016. DOI: 10.1002/14651858.CD010407.pub2 It found benefit but noted evidence was poor. It was also unhelpful because none of the trials involved progesterone. A BI practitioner would very rarely give only oestrogen.
But when reviews do reveal a number of positive possibilities they are usually ignored and rarely followed up. Back in 2008, for instance, a review of the effects of bio-identical oestrogen and progesterone had this to say. ‘Recent evidence shows that natural progesterone displays a favourable action on blood vessels and on the brain, (which) might not be true for some synthetic progestins.’6)Maturitas. 2008 Jul-Aug;60(3-4):185-201
It goes on to report that giving progesterone with oestrogen: ‘confers less or even no risk of breast cancer as compared to the use of synthetic progestins.’ The review details some of the effects of non-identical progestins. These included being likely to increase the risk of heart disease, cancer and other disorders; raising blood pressure, damaging the lining of blood vessels, increasing inflammation and causing insulin resistance.
French women who avoid cancer risk with progesterone
A combination of oestrogen and progestins has been consistently found to increase the risk of breast cancer while the oestrogen progesterone combination does not7)Carlo Campagnoli, Françoise Clavel-Chapelon et al, Progestins and progesterone in hormone replacement therapy and the risk of breast cancer. The Journal of Steroid Biochemistry and Molecular Biology Volume 96, Issue 2, Pages 95-228 (July 2005) . As detailed below, the failure to follow up on this particular finding has been highly damaging to thousands of menopausal women.
This evidence for the ability of bio-identical progesterone to protect against breast cancer is also supported by a large, long, observational French study, known as E3N. It involved 80,000 post-menopausal women who all took oestrogen. Some took nothing else, some combined it with progesterone and a third group added a non-identical progestin8)Fournier A1 et al, Unequal risks for breast cancer associated with different hormone replacement therapies: results from the E3N cohort study. Breast Cancer Res Treat. 2008 Jan;107(1):103-11. Epub 2007 Feb 27. .
Those who only took oestrogen had a 29% rise in their risk of breast cancer; combining it with progesterone eliminated the risk. Combining it with various progestins however, pushed up the risk by as much as 69%.
Such observational trials are often dismissed as only proving correlation not causation. Causation becomes much more likely, however, if there is a plausible mechanism. One emerged in a paper in Nature in 2015 which reported on a study that had investigated the effects of oestrogen and progesterone at a cellular level9)Mohammed H1 et al, Progesterone receptor modulates ERα action in breast cancer. Nature. 2015 Jul 16;523(7560):313-7. .
Nature report: MPA increases breast cancer risk
It found that a receptor for progesterone was far more active than previously thought and was able to trigger events within breast cancer cells; ‘resulting in a unique gene expression programme that is associated with good clinical outcome.’
The report goes on to say: ‘There is compelling evidence that inclusion of a progestin –especially MPA ( the one used in WHI) as part of HRT increases the risk of breast cancer …the relative risk is not significant when native progesterone is used.’
If you are still unconvinced that progesterone has significantly different effects and is safer, what about this undisputed fact. IVF clinics around the world routinely use very high doses of micronized progesterone to protect a successfully implanted fertilised egg? The primary purpose of natural progesterone is to support pregnancy and prevent miscarriages.
Yet progestins are all contraindicated in the event of pregnancy because they can masculinize (virilise) the external genitalia of a female fetus during susceptible times in pregnancy10)Carson, Sandra A.; Simpson, Joe Leigh (1983). “Virilization of Female Fetuses following Maternal Ingestion of Progestational and Androgenic Steroids”. In Mahesh, Virendra B.; Greenblatt, Robert B. Hirsutism and Virilism: Pathogenesis, Diagnosis and Management. Boston: John Wright PSG Inc. pp. 177–188. ISBN 0-7236-7045-5 . It is hard to imagine a clearer demonstration of the difference between the two sorts and the greater risk posed by non-identical progestins.
Why has the obvious trial never been done?
This is just a small selection of trials that all point in the same direction: that progesterone is very safe and when taken together with BI oestrogen has a low to zero risk of breast cancer. This could, of course, be wrong but the benefits would be so large that it’s appalling that no attempt has been made to test it in a large properly conducted trial. If it were correct how many women would have avoided the impossible task of weighing the benefits of avoiding hot flushes, irritability and loss of libido against a raised risk of breast cancer?
What makes the failure even worse is that result of the latest study that found that the breast cancer risk had been significantly underestimated, point to progestins as the culprit. Those women who had oestrogen-only HRT were less than half as likely to develop cancer as those who took HRT plus a progestin.
Buried in the full report was a shocking fact. One of the most commonly used HRT combinations was a CEE oestrogen (the one that comes from mare’s urine) plus the progestin medroxyprogesterone acetate (MPA). This is exactly the same combo used in the big WHI trial in 2002 which first flagged up the raised risk of breast cancer with HRT. Why is MPA still being used fourteen years later?
Footnotes [ + ]
|1.||↑||Michael E Jones, Minouk J Schoemaker at al Menopausal hormone therapy and breast cancer: what is the true size of the increased risk? British Journal of Cancer (2016) 115, 607–615|
|2.||↑||Evan Simpson & Richard J Santen, Celebrating 75 years of oestradiol (T1–T20), Journal of Molecular Endocrinology V.55 (2015)|
|3.||↑||Pattimakiel L1 et al, Bioidentical hormone therapy: clarifying the misconceptions. Cleve Clin J Med. 2011 Dec;78(12):829-36|
|4.||↑||Evan Simpson & Richard J Santen, Celebrating 75 years of oestradiol (T1–T20), Journal of Molecular Endocrinology V.55 (2015)|
|5.||↑||Ana Marcia IS Gaudard et al, Bioidentical hormones for women with vasomotor symptoms. The Cochrane Library; 1 August 2016. DOI: 10.1002/14651858.CD010407.pub2|
|6.||↑||Maturitas. 2008 Jul-Aug;60(3-4):185-201|
|7.||↑||Carlo Campagnoli, Françoise Clavel-Chapelon et al, Progestins and progesterone in hormone replacement therapy and the risk of breast cancer. The Journal of Steroid Biochemistry and Molecular Biology Volume 96, Issue 2, Pages 95-228 (July 2005)|
|8.||↑||Fournier A1 et al, Unequal risks for breast cancer associated with different hormone replacement therapies: results from the E3N cohort study. Breast Cancer Res Treat. 2008 Jan;107(1):103-11. Epub 2007 Feb 27.|
|9.||↑||Mohammed H1 et al, Progesterone receptor modulates ERα action in breast cancer. Nature. 2015 Jul 16;523(7560):313-7.|
|10.||↑||Carson, Sandra A.; Simpson, Joe Leigh (1983). “Virilization of Female Fetuses following Maternal Ingestion of Progestational and Androgenic Steroids”. In Mahesh, Virendra B.; Greenblatt, Robert B. Hirsutism and Virilism: Pathogenesis, Diagnosis and Management. Boston: John Wright PSG Inc. pp. 177–188. ISBN 0-7236-7045-5|