We have seen how hormones rule women’s lives during their reproductive years. Although some may complain about their periods, they would still rather have them than not. That monthly bleed is a reassuring constant both of health and of womanhood.
But from the age of about forty-five, it becomes clear that your periods are not as they were. The pattern changes, losing that familiarity of what has become normal for you. Shorter, longer, heavier, lighter, every twenty-three days or at forty-day intervals, there is certainty no longer. Your world is changing and your body is in hormonal revolt, with your ovaries apparently deaf to the increasing volume of internal hormonal messages arriving on their doorstep, from the pituitary gland in the brain. Your reproductive hormones are about to crash, to less than 10 per cent of their former values. They are also about to become villains.
The effects of repeated cycles and of the body’s exposure to sex steroids, so welcome at one time, are now increasing susceptibility to breast, ovarian and endometrial cancer. Without oestrogen to bathe the tissues, skin thins, fat redistributes itself, hair dulls, cognition becomes woolly, sex less important. This is the menopause. Although their hormones drop less precipitously, men too experience a steady decline of their hormones with age. The effect of these hormone crashes is momentous. So too is the decision whether to replace what has been lost and what with, and this decision has had a major cultural impact on society.
The menopause has been deemed a kind of physiological ‘terrorism’, but to blame hormones in this instance would simply be shooting the messenger. The word itself comes from two words of Ancient Greek, menos (a month) and pausos (an ending), hence our word menopause, which strictly means the end of the monthly or menstrual cycles.
By the age of twenty weeks, a female fetus already has between six and seven million eggs, which given that we are only likely to have 450 cycles in our lifetime, is monumental over-provision. A process of reduction begins soon afterwards and by birth we have between one and two million. When we hit puberty we have only 400,000 and by the time we get to menopause, that’s it, we have no more. But you’re right, the maths doesn’t add up. It is estimated that 99.998 per cent of our eggs go to waste, having been rejected, zapped, shrunk or left by the wayside, with just 450 or so eggs being selected as stars, destined for ovulation.
The average age of menopause in Britain is fifty-one, yet there is evidence that once upon a time it occurred earlier, at around forty or so. It still does so in parts of the developing world, and this probably reflects, since eggs are made in fetal life, the better nutrition in pregnancy enjoyed in the developed world. Nevertheless the age of menopause, unlike the age at onset of periods, has been reasonably constant over the last century. This may alter, since obesity – which is rising – results in a slightly later menopause. Regular smoking can also bring it forward by two years.
The ovary is a bit like a giant egg-timer, set for roughly fifty years. It doesn’t run at a constant rate, but speeds up dramatically after the age of thirty-seven, with egg numbers halving every three years, instead of every seven years before this age. If there weren’t this late rush, it has been estimated that our eggs would last until the age of seventy. The fall in the number of eggs can also speed up dramatically if eggs are destroyed for any reason, through chemotherapy for cancer, or autoimmune disease, for instance. This would then result in premature ovarian failure and menopause before the age of forty.
Although taking the contraceptive pill suppresses ovulation, unfortunately that doesn’t mean that you can eke out your egg store and have a later menopause. Five years’ worth of cycles is just sixty or so eggs, trivial in comparison to the thousands being lost each month. Anyway, if this were true, women who had many pregnancies (and so fewer ovulations) would have a later menopause too – but they don’t. Incidentally, if you start periods earlier, it doesn’t mean that you finish earlier, having got through your store ahead of time. In fact, if anything it’s the reverse: women who start earlier simply seem to have more on their egg-timer clock than those who start late.
If you could count how many eggs were left in the ovaries, you would have a good idea of when menopause was likely to occur – an important piece of information, perhaps, for career women counting on being fertile later in life. Two researchers from Scotland claimed to have cracked this in June 2004 with a new test which used ultrasound scanning of ovarian volume in combination with a mathematical formula. ‘Tests that give a deadline for childbirth’ in the Daily Mail was typical of headlines at the time. In fact, it had never been tested on women, so was a little premature. Menstrual diaries are probably more accurate. When the range between shortest and longest cycles reaches at least forty-three days, you probably have no more than twenty cycles left on the clock and menopause will occur in one to two years. Menstrual cycles not only become more irregular, but are more likely to be anovulatory ones, in which no egg is released at all.
‘Menopause’ means the end of menstruation, which is a single event. The word ‘climacteric’ more accurately describes the changes of mid-life, which spans the ages of forty to sixty.
Every month, during the reproductive years, about twenty follicles compete to be ‘the one’. The follicle is a nursing unit. The cells that tenderly enclose the egg, which sits in a puddle of fluid, are actually called nurse cells. They secrete steroid hormones, such as oestrogen and progesterone, into the puddle. Nurse cells and eggs are entirely interdependent – without one, there is no need for the other. As the eggs are killed off, so are the nurse cells. Equally, as you get older, the pituitary gland begins to rev up the production of FSH, perhaps because there is less ‘noise’ from returning messages provided by oestrogen and progesterone. It might also be that a rising level of FSH is simply a function of chronological age, the first step in reproductive ageing, rather than a consequence of it. Whatever the truth here, the pituitary sends out more and more FSH in an effort to get things back on track, but to no avail. So much FSH is being pumped out, that huge quantities get excreted into the urine. Once FSH gets to a certain level, the writing is on the wall. Menopause will follow as night follows day – and in fact, bloodstream FSH levels are the basis of tests for the menopause.
One woman’s hormones, however, can be another’s salvation. Because the urine of post-menopausal women contains so much follicle stimulating hormone, it is one of the best sources of the hormone for the induction of ovulation prior to IVF treatment. Thus it was that the urine of nuns living in convents close to the Vatican was collected by pharmaceutical companies. A small donation was made to the nuns for their services and this pee fee went to the very same Catholic Church which condemned the fertility treatments. The demand for FSH was so great that the companies extended urine collection to convents in Eastern Europe. When genetically engineered FSH became available, the demand for menopausal urine from nuns slumped. However, urine-sourced FSH is still available and is considerably cheaper than the recombinant variety. Pharmaceutical companies are cagey about where they collect their urine, but much of it is thought to be from South American women and not even nuns either.
So programmed egg-death destroys the nurse cells, source of the hormones that will help each one achieve its destiny of being the egg that is not only released, but gets to be fertilized and implanted too, thus forming new life. One cancels out the other. If that’s the ‘how’ of menopause, with hormones playing a key role, the ‘why’ is more tricky. Risks associated with pregnancy, such as life-threatening haemorrhage, increase with age (or more accurately, with the number of previous pregnancies). More importantly, by forty, your eggs, with you since birth, are beginning to show their age just as you are. This means a far greater likelihood of chromosomally abnormal eggs – it’s one of the reasons why older women have higher numbers of miscarriages because even more embryos than normal fail the criteria for implantation imposed by the womb lining. If it weren’t for menopause, many more abnormal babies would be born.
In a trade-off between the things that make for a healthy and easy old age and efficient reproduction, there is no contest. Begetting more of us is what we are engineered to do. Everything is geared towards having babies, and frankly, if we die after with our last period, having produced babies that we keep alive until puberty, when they can also begin reproducing themselves, our genes can congratulate themselves on a job well done. Having moist vaginas so we can go on enjoying love-making until our dying day has never been part of the plan. Thus the fact that we experience menopause at all is a consequence of women living longer than allowed in the original grand scheme of human beings. There are some scientists who believe that women are geared to live for an infertile decade after menopause, shepherding their last child through its crucial first ten years while dispensing pearls of wisdom to younger women. I’m not convinced, are you?
So now we have tens of millions of fifty-plus women, with the varied ailments of menopause, from hot flushes (‘flashes’ if you’re an American), sweating and palpitations to insomnia and dry skin. Although some oestrogen is still produced, it is not oestradiol, which is one of the most potent forms, but oestrone, a much weaker oestrogen. And it no longer comes from the ovaries but, of all things, from fat and muscle.
Fat cells contain an enzyme called aromatase, which changes the weak androgens produced by the adrenal glands into oestrone. This is the reason why it is better to be fat than thin at the menopause.
The more oestrone you can get, the less severe your menopausal symptoms. It’s also why exercise is so crucial to well-being post-menopause because it too stimulates conversion of androgens into oestrone. One of the ways to self-medicate, therefore, is to indulge in vigorous exercise.
Oestrogen has many hundreds of actions throughout the body and at each site where it’s active there are oestrogen receptors, which hook in passing oestrogen and set it to work. There are oestrogen receptors throughout the brain and without it the hippocampus (the site of memory formation) functions less well, making us more forgetful. Certainly women complain of that amnesia moment, forgetting what you are talking about in the middle of a sentence. It is also claimed that cognitive function is affected, with conceptual thinking in particular becoming more difficult post-menopausally. Then there are the well-documented emotional swings that are a feature of mid-life for some – but not all – women, including anxiety, irritability, tearfulness and depression.
Depression is a major complaint of the post-menopausal years but I’m reluctant to lay too much of this at oestrogen’s door. Life is about more than hormones and there are many other drivers of depression that coincidentally occur in mid-life: the death or serious illness of a parent, retirement, or your children clearing off and leaving you alone with a man you’ve hardly spoken to in twenty years, for example.
One of the most noticeable effects of the menopause is on skin, which thins throughout the body, both the bits you can see (more wrinkles) and the bits you can’t. The wall of the bladder and the vagina become thin and the vagina tends to dryness, with what secretions it has becoming less acidic, meaning that infections in both vagina and bladder are less easily rebutted.
The idea, however, that the vagina is a permanent desert zone after menopause, with older women incapable of lubrication unless blessed with the contents of a tube of K-Y jelly is simply wrong. Sure, dryness can be a problem and yes, arousal takes longer, but older women (look away now if you are a nervous twenty-five-year-old), once aroused, can lubricate with the best of them. Although female sex steroids are hugely important to sexuality, they are not what drives desire. True, in many animals it is the female sex steroid hormones which limit mating to the period of ovulation. In primates and humans, it is the hormone primarily seen as the architect of male desire and libido, testosterone, that is responsible for women’s sexual desires. Oestrogens enable sex, testosterone makes us want it.
In women who have their ovaries removed, libido may disappear altogether – not because of the lack of oestrogen, but through lack of testosterone. It took a very long time for gynaecologists to realize that this was the case. Male hormones remain in our bodies after oestrogen so catastrophically takes flight. The inner cortex of the ovaries continues some sex steroid production, but it is of the male hormones, testosterone and androstenedione. The adrenal glands also continue to produce androgens as they did before the menopause.
To go back to oestrogen, one of the most noticeable effects of lower levels are hot flushes. They are a bit of an enigma and their exact mechanism remains unknown. Apparent surges of heat occur across the whole surface of the body, although women mostly only notice it on their upper half and face. The brain, thinking it’s hot, sends signals to the peripheral blood vessels in the skin, telling them to dilate, which allows excess heat to be lost through radiation. Actually, more often than not, it’s not hot at all but the brain has been tricked by the strange behaviour of the body’s thermostat. It lies very close to the hypothalamus which is the source of gonadotrophic hormones.
It’s the long-term effects of oestrogen loss that have been the driver for the hormone wars of the last three decades. Cardiovascular disease (not, please note, breast cancer) is the single most important cause of mortality in post-menopausal women. Arteries are more rigid after the menopause, clotting factors change, cholesterol increases – all risk factors for heart disease. Prior to the menopause, women’s risk is lower than that of men, but climbs steadily thereafter. The steadiness of this rise, which starts before the menopause, is interesting because if loss of sex steroids were the only key factors, given a 90 per cent fall, surely the increase in coronary heart disease (CHD) would show a steep sudden rise at menopause? Nevertheless, it is the increase in CHD in older women and the possibility of preventing it that has been one of the principal factors in recent thinking on hormone replacement therapy, of which more in a moment.
Another major consequence of oestrogen loss is in bone density. Oestrogen facilitates full utilization of all the panoply of hormones, including calcitonin and parathyroid, vitamin (D) and minerals (calcium) (Vitamin D, calcium) that are all essential to bone health. Oestrogen also affects the balance between the two opposing camps of cells in bones – the builders and the removers – by favouring the builders and adding oomph to their activity. After menopause, without its influence, the activities of bone-removing cells become greater than those of the building ones, resulting in net loss of bone mass. The condition of thin, fragile bones that are susceptible to fracture is known as osteoporosis, and it is responsible for over 200,000 fractures each year in the UK, as well as great pain and disability. The most common fractures are in the hip, wrists and spine. About a third of women with hip fractures will die within a year, not from the fracture itself, but from the deadly consequences of immobility, such as infection and embolism, that it causes. Those who have osteoporosis typically lose height as their bones crumble, developing a typical ‘dowager’s hump’. Osteoporosis is partly inherited and is also influenced by lifestyle factors such as smoking, poor diet and lack of exercise. Nor is this just seen at menopause. One of the severest consequences of the disturbance of reproductive hormones seen in anorexic women, ballet dancers and over-exercising athletes is bone loss.
For many years, oestrogen (supplied via HRT) was not just the gold standard treatment for osteoporosis, it was the only treatment. It is only relatively recently that new drugs such as the biphosphonates have become available for treatment of brittle bones. Men (who suffer from osteoporosis to a much lesser degree) are given testosterone – which has an effect on their bone mass only because it is converted by their bodies into oestrogen.
Osteoporosis is a major public health problem, costing the NHS over £1.7 billion annually. Yet it is largely invisible, ignored by the media and public alike because it principally affects old women and causes disabilities we would rather ignore because society regards them as conditions of ageing, rather than as a disease process.
Oestrogen is also a promoter of other hormones, working hand in glove with growth hormone, for instance, to enhance its production. Certainly blood levels of growth hormone drop like a stone at menopause and are restored somewhat with HRT. Might it be that the rising incidence of heart disease after menopause in women is not the direct result of oestrogen loss, but instead something to do with growth hormone? It is now known that the heart is riddled with receptors for IGF-1, the mediator of growth hormone and that low levels of IGF-1 are associated with some types of heart disease in the elderly. It is certainly an avenue for future research.
Hormone Replacement
So there you are. A catastrophic loss of hormones in mid-life. Replacement has to be the answer – or at least, that’s what seemed glaringly obvious at the time of Brown-Séquard. Augusta Brown was a Parisian midwife in the early twentieth century and inspired by La Méthode Séquardienne, she prepared extracts of guinea pig ovaries, which she injected into older women. She claimed success but since she used water rather than alcohol to prepare her potions, there would have been little, if any, oestrogens in them. But she was possibly the first person to try hormone replacement therapy for women.
Those women who were understandably squeamish about the ferocious hypodermics of the time were urged to eat fresh raw pig or cow ovaries, thinly sliced in sandwiches. There were also many varieties of tablet and sugar-coated pastilles, which were claimed to contain ovarian ‘juices’. Although we now know that these would have had no effect, at the time they were hugely popular.
When hormones were first isolated and synthesized, they were drugs looking for diseases to treat. Some illnesses caused by deficiency – diabetes or hypothyroidism – were obvious candidates but sex hormones had less of an obvious market. It is not clear when menopause moved from being a natural part of ageing to being considered a disease of hormone deficiency. Certainly prior to the Second World War there were those, including the renowned endocrinologist Fuller Albright, Professor of Medicine at Harvard, who were beginning to label the menopause as a deficiency syndrome. When, in 1939, Ayerst developed a process of extracting oestrogens from mares’ urine, the ‘indications’ were very modest – relief of menopausal symptoms, principally for those women who had had their ovaries surgically removed. Ayerst marketed Premarin, the very first oestrogen replacement therapy, in Canada in 1941; in 1942 it was approved for use in the United States. Premarin tablets were first available in the UK in March 1956, when they were supplied by Imperial Chemical (Pharmaceuticals) Ltd, and were pills designed for a very specific condition. What the pharmaceutical companies really needed, however, was a much wider ‘ill’ to treat, if a drug was to be really successful.
Help was at hand. In 1966 a New York gynaecologist and oestrogen cheerleader called Robert Wilson wrote a bestselling book called Feminine Forever, in which he likened menopause to ovarian castration. Wilson, who was partly bankrolled by the manufacturers of Premarin, Wyeth-Ayerst, was a strange character with – judging from his prose – an apparently morbid fear of old women. He claims in the book that he could recognize a woman who has had HRT by the ‘outward signs of age-defying youthfulness’, which are:
a straight-backed posture, supple breast contours, taut smooth skin on face and neck, firm muscles and that particular vigour and grace typical of a healthy female. At 50, such women still look attractive in tennis shorts or sleeveless dresses.
This is how he describes those women not on HRT:
I have seen untreated women who had shrivelled into caricatures of their former selves. Some had lost as much as six inches of height by the pathological changes caused by lack of oestrogen.
No wonder women wanted oestrogen. Within a year, the book had sold 100,000 copies. The resulting enthusiasm for oestrogen replacement meant that sales quadrupled between 1963 and 1973. Half the post-menopausal women in the States were using HRT – and who can wonder, with their shrivelled desiccated future laid out so helpfully before them by Dr Wilson and his acolytes who likened menopause to living decay? Menopause was not a life-change: it was a disease that required treatment.
Instead of simply being prescribed for symptoms such as hot flushes, HRT gradually became touted as a cure for everything from heart problems to ageing skin and, regrettably, for problems that were mostly not much to do with medicine but about relationships grown stale with age and familiarity – such as lack of a fulfilling sex life. Then came the first reports of endometrial cancer.
In 1975, the New England Journal of Medicine published two studies documenting a strong association between cancer of the lining of the womb (the endometrium) and oestrogen therapy. Progestogen (a synthetic form of progesterone) was then added to the monthly oestrogen regimes to protect against the thickening effect (hyperplasia) caused by oestrogen, which can lead to cancer. Oestrogen alone is associated with a 7–15 per cent risk of hyperplasia, which is reduced to 5 per cent when progestogen is added each month (this is called opposed therapy). The risk reduces to zero if progestogen is taken for 12–13 days per cycle. Thereafter, unopposed therapy (oestrogen only) was given only to women who had had a hysterectomy.
Feminism didn’t always know what to think of HRT. The right to remain juicy, espoused for a while, quickly became tempered by concern over the use of steroid hormones and the way in which menopause was being medicalized as a disease. Meanwhile, during the 1980s, HRT continued to gather popularity and women continued to demand it, despite a plethora of studies which were indicating increased risks of breast cancer with long-term use.
HRT is now worth about £2 billion a year worldwide. That, plus the wide range of products competing for market share, ensures that it is heavily marketed. But for feminism to deride all those who opt for HRT as victims of a marketing or medical conspiracy – a view typically espoused in Sandra Coney’s book The Menopause Industry: How the Medical Establishment Exploits Women or as gullible fools in search of lost youth, one of the views taken by Germaine Greer in her book The Change – makes a mockery of sisterhood. Women whose lives are made a misery by night sweats, insomnia and hot flushes want something that enables them to live a normal life again, thank you very much, without being told that they are patsies in an androcentric universe. The media, too, has a particularly ambivalent attitude to HRT, with the more misogynistic papers, such as the Daily Mail, seemingly seizing on every new study of adverse effects with glee. For surely this is all women’s fault for wanting to have it all? No, actually. Some women just want to sleep through the night without drenching the bed in sweat or living their life as an additional radiator in the house.
Another factor which heavily influences our view of HRT – and indeed of many things – is fear of cancer, or rather fear of one cancer. Breast cancer occupies the highest rung of our fear ladder, because we perceive it to affect femininity during those years when sexual attraction is still important to us. There are many breast cancer charities, all competing for the same pool of money and some among them deliberately exploit women’s natural fear of breast cancer. When challenged, they will claim that the end justifies the means – for how are they to raise funds for research otherwise? What they mean, of course, is how are they, rather than their competitors, going to raise funds? Thus breast cancer has been assiduously promoted as a killer that affects one in ten. Of course breast cancer can kill, but four out of five women diagnosed now survive in good health. The news is not so good for colon cancer, against which HRT has a definite preventive effect, but in the game of life, breast trumps bowel every time. Meanwhile osteoporosis, the Cinderella disease hidden behind closed doors, causes chronic disability for the remainder of life and, as I have indicated, kills too. But this disease does not generally appear on the radar because just as teenagers cannot perceive the dangers of smoking twenty years on, neither can fifty-year-old women perceive the dangers of osteoporosis twenty years on. Our HRT riskometer is driven not by the totality of risk, but seemingly by that of breast cancer alone.
The irony is that those who fear breast cancer most are those least likely to be affected themselves. There is indeed a one in ten lifetime risk of breast cancer, but the chances of a twenty-five year old developing it are vanishingly small. The association of breast cancer with youth, through campaigns which feature young women celebrities, has led those women most at risk – the over-fifties – to assume that it is a young woman’s disease. It is not. Age is the single biggest risk factor for breast cancer. Meanwhile, the greatest health risk to older women – coronary heart disease – is also largely ignored.
However, the risks of CHD are not lost on the medical profession. The majority of HRT studies in the 1980s showed a reduced risk of coronary heart disease in users of HRT compared to non-users. Certainly oestrogen has well-documented beneficial effects on the vascular system, but even so there was surprise when some studies suggested an extraordinary drop of 50 per cent. Suddenly HRT became the preventive cardio-protective drug. Such extravagant figures should have rung warning bells. The pharmaceutical companies, however, sensing at last the nirvana of a pill for all, instead of a pill for the few, poured money into the marketing of this new wonder drug. But one of the problems of many of these studies was that they compared women who had chosen to take HRT. On the whole, they were better educated women, who exercised more, had lower blood pressure and who were more likely to engage in preventive health measures. In other words, like was not being compared to like. Not all was hyperbole, however. There were many more sober studies from a wide range of independent sources showing benefit, which propelled doctors towards recommending HRT. The 20:20 vision afforded by hindsight allows one to say that doctors should have known that they were prescribing something with long-term dangers. But at the time, available evidence showed benefits in terms of cardio protection, which skewed thinking on HRT dramatically.
Opinion was still fiercely divided about HRT. On the one side were the enthusiasts, largely gynaecologists, who called it the greatest preventive drug ever developed, and on the other were those like Germaine Greer, whose piercing analysis of the ‘menopause industry’ – The Change – was published in 1991, who felt sure that menopause was not a disease and that many of the medical theories and treatments were contradictory, excessive and at times dangerous. There were also those in the middle who considered HRT invaluable, in the short term, to treat women with unbearable menopausal symptoms, but who had no truck with the extremists of either persuasion.
The first suggestion that HRT might not be cardio-protective came in 1998 from the so-called HERS study (Heart and Estrogen/progestin Replacement Study). It showed that HRT did not prevent further heart problems in those women who already had heart disease. This made the idea of protection from heart disease for those who had not yet developed it a less tenable proposition. Since heart protection was now a major part of the equation that made doctors recommend HRT, once this benefit fell away, it suddenly made much less sense as a preventive medicine.
The Women’s Health Initiative (WHI) study was a randomized, double-blind, placebo-controlled study that was conceived and carried out in the US in the 1990s. It reported in 2002. It was designed to test the efficacy of HRT on coronary heart disease and had two groups: one of oestrogen-only (5,310 women) and the other of a combined preparation (8,506 women). Women in Britain tend to be prescribed HRT in their forties and fifties, but the average age of the women in the study was sixty-three. The first group was followed up for 6.8 years and the second for 5.2 years. Both were stopped early, the oestrogen-only group because there was an increased risk of stroke and no evidence of benefit for CHD, and the combined group because of the risk of breast cancer exceeding the safety threshold set for the study in advance.
The study found, as expected, an increased risk of breast cancer with the combined preparation but a decreased one with oestrogen only (which was a very considerable surprise and completely counter-intuitive). It found reduced risks of colorectal cancer and fractures with combined use, and increased risk of colorectal cancer, stroke and blood clots with oestrogen only. Neither preparation had a beneficial effect in coronary heart disease; in fact, it seemed the reverse was true.
The headline findings were, to any woman taking HRT, horrifying – ‘26 per cent increase in breast cancer, a doubling of clots, strokes increased by a massive 41 per cent, heart attacks by 29 per cent’. In the UK, it was estimated that over 350,000 women stopped taking HRT. I’m astonished it was so few.
As ever, the figures weren’t quite what they seemed. Professor David Purdie, an expert on HRT, was challenged by John Humphrys on the BBC Radio 4 Today programme on these apparently enormously increased risks. ‘I call it the Judas factor,’ said Purdie. Intrigued, Humphrys asked what he meant. ‘Jesus was betrayed by 8 per cent of his disciples.’ ‘But surely, there was only one – Judas,’ protested Humphrys. ‘Precisely my point,’ said Purdie. ‘Judas was alone among the twelve but he was 8.3 per cent of them. We can easily be misled by the used of percentage values – especially when the numbers are small. That’s why you should always insist on absolute values for do you not deserve the absolute truth, not a percentage of it?’
Now let’s look again at that HRT study but in real numbers (these were released at the time by the Committee on Safety of Medicines). Of every 1,000 women aged 50–69, not on HRT, 45 would normally be expected to develop breast cancer. The extra cases that would occur if they took HRT would be 2 per 1,000 after five years’ use and 6 after ten years’ use. Of those women aged 50–59 not taking HRT, 3 per 1000 would be expected to have a stroke over a five-year period. One extra case would occur in those taking HRT. Meanwhile, there was a reduction of four cases per 1,000 women aged 50–69 of colorectal cancer and a 9 cases per 1,000 reduction of hip fracture. So this black and white study was more of a muddy grey, with risks and benefits to be weighed. All the same, it firmly quashed the idea that HRT was cardio-protective.
The Committee on Safety of Medicines in Britain had taken a fairly sober view, albeit blown out of proportion by the media. This was not the case elsewhere in Europe. The head of the German Committee on Safety of Medicines likened HRT to thalidomide and raged about the way that a hormonal sickness had been created by the big pharmaceutical companies out of a natural phase of life. It wasn’t a happy time for a woman on HRT.
The Million Women Study (MWS) began in 1996 and reported in The Lancet in August 2003. The MWS was an observational study which reviewed a wide range of different HRT regimens and administration routes (patches, gels, tablets and so on) among over a million women aged 50–64 who attended the NHS breast-screening programme and completed a questionnaire about HRT use. The analysis was based on 828,923 of them. The study was led by Professor Valerie Beral, one of Britain’s most distinguished epidemiologists (scientists who study the distribution of disease determinants and risk amongst populations).
In sum, short-term use of HRT at the menopause results in very low additional risk of breast cancer. Longer use will give a higher risk, with the greatest risk being associated with implants and the least with patches. In real numbers, by the age of 65, one extra case of breast cancer per 1,000 women will have been caused by using oestrogen-only preparations for five years, or 5 extra cases if used for ten years. The comparable figures for combined preparations are 6 and 19. One curious finding was that an increased risk of breast cancer was seen after one year’s use of combined HRT, but this was not seen in the WHI trial, where an increased risk was noted only after 3–4 years’ use.
The MWS postulated (by extrapolating data) that HRT had been responsible for 20,000 additional cases of breast cancer over the past ten years in women aged 50–65. The reaction in the media was first, as you would expect, vilification of a profit-driven pharmaceutical industry, but there was also a significant under-current of this being women’s own fault. If you try and hold back ageing, what do you expect? For comparison, using the same sort of extrapolation, amongst 50–65 year olds over the last ten years, 50,000 breast cancers have been caused by obesity and at least 16,000 breast cancers by alcohol intake, yet where is the censure from the media here?
The Committee on Safety of Medicines issued further advice on HRT in December 2003: it was to be used for relief of menopausal symptoms only. They also concluded that the risk/benefit ratio for osteoporosis was unfavourable and recommended other approaches. This recommendation flew directly in the face of information from the WHI study, which showed a considerable reduction in fracture rate, even among a group of women who were not at particular risk of osteoporosis.
What are ordinary women to make of all this information, some of which is contradictory and a lot of it alarming? The long and short of it is that some of the beneficial effects of HRT were exaggerated. HRT is absolutely not the heart-protecting medicine it was claimed to be and there is no justification for this use. Protection from Alzheimer’s, once believed to be a benefit of HRT, is also unlikely. If you have miserable severe menopausal symptoms, HRT is an effective medicine to get you over the worst of them and there is no evidence that it causes harm with short-term use – benefits here outweigh risks. Thereafter, there is thinner ice and you have to let your own riskometer guide you, with what’s important to you taking precedence. If you are at risk of osteoporosis, because of family or medical history, then you may feel comfortable trading knowledge of an increased risk of breast cancer for a reduction in something that you personally fear rather more. The evidence is that you should take it sooner rather than later, i.e. at the menopause, not years afterwards. HRT is emphatically not going to make you look or feel younger – that comes from inside and is as much about exercise, good food, not smoking and whose company you keep. My guess would be that a prescription for a toyboy who tells you how gorgeous you are before driving you wild with desire is probably more effective a rejuvenator than anything in pill form. When I mentioned this to a gynaecologist, he looked me up and down and said, ‘We call that the noisy version of a testosterone patch.’ Sign up for it now.
If you have local symptoms – dry vagina, urinary tract problems, a local agent would be first choice, rather than HRT pills. On the subject of pills, not all HRT preparations are the same. Lower doses of hormones can still be effective if given via patches or gels, whereas pills have to contain higher doses in order for sufficient active ingredient to survive breakdown by the liver. It is significant that these forms of HRT were those least associated with significant side effects in the Million Women Study.
Is HRT dead in the water? As a wonder protective drug – absolutely. It has taken fifty years for this hormone medication to come full circle and it is now back to exactly its first indications – symptomatic relief of severe menopausal symptoms. It is also effective for osteoporosis prevention if started early and maintained for a sufficient number of years, probably ten to fifteen, but may no longer be prescribed for this reason. The outrage from those who fear breast cancer has effectively ensured that the faint voices of the dispossessed crippled by osteoporosis have been drowned. Who cares about old ladies? Clearly not the CSM.
Don’t misunderstand my message here. HRT was egregiously and sometimes wickedly over-promoted, partly by presenting menopause as a disease state. And medicalization of the menopausal state continues: a classic example is the way that Novo Nordisk promoted sales in Australia of their topical oestrogen, Vagifem, once HRT was under suspicion. In a textbook case of disease-mongering, they set up a website called www.whylovehurts to promote the more comfortable sex that women newly off HRT might have if they used the Vagifem product. They sent hairdressers scripted messages to use with clients, plus free capes for their salon, emblazoned with the web address.
To the disappointment of drug company shareholders, the market has returned to servicing a select few, not dosing the many. As a rule mass prescription does not suit the individual. The reverse is also true, that what is bad for the mass can still be right for certain individuals. This seems especially true of hormones, and it is easily forgotten that we are all individuals, with varying risk factors and highly varied hormone levels, and that each of us requires a personal hormone regime, not one designed for every-woman. For some women HRT is still the right choice.
My guess is that we will see increasing promotion of lower dose products and ones in which progesterone is substituted for progestogens (the natural rather than the synthetic), or of those that you dose level for yourself – in other words, adjusting the dose until you find the minimal level to relieve your symptoms.
Meanwhile, we may see increasing use of Selective Oestrogen Receptor Modulators (SERMS) which, as their name suggests, only act on oestrogen receptors in certain sites – for instance, not on womb-lining receptors (which you wouldn’t want) but those like oestrogen receptors in bone. I suspect that there will be many more of these ‘designer’ types of HRT, which spare some tissues while targeting others.
Before leaving hormone replacement, let me issue a health warning. ‘Natural’ hormones are touted all over the internet as the answer to menopausal symptoms. Wild yam cream, for example, is promoted as containing natural hormones without the side effects: ‘Stimulates the body’s own production of hormones with natural progesterone.’ ‘Converts naturally to oestrogen and DHEA.’ ‘Prevents osteoporosis.’ The only reason, these ‘natural’ hormone sites claim, that natural progesterone is not prescribed is because there’s more money in patented synthetic sorts – progestins – even though they are dangerous. It’s a seductive argument, but untrue.
For a start, the Mexican yam, Dioscorea villosa, is not actually a source of progesterone. The plant contains large amounts of something called diosgenin, which can be used to synthesize steroid hormones, including progesterone (a discovery which led to the first contraceptive pill). So if there is progesterone in wild yam cream (which is often doubtful), it’s only there because it was synthesized in a lab first. Hardly the natural product you thought it was. Progesterone does indeed get converted in the body to other hormones (remember the description of steroid production as a conveyor belt, with progesterone being a steroid en route to oestrogen and testosterone) and that is why synthetic progestins are preferred to the natural variety, because they don’t get instantly converted into other hormones. All hormones, synthetic or natural, have the ability to cause side effects.
Hormones are not available without prescription in Britain and quite rightly so. If there is enough hormone in a product for a company to make a medical claim, then it should be subject to all the stringent tests that are insisted on for medicines, including iteration of all possible side effects. The fact that these companies operate from offshore sites should tell you all you need to know. Will these people be around in twenty years’ time when you discover that their product hasn’t prevented osteoporosis? Quite. Don’t go there.
There are some natural progesterone products available on prescription, including progesterone creams which do actually have enough progesterone in them to raise blood plasma levels of the hormone (unlike the products I have just mentioned). One is called Progest. It is said to be effective against osteoporosis, but there’s no evidence whatsoever that these products have any effect in building bone. In fact, two separate trials, including one funded recently by the National Osteoporosis Society at the University of Southampton, have shown that they have no effect.
A vaginal progesterone gel (Crinone) is available to rub into the skin, rather than taking progestins with your oestrogen in tablet form. The gel can be used to protect the womb lining, though it has no licence for such use in the UK. It is also available as a pessary (Cyclogest). Both are reputable products only available on prescription but they do have the side effect of causing sleepiness. As you will remember from the chapter on pregnancy, progesterone in large doses can also be used as an anaesthetic. In the future, natural progesterone may be available as a nasal spray. Such developments mean that in future it may be possible to bring down the dose of hormones required for effect, thus minimizing side effects, and to tailor HRT to individual needs.
Eating for Your Hormones
Hormones are produced in response to change. The onset of winter or the appearance of a lover are two types of situation which get the brain sending out hormones – eating is another. There is a huge hormonal response when you eat: dozens of hormones are at work – insulin, glucagon, secretin – trying to bring you back to a state of equilibrium after you indulge. What you eat also influences hormone production and you can manipulate what you eat in order to manipulate your hormones. High-fat, low-fibre diets are associated with higher circulating levels of oestrogen – and we’ve already discovered that obesity is associated with later menopause. High fibre speeds up the clearance of oestrogen from the body. Severe constipation is associated with menstrual problems and with low circulating levels of oestrogen. There are also hormones in food, almost all derived from plants.
Plants have hormones just like humans. One plant hormone is the gas ethylene, which is involved in ripening. It’s the invisible X-factor that infects green bananas with yellowness the instant a black banana is put next to them. Plants also contain substances which act like hormones when ingested by humans but which have no active hormone role in the plant. In the human gut they are transformed by intestinal bacteria to hormone-like compounds which produce an oestrogenic effect by binding to oestrogen receptors. Some may have an anti-oestrogenic effect, too, in that they compete with oestrogen for the receptor spaces. Collectively, they are called phytoestrogens and first came to attention some half a century ago when it was noticed that sheep grazing in clover pastures had oestrogen-related infertility. Their potential for preventing menopausal symptoms and also in mitigating breast cancer came to light when it was observed that in those countries, such as those in Asia, where large amounts of soy products (up to 100 mg per day) are consumed, the women had a lower rate of breast cancer than western women, who consume on average 5 mg per day.
There are three main groups of phytoestrogens: coumestans and isoflavonoids, which are very similar chemically, and lignans. Isoflavones are the largest group of natural isoflavonoids and are found in most plants of the pea family, including soy bean, clover, mung beans and alfalfa. The highest concentrations are found in a plant called kudzu root, followed by those in soy. There are several different forms of isoflavones in legumes: the most biologically active form is genistein. Coumestans are even more potent, and are found in bean shoots and sprouts, as well as in soy beans and spinach. Flaxseed (linseed) is the richest source of lignans followed closely by lingonberries, eaten by the Finns as part of a rye porridge meal, though lignans are also found in cereals.
Humans eat hundreds of milligrammes of phytoestrogens every day. To give you an idea of the scale of magnitude here, we eat 40 million times more natural oestrogen-mimicking products than we ingest synthetically produced ones. Phytoestrogens in food are a very common part of our diet.
Many women do not like taking hormones, or take them briefly and then find that they can’t get on with them. If you do want to take HRT, accept that you may have to try several sorts before finding the one that’s right for you. If you don’t want to take hormones and have symptoms that are unpleasant, but not too serious, then you might want to consider upping your intake of phytoestrogens, or consider some of the herbal therapies. Black cohosh, a perennial plant of the buttercup family, is a native of North America and has the best evidence of oestrogenic activity. The dose is 8 mg of standardized extract per day in divided doses.
The effects of phytoestrogens are also subject to hype. If you have severe menopausal symptoms, you will not get the same level of relief from phytoestrogens as that given by HRT, although many women do say they work for milder problems. Even so, formal trials have been disappointing. Red clover proved no more effective than a placebo in preventing hot flushes, a multicentre trial reported in the Journal of the American Medical Association (JAMA) in July 2003. Nor is their overall activity proven. A recent study in 2004 (once again in JAMA, from the University of Utrecht) concluded that soya supplements did not protect bone mineral density or affect plasma lipids. Nevertheless, the flight into phytoestrogens continues apace, with two full bays of my local health-food store given over to ‘phytoestrogens’, with all sorts of claims made about their effects.
At this point, can I give you a further health (and wealth) warning? Just because something is natural, does not mean that those who manufacture it are automatically on the side of the angels. The big pharmaceutical companies are not the only ones making money out of hormones. HRT mayhem has created a gold rush for ‘natural’ products (most of which are processed chemically of course). There is almost no regulation in the supplement field and what enforcement there is, falls through a crack in the floor, somewhere between the Food Standards Authority and Trading Standards. There is acknowledged to be a particularly large placebo effect in relief of menopause symptoms, which means that it is easy for companies to make a killing at your expense. Moreover, where there is evidence of a dose-related response to a particular substance, many preparations fail to provide the appropriate dose, either because too little is put into a ‘do-it-all’ type of preparation or, and this is more common, simply because the product is not what it claims to be on the label. ConsumerLab (www.ConsumerLab.com) is a respected independent American organization which regularly tests supplements. It recently tested eighteen soy or red clover products and out of those five failed the test as they contained only between 50 and 80 per cent of the amount of active ingredient advertised on the label. I doubt the situation is any different in most of Europe.
If I were choosing a ‘natural’ product, I would avoid the combined sort (menopause formulas) and choose a single product from a reputable manufacturer. If it doesn’t work for you, stop using it. I would also only consider using these products for relief of symptoms that you can monitor yourself – hot flushes, vaginal dryness etc. There are many claims that isoflavones will prevent bone loss but there are no long-term trials that support this assertion and the results of shorter trials are conflicting. One, from Denmark, noted bone loss when use of isoflavones was combined with a transdermal progesterone cream. A synthetic isoflavone, ipriflavone, has been under trial for some time and is available in some European countries and seems to preserve bone mass by increasing the effect of oestrogen.
If you are at risk of osteoporosis, stick to something proven – which means a prescription medicine. Osteoporosis isn’t a hot flush, it’s a condition which causes the death of tens of thousands of women each year and disables many more. If your life, not to mention quality of life, is potentially on the line, stick to something about which there is good evidence, not three twigs in a plastic bag costing an arm and a leg.
Is there harm associated with phytoestrogens? Soy milk, which enjoyed a brief surge of popularity as an alternative to infant formula, is currently not advised for babies as it has been found that the level of isoflavones known to cause menstrual disturbance in women is the same as that found in infant formula. The concern is particularly for baby boys, in whom disruption of normal hormonal-directed development may occur, resulting in an increased number of cases of testicular cancer, infertility or hypospadias. And yet there is no evidence of such problems in men in Japan or China; indeed, the high level of phytoestrogens consumed by men in Asia seems to protect them from cancers, in particular from prostate cancer. Phytoestrogens also have beneficial effects on heart health and it is worth making an effort to have more of them as you get older – but preferably from foods, not from supplements, as it is the combination of molecules in foods that appears to achieve some of the effects, rather than specific molecules alone.
Hormones and Cancer
BREAST CANCER AND OESTROGEN
So why does the risk of breast cancer rise so much after the menopause? Anything to do with hormones? Here is the truth about hormones and breast cancer – and it’s not pretty. For the hormone women love for its softening, moistening and plumping effect is about to turn nasty.
Oestrogen is also the fuel for most breast cancers. About two thirds of all breast cancers are studded throughout with oestrogen receptors and are dependent on the hormone for growth.
Once upon a time, breast cancer was a relatively rare disease, except in nuns, and it was believed that it occurred if breasts were not used for their natural purpose. This has some truth in it. Oestrogen was first linked to breast cancer a century or so ago, when it was noted that removing the ovaries of women with breast cancer improved their chance of survival. Now it is known that naturally high levels of sex hormones, particularly oestrogens, double the risk of breast cancer for older women. Why should oestrogen have this effect?
We have seen how the menstrual cycle and the hormones that control it – oestrogen and progesterone – drive women’s reproductive systems for the best part of four decades. You know yourself how your breasts alter in size with each cycle, going from perky insouciance just before a period to diving beneath your armpits when you lie down shortly after one. Breast tissue is one of the most active in the body, constantly being ‘remodelled’ each month in anticipation of a potential pregnancy. This activity is driven by both the reproductive hormones, but especially oestrogen.
Key ‘target tissues’ for oestrogen are the womb lining and breast, which are littered with receptors. As oestrogen docks with these receptors, it delivers its message loud and clear: divide. Oestrogen and the receptor travel together as a unit into the command centre of the cell, the nucleus. The unit instructs oestrogen-responsive genes to be switched on, and these then make the proteins that signal the cell to divide. A similar story applies to progesterone.
Every time your cells divide, your genetic material gets copied. The greater the number of cell divisions, the greater the chance of there being an error. It’s a bit like photocopying a copy of a map – many, many copies later, a small detail may become too faint to read, sending you the wrong way. There is, however, a very efficient cellular housekeeping service, which ensures errors get corrected. This service becomes less efficient with age, meaning that some errors will get through. If the mistake affects one of the crucial genes that provide checks on cell growth, cells will suddenly proliferate uncontrollably, forming a cancer. So, that’s why the greatest single risk factor for most cancers is age.
With breast cancer, it is not just chronological age that counts but, crucially, the length of time that your breast tissue has been exposed to both hormones, especially oestrogen, and all the cell division that this implies. That’s why earlier age at first period or a late menopause are risk factors – more cycles means longer exposure to oestrogen than someone who started later. And having many children is also protective – every time you are pregnant, you stop ovulating for the best part of a year. The reverse of this is that, as with nuns, childless women are at greater risk because their breasts have not had a break from the relentless ebb and flow of hormones. All this is despite the fact that pregnancy subsumes women in a tidal wave of oestrogens, which might lead you to suppose that having many children would increase risk. But it doesn’t and it seems that during pregnancy breast cells are protected in some way from damage and that, following birth, through irreversible changes which occur in the breast tissue, some degree of protection against breast cancer is conferred for life. This appears to be strengthened by breastfeeding. Much of the difference in breast cancer rates between developed and developing countries is related to breastfeeding and children, not just to diet as many people assume. It is estimated that if we had as many children as women in developing countries and breastfed for as long, our cumulative breast cancer incidence by the age of seventy would be halved to 2.7 per 100 women, an incidence not so dissimilar to that in developing countries of 2 per 100 by seventy.
Being obese after the menopause is a risk factor because the enzyme aromatase in fat cells can convert male hormones in the body to weak oestrogens, so that you continue your oestrogen exposure beyond the menopause. Remember that the breast is largely fat, so the breast also makes oestrogen post-menopausally, as well as being sensitive to it. Obesity has a double whammy effect for not only does it push up blood oestrogen levels, but also it reduces the amount of sex hormone binding globulins, the blood chaperones that keep steroid hormones in check. Work from the Endogenous Hormones and Breast Cancer Collaborative Group, led by the Cancer Research UK Epidemiology Unit in Oxford, established in 2002 that high circulating levels of oestrogens were associated with an increased risk of breast cancer in older women. High-fat, low-fibre western-style diets also increase risk because levels of circulating oestrogens are raised. This type of diet is the one most likely to make women obese.
Alcohol is a risk, again because it raises circulating levels of oestrogens, although the exact mechanism is unknown. Since heavy drinkers often have an unhealthy lifestyle generally (70 per cent of female heavy drinkers also smoke), it is not always easy to tease out the exact role of alcohol, although it seems that there is a dose response. The more you drink, the greater the risk.
The progression from a normal cell to one that is an out-of-control cancer cell consists of many steps. Some women are born with the first step already taken, in that they have a mutation in their genes – the best-known ones are BRCA1 and BRCA2. Breast cancer genes are thought to cause about one in twenty breast cancers and typically can be seen at work in ‘cancer families’, where several relatives have had either breast or ovarian cancer, usually before the age of fifty.
Having told you about the risks, let’s rank them to get an idea of how they compare. The way risk factors are compared is using relative risk (and this is often the figure you see quoted in the press) as you can see in the table below. A relative risk of 1 means no increase in risk. A risk of 1.5 increases risk by 50 per cent, a relative risk of 2 doubles it. This might sound a bit alarming but remember that relative risk means relative to people without the risk of a similar age.
| RELATIVE RISK FACTORS FOR BREAST CANCER (a relative risk of 1 is no risk) |
|
Mother and sister affected |
14 |
Age |
8 |
Dense breasts |
6 |
High plasma level oestrogens |
5 |
Age at first birth over 35 |
1.9 |
More than 2 drinks a day |
1.8 |
Never had children |
1.6 |
Combined HRT |
1.24 |
Let’s say you are twenty-four and that eating zebras (to choose something totally false) has been discovered to have a relative risk of 2.0 with regard to breast cancer. The headlines for this might be ‘Zebra meat doubles breast cancer risk’, which is very alarming, particularly for you since you eat zebra daily. You might think, because you’ve heard that there is a 1 in 12 lifetime chance of breast cancer, that this means your risk is now 1 in 6, which would be very worrying indeed. It doesn’t mean this.
To understand what a relative risk means for you, you have to know your risk of breast cancer right now, let’s say you are twenty-four. Actually, before the age of twenty-five, risk of breast cancer is 1 in 200,000. A doubled relative risk for you means that instead of 1 per 200,000 women of your age being affected, in zebra eaters, it would be 2 per 200,000. Twice a small risk is still a small risk.
The woman most at risk from breast cancer is an old, fat, white nun, living in the West, who started her periods early, eats at McDonald’s every day, and had a late menopause.
The biggest risk factor of all is being female, followed by age. There’s not a lot you can do about either of those, nor about the genes you inherit. Apart from keeping yourself sober and trim there’s not much on this table that is directly under your control, which is perhaps why something we can control (although right down at the bottom of the risk list) assumes such importance for us.
So oestrogen makes cells divide often and ups the chances of copying errors. Oestrogen can also tell breast cells how to respond to other hormones, such as progesterone, and growth factors. It has been discovered recently that breast tissue produces growth hormone and that cancerous cells make even more of it, transforming some breast cancers from relatively benign pussycats to ferocious tigers that break out and spread through the body (metastases). The mechanism is unknown as yet, but it wouldn’t be a shock to discover that oestrogen had a hand in it.
Oestrogen is so far a proxy villain, engineering villainy rather than being caught red-handed, directly affecting cancer-causing processes in the cell. Current evidence suggests that sex hormones promote the growth of pre-existing cancers.
There are higher levels of oestrogens in breast tissue surrounding cancers than there are surrounding benign breast cysts. Something clearly is turning weak oestrogens into very potent ones. That enzyme, aromatase, is the culprit here, and aromatase inhibitors – things that prevent aromatase manufacturing oestrogen – are even more effective at preventing breast cancers than the oestrogen-blocking drugs, such as tamoxifen, which post-menopausal women are currently given. Because an aromatase inhibitor is more effective than an oestrogen-blocker, it suggests that aromatase activity is crucial in terms of increasing and enhancing the effects of oestrogen. This all sounds gloomy. Your own hormones turning on you – hormones with such widespread and powerful effects too. The good news about this is that hormonal therapies – or should I say, anti-hormonal therapies – are the great success story of breast cancer.
The drugs that block oestrogen receptors stop oestrogen latching on to breast cancer cells and making them grow. Tamoxifen is the best known and is used after surgery (adjustment therapy) in those women that have oestrogen receptor-positive cancers: one tablet is taken a day for five years. It is thought to be responsible for a good half of the drop in deaths from breast cancer in post-menopausal women. For such women, aromatase inhibitors like letrozole and exemestane are now being evaluated in large clinical trials. These drugs probably confer a small but absolute increase in survival compared with tamoxifen but data about their side effect profile (for instance, their effect on bones) is still incomplete and they are not yet currently licensed for adjuvant treatment in the UK.
Another way of stopping oestrogen is to remove the ovaries or stop them working with radiotherapy (ablation). This is clearly an irreversible strategy and is only suitable for women past the menopause. A potentially reversible way of achieving the same effect is to use something called a pituitary down regulator. The best known of these drugs is goserelin (Zoladex). It stops production of luteinising hormone and follicle stimulating hormone (which, as you will recall is what tells the ovary to produce oestrogen). In effect it brings on a premature menopause.
A final word on breast cancer. No doubt you have heard some very alarming figures about the increase in breast cancer. Breast cancer incidence (which reflects the numbers of women diagnosed with breast cancer, not those who die from it) increased in the UK all through the 1980s, from 79 per 100,000 in 1980 to 114 per 100,000 just twenty years later. It reached a peak in 1992. Our genes don’t change in such a short space of time, so the logical conclusion is that there is something about our modern lifestyle which is causing this huge increase in numbers of women with breast cancer.
Much of the increase since 1988 has occurred in women aged 50–64, who had been invited to attend the national screening programme started at this time. In other words, women who previously had died of something else, or who had tumours that never became invasive, were now being spotted and were being added to the breast cancer statistics, pushing up the incidence rate dramatically.
Another reason for the increased numbers is that we are an ageing population: more older women, more breast cancer. But the figures have age ironed out of them using a system called age weighting. In Britain, for example, comparing breast cancer incidence in Eastbourne, which has a high number of retired people, with an area which has a lot of young families would be an unfair comparison, so the figures are adjusted using mathematical formulas in order to compare areas on the same basis. Recently the age weightings in the US have been revised – they had not been changed since 1970. Nassau County, for instance, had an incidence of 112.8 per 100,000. New age weighting meant an incidence rate of 136 per 100,000. There were exactly the same number of breast cancer cases, just a different age weighting formula. In other words, figures aren’t always what they seem and you always need to be sure that you are comparing like with like before jumping too quickly to a conclusion.
Age apart, there is still an increase and some of it is readily explainable by what we already know about breast cancer risk factors. For instance, earlier puberty, obesity, greater alcohol intake amongst women, the marked trend for later pregnancy and fewer children, have all increased incidence rates. That leaves about 5 per cent of the recent rise unexplained, which is a cause for concern, but not for panic and self-flagellation.
PROSTATE CANCER AND TESTOSTERONE
Men have the same problems with testosterone as women do with oestrogen – friend becomes foe over time. The prostate is a troublesome muscular gland that sits below the bladder, surrounding the tube leading from the bladder to the outside (urethra). It makes prostatic fluid, an important component of semen, and then squeezes it out at ejaculation (something which incidentally stops men peeing at orgasm). The gland is troublesome because it increases in size with age, the growth being testosterone-dependent. The body is normally good at controlling testosterone so that the gland doesn’t get too big even during the testosteronefest that is adolescence. The control system appears to be less effective with age, because, even with less testosterone in the system, the prostate gets bigger than it should. This condition – benign prostatic hyperplasia or BPH – is usually seen from middle age onwards. Because the urethra effectively goes right through the middle of the prostate gland, it can get squashed when the gland becomes enlarged, causing poor urine flow, and many urinary problems for older men. The prostate gland, for reasons that are unknown, also seems prone to becoming cancerous and almost all men reaching extreme old age will die with prostate cancer, though not of it.
Prostate cancer can become aggressive, however, and is the cause of death in 10,000 men each year in Britain. Just as in breast cancer, one of the ways to choke its growth is to starve it of the hormone it needs. Just like breast cancer, pituitary down regulators like goserelin can be used to shut down luteinising hormone, which is telling the testicles to produce testosterone. There are also anti-androgens, which perform the same sort of job as tamoxifen. And there are oestrogens. Stilboestrol is a synthetic oestrogen which fools the body into thinking that it must switch off testosterone production. The side effects for men undergoing hormonal therapy can be substantial, and include loss of libido, impotence and hot flushes. This is why hormonal therapy is usually only offered when the cancer has spread. Even when the cancer is no longer in the prostate, it is still driven by testosterone, with many receptors for it, wherever it has lodged. You might be thinking at this point that we’d be better off without our reproductive hormones. Yet the benefits still outweigh the risks that they inflict on us in later years.
We have talked about the crash of hormones in women, but not yet discussed the male equivalent. Is there a male andropause? The question of whether men experience a ‘change of life’ because of falling hormone levels as they age is controversial. We are certainly all familiar with male mid-life crisis. The sudden conversion to black T-shirts, rather than shirt and tie, the soft top car that appears in the driveway, air guitar to Led Zeppelin and the pursuit of women young enough to be their daughters. Is it a hormone crash or just a sudden realization that there are not enough years left to do everything they ought to have done in their youth? A medical crisis requiring treatment – or part of life’s rich tapestry?
That it might be a medical matter is not a new concept. In 1813, a paper by Sir Henry Halford was read at the Royal College of Physicians. In it he talked of a disease affecting men aged between fifty and seventy-five: ‘Sometimes the disorder comes on so gradually and insensibly that the patient is hardly aware of its commencement … in process of time his appetite become seriously impaired, his nights are sleepless … his face becomes visibly extenuated or perhaps acquires a bloated look. He suspects he has a fever.’ Sir Henry had no suggestions as to treatment other than warm purgatives and local evacuations. (No, I don’t know what they involved either, but fear the worst.)
A hundred years later, the word ‘climacteric’, previously applied only to women and the menopause, was being used for the first time of men. In 1909 Archibald Church, a famous neurologist of his day, published an article on ‘Nervous and mental disturbances of the male climacteric’, dealing with symptoms that he claimed had a monthly rhythm in men and of the ‘minor psychoses and neurotic disturbances of men aged between fifty and sixty-five’. He claimed that criminal behaviour in men peaked in the sixth decade. Certainly it’s the age at which men start to dress criminally.
Organotherapy was of course the solution. In 1916, the sexologist Max Marcuse from Berlin was treating male climacteric patients with his own preparations – Testikulin, Testogan or Hormin – prepared no doubt from testicles, although their exact contents were like the Coca-Cola formula, a secret that Mr Marcuse guarded closely. It’s unlikely that they had any effect. The unlucky ones were subjected to faradization – given a bolt of electricity to the prostate gland – which sounds eye-wateringly awful.
The first standardized preparations of male hormones appeared in the early 1930s. This was relatively late, a reflection of the technical difficulties, but also of the beliefs spawned by the gland-grafters that male ageing could be restored only by implanting donor testicular tissue (rather than an extract) into the host. The gland-grafters (not to mention the organotherapists before them) had created an atmosphere in which all hormones, and particularly testosterone, were associated with quackery, and those companies that had testosterone products were unwilling to market them aggressively, fearing that if they did, they would be damned by association. When testosterone was first brought to market, by the Dutch company Organon, it was prescribed for male urinary complaints, and marketed through urologists in a deliberate attempt to distance the product from the dubious activities of the rejuvenators.
The hormone preparations of this time were, as noted previously, drugs looking for medical diseases to treat. Sexual problems were not considered a medical problem at the time, with very few men even admitting that they had them. Although there was an interest in the male climacteric, the pharmaceutical companies of the time wanted to project themselves as being science-based, and were wary of doing anything that might possibly tar them with some of the wilder claims of the organotherapists.
Organon produced the first standardized testicular extract, Hombreol, obtained from bulls’ testicles, in 1931, later switching to urine as a source, obtained from thousands of Dutch soldiers at a nearby barracks. It was at this time that so-called paradoxical hormone treatment began, in which male hormones were given to women and, rather less frequently, female hormones given to men. Prior to this time, the sexes and their hormones were strictly delineated. Then it was discovered that, counter-intuitively, the testicles of stallions, rather than ovaries of mares, were the richest source of the oestrogen, oestrone, while androgens were found in quantity in female as well as male urine. Later it was realized that sex steroids come not just from the ovaries or testes but from the adrenal gland too. Nowadays testosterone is advocated for loss of libido in older women. It was synthetic testosterone’s availability that prompted its wider application – especially for age-related sexual problems – when it first appeared in 1935. This time, the hormone ‘drug’ appeared to have found its ‘disease’ – sexual difficulties.
By 1939, there was alarm from the Council on Pharmacy and Chemistry, who thundered in the Journal of the American Medical Association: ‘Within the past few months extravagant claims for the action of the male sex hormone testosterone have appeared in professional and lay publications … it is the Council’s belief that many claims for it have been grossly exaggerated.’ War intervened, but still the testosterone fires were raging. The Journal of the American Medical Association felt it necessary to write a dampening editorial in 1942: ‘Brochures circulated by pharmaceutical manufacturers depict the woeful course of aging man. None too subtly, these brochures recommend that male hormonal substance, like a veritable elixir of youth, may prevent or compensate for the otherwise inevitable decline. What of the postulated occurrence of a climacteric in men?’ What indeed?
The ‘male climacteric’ is not a phrase that finds much favour amongst the public – how do you pronounce it for a start? The word ‘andropause’ finds equal disfavour among doctors because it implies a biology in men that is comparable to that in women, in whom there is a precipitous fall in hormones, a 90 per cent drop from oestrogen pre- to post-menopause, for instance which is certainly not the case in men. Perhaps a new phrase is needed: the current favourite seems to be androgen deficiency in ageing males or ADAM.
It is clear that testosterone falls with age, but nowhere near as dramatically as oestrogen does in women. By the age of eighty, the blood free testosterone of a man is about half what it was at twenty. This is not simply caused by a decrease in production of testosterone but by a well-documented increase in the steroid ‘chaperones’ in the blood, the sex hormone binding globulins. Free testosterone begins to decline about the age of thirty with a consistent decrease of about 2 per cent a year thereafter. This decline is hastened in particular by obesity but also by diseases such as heart failure and lung cancer, inflammatory disease, and by heavy drinking. There seems to be an alteration in the rhythms of testosterone production, with the usual night-time elevations reduced. If blood levels of testosterone fall, the body would normally ramp up its gonadotrophin releasing hormone, so generating more luteinising hormone, which in turn stimulates the testicles to produce more testosterone. As men age, the hypothalamus seems to become selectively deaf as far as low testosterone levels are concerned, with all parts of the system less efficient than they were. The siren call of gonadotrophin releasing hormone (which controls testosterone production) is somehow less compelling than it was. It appears that the testes, too, have become deaf to the calls for action arriving on their doorstep.
There is a lot of debate about the prevalence of low testosterone in older men and what is a ‘significant’ decrease. The situation is bedevilled by arguments about exactly how you measure testosterone and also by the fact that there is no consistency about levels at which symptoms appear – what’s low for one man is perfectly fine for another. The defining level for diagnosis of hypogonadism (a medical condition in which testosterone production is regarded as deficient) is a total testosterone of less than 8.7 nanomoles per litre – by this measure, less than 10 per cent of older men are testosterone deficient. Other studies use reference levels of 10.4 or even 11 and find by that measure, 20 or even 30 per cent are deficient. The long and short of it is that you can create as big a population as you like of ‘deficient’ men by playing about with the definition of ‘low’. When we talk about ‘low’, are we talking low as in low for sixty, or low compared to a twenty year old, which would include three quarters of older men?
You might ask whether testosterone decreases because it is no longer required for the fathering of babies. In fact, although fertility declines in men with age, they can, and do still father babies when in their eighties and nineties. So, the fall in testosterone seems to be a consequence of ageing, not a cause of it. Thus technically speaking, male fertility ends with death, and in that sense there is no comparison between andropause and menopause because women continue to live beyond their fertility, while for men, the ending of fertility is likely to be a lethal condition.
The gradual decline in testosterone does affect fantasies and sexual thoughts, which become much less common as men age. Thinking of sex every six seconds is definitely a pursuit of the young. However, it should be said, such is the variation between men that some men will be enjoying sexual thoughts even as they knock on the pearly gates. By the way, it is a myth that many older men die in flagrante. Statistically, golf is much more dangerous.
Perhaps the decline in libido is for the best, because impotence is a major and deeply frustrating problem of ageing, affecting about half of all men over forty. It is tempting to attribute the declining frequency of sex with age to decreasing levels of testosterone, but although impotence can be caused by low testosterone (hypogonadism), it is an uncommon cause (less than one in twenty). A much more usual reason for erectile dysfunction is anything that affects blood flow to the penis, thus disturbing the elegant hydraulic system which powers its tumescent activity, such as smoking, atherosclerosis or diabetes. Circulating levels of testosterone in older men experiencing erection problems are normally well above those required for a normal sexual response and, sadly, restoring testosterone levels will not rejuvenate a penis flagging because its blood supply is weak compared to that of its glory days.
To my mind, age is never an acceptable excuse for tackle that doesn’t do what it should, and men should no more accept it than women should. Women need to be close to have sex, but for men sex is the route to closeness. If sex is taken away, a hugely important reservoir of comfort and self-esteem is removed. It is not surprising that men, believing that testosterone is the route back to the comforts as well as the thrill of sex, hanker after it so much.
What is certain is that decreasing levels of testosterone are associated with decreased muscle, thinner bones, reduced body hair, skin thickness, cognition, endurance, mood and well-being. Who wouldn’t hanker when told that testosterone can improve sexual interest, erectile function, muscle mass, mood and body hair – which is what is promised in a leaflet from the US-based Hormone Foundation, supported by an unrestricted grant from Solvay Pharmaceuticals US, makers of Androgel, a testosterone preparation.
So should replacement testosterone be offered to men? Is there any point in pouring androgens into a system which has become less responsive to them, perhaps even to the point of no response at all? There have been many poor pieces of research in this field, but a careful and important study by Peter Snyder and his team from the University of Pennsylvania in 1999 showed clear, although modest benefits over a three-year period for older men given 6 mg per day via a patch, with striking dose-dependent testosterone effects which were inversely proportional to plasma testosterone at the start of the study. In other words, those that had the lowest levels to start off with, benefited the most. This was a short-term study, however. There are major concerns with longer term safety, principally that increasing testosterone will result in prostate enlargement (leading to urinary problems) and accelerate prostate cancer. The data on increased heart disease is equivocal. High red-blood cell counts and behavioural problems are also a risk. The studies are rather opaque on what these behavioural difficulties might be – I’ve always imagined that it is sixty-five year olds having teenage temper tantrums rather than sixty-five year olds going out to buy a Harley Davidson. What’s more, it is a sad irony that one of the symptoms of prostate cancer and of coronary heart disease is erectile dysfunction – thus the very elixir taken to spur a flagging member on has the potential to cause precisely that same problem.
Another concern is that the focus on testosterone may distract from proper assessment and treatment of the underlying health problems that have prompted men to seek help. For those men that are genuinely hypogonadal, constantly fatigued, with testicular atrophy, fading bones and a low libido, there is surely a place for testosterone. What is truly concerning is how ADAM has suddenly become a medical disease, requiring aggressive treatment. It is noticeable, too, that the ‘low’ number is inching its way upwards. At the time of writing this book, yet another company announced that it would be entering the androgen market. Meanwhile, other pharma companies (and not just those that don’t list androgens among their products) are becoming alarmed by the way in which testosterone is being marketed. They fear a disaster ahead, and they are right in that apprehension.
While women are concerned about risk – the flight from HRT after the Million Women Study was published is but one illustration – men are much less risk averse. Three years of hot sex and then you die? Fine, lead me to it, seems to be the attitude of some older men. They seem to think, in this testosterone-induced nirvana, that one day they will be felled by a massive heart attack while pleasuring some nubile woman, and out they’ll go, the envy of their mates. Life isn’t like that. A long miserable decline into chronic ill-health is more likely and it is at this point that men will finally wake up and realize that they were misled. Yes, it was their hormones (or the remants of them) that led them by the nose, but they were actively seduced too. This is also the point – when the miseries of prostate cancer or chronic heart disease become intrusive and all pervading, men will turn around and sue the drug companies. If this were a no-risk exercise, then I’d be manning the barricades on behalf of men, but testosterone, as we’ve seen time and time again, is a very powerful hormone and the risks of taking it are considerable. Men need to be protected from themselves. Fat chance.
My prediction is this: I think that we will see the pattern of HRT repeated with testosterone-replacement therapy. Early enthusiasm, tempered by the exposure of dangers, followed by the development of designer testosterones (in the way that we have had selective oestrogen receptor modulators (SERMS) like raloxifene for osteoporosis), which can deliver the good things, but not the bad. Unlike HRT, expect to see these products as street drugs, peddled as Viagra is today, to young men on street corners, not just prescribed to older men in doctors’ waiting rooms. For surely, you can never have too much of a good thing?
So here ends the story of how our hormones turn on us. We are still better off with them than without them and perhaps, having read this chapter, you have a better understanding of their malignant power, as well as their benefits. One final observation: Brown-Séquard, the pioneer of hormones, brilliantly brought us the concept of internal secretion, and then with his youth elixirs brought testosterone into disrepute, making it a no-go hormone thereafter for science-based business. But for this, the pharmaceutical giants might not have concentrated on hormonal products for women but started with those for men. This could have changed the course of medical history.
