Breast Cancer and Hormone Replacement Therapy

Recent findings from a large observational study conducted in Great Britain show that current use – but not past use- of postmenopausal therapy is associated with an increased risk of breast cancer as well as an increased incidence of breast cancer fatalities.

This large cohort study1 confirms the findings from the Women’s Health Initiative (WHI) (2,3) that current users of estrogen plus progestogen (EPT) are at an increased risk of invasive breast cancer (RR 2.0). This study also confirms prior observational studies4 that estrogen therapy alone (ET) increases the risk of breast cancer (RR1.30).

Over one million women (1,084,110) ages 50 to 64 years (average age 55.9 years) who were initially cancer-free were followed from 1996 to 2001 in a national screening program. Mean follow-up was 2.6 years for breast cancer incidence and 4.1 years for mortality. Primary endpoints of the study were diagnosis of breast cancer and deaths from breast cancer. Overall, current use of ET/EPT (Estrogen therapy/Estrogen and Progesterone therapy) was associated with a statistically significant increased risk of breast cancer incidence (RR 1.66; 95% CI 1.58-1.75) and breast cancer mortality (RR 1.22; 95% CI 1.00-1.48) compared to nonusers. Past use did not increase the risk of incidence or mortality and the risk of breast cancer decreased with time since last use. Current users of estrogen plus progestogen were at the highest increased risk (RR 2.0; 95% CI 1.88-2.12) of invasive breast cancer, compared to current ET users (RR1.30; 95%CI 1.21-1.40). In current users of each type of HRT, the risk of breast cancer increased with duration of HRT use. This risk appeared to be linear over time and was less in heavier women. In women with a BMI > 25, the relative risk of breast cancer for all users of HRT was 1.46 versus 1.97 for those with a BMI < 25. Of note, vaginal or other local EPT formulations did not increase the risk (RR 0.67; 95% CI 0.30-1.49). No significant differences in risk were found between specific types or doses or regimens of systemic ET or EPT. However, breast cancer risk increased as duration of use increased.

Although this study is observational, the results are very similar to those of the WHI and the results predicted by the Collaborative Group on Hormonal Factors in Breast Cancer Study4, which lends credence to these findings. Prior observational studies have suggested that ET alone increases the risk of breast cancer (RR 1.3). Ten years of HRT with ET alone is estimated to result in five (95% CI 3-7) additional breast cancers per 1000 women, and EPT combination to result in 19 (95% CI 15-23) additional cancers per 1000 women.

Evaluating a broader range of hormone therapy products than the WHI (which examined just one specific type of estrogen and progestogen, conjugated equine estrogen plus medroxyprogesterone acetate), the Million Women Study found very little variation between specific estrogen and progestogen products, their doses, their routes of administration, or whether the regimen was continuous or sequential. For estrogen-only users, increased risk was seen with oral, transdermal, or implanted formulations. No increased risk was seen with vaginal or local estrogen preparations. Progestogen only preparations were associated with an increased risk, but based on only nine incident breast cancers. Tibolone was also found to increase breast cancer risk, but less than combined EPT.

On an absolute basis, the breast cancer risk from ET is not very high. Many physicians are awaiting the results of the estrogen alone arm of the WHI to determine if estrogens in the absence of a progestin also increase the risk of breast cancer. However, a calculation of expected breast cancer incidence rates in the ongoing WHI ET arm estimates that there would be 70 new breast cancer cases in the women taking placebo and 78 in those taking estrogen alone. Thus, the WHI trial may not have sufficient statistical power (i.e., enough women in the study) to detect the slightly increased relative risk seen in the Million Women Study.

In this study, the follow-up was 2.6 years for cancer incidence and 4.1 for mortality. The increased risk in breast cancer became apparent within 1 to 2 years of starting treatment, irrespective of type of hormone therapy used. Once hormone therapy was stopped, the risk began to decline, and by 5 years reached the same level as never users. Increased mortality was seen, but it was of borderline statistical significance. Longer follow-up is needed from this study and the WHI to determine any effects on mortality from breast cancer.

About Testosterone Levels

Testosterone can be considered as an anti aging wonder drug (the decline of testosterone production with age has led to a demand for Androgen Replacement Therapy). It is often administered to female-to-male transsexual men as part of the hormone replacement therapy, with a “target level” of the normal male testosterone level.

Likewise, male-to-female transsexual women are sometimes prescribed drugs (anti-androgens) to decrease the level of testosterone in the body and allow for the effects of estrogen to develop. Women may also use testosterone therapies to treat or prevent loss of bone density, muscle mass and to treat certain kinds of depression and low energy state.

There are some interesting cases where testosterone level in the body can be increased:

No 1:
Experts recommend one of the safest ones and most importantly legal ones is to increase zinc mineral intake.Also brewers yeast, whole grains and wheat have high levels of zinc in them and they are totally natural.The minimal dose of zinc for men is 15 mg per day, but up to 50 mg daily can be taken, anything more than that can cause unwanted side effects and can be hazardous for your health.

No 2:
In a 2003 study, it show that serum testosterone levels reach a peak seven days after abstaining from ejaculation.

No. 3:
Recent research has suggested that alcohol consumption in women can temporarily raise testosterone levels. A 2006 BBC article states : “ According to medical research, testosterone – the hormone connected to male characteristics such as aggression and sex drives – rises in women by up to 50% when they are drunk. In men, its level drops down.”

Skepticism about Hormone Replacement Therapy

In 1993 in an article in Science a group of researchers recommended caution regarding the ever-changing practices of prescribing hormone replacement therapy (HRT). In Britain the so-called Disablement Association of Hillingdon has begun a campaign to increase skepticism about the magical effects of exogenous estrogen, especially in view of heightened susceptibility to thrombo-embolic disorders and the waning of estrogen’s effectiveness as a preventive of osteoporosis. Even the case for HRT as a protective against heart disease has been questioned.

Women have given HRT a fair trial and rejected it. Not to take their HRT is almost as bad as smoking. Why, they will get heart disease like men do (though probably fewer thrombo-embolic disorders). They will die younger without HRT, goes the argument, which does not go so far as to point out that this represents a valuable service for the public health authorities. It is unthinkable that women would not be delighted to live out their lives dependent upon chemotherapy supplied at a price by the pharmaceutical biochemical superpowers.

Modern women are much more highly estrogenized than their recent ancestors. An zoologist from Oxford calculated that over a mere 200 years the average number of menstrual cycles experienced by a European woman in her lifetime had increased from about thirty to 450. Her calculation is based upon the menarche’s occurring earlier and upon the infrequent pregnancies that modern women can expect to carry to term together with shorter periods of lactation. If we add to this the artificially estrogenized condition of modern woman post-menopause we end up with an astonishing 600 or so cycles. There is no precedent in the history of the human female for the raised and sharply fluctuating levels of circulating steroid hormones that we endure but, as we did not know what made the nineteenth-century female feel well or even if she felt well, we can hardly guess whether the modern women is better or worse off because of her vastly altered endocrinology. Only the rising cancer figures tell us that she is worse off.

How you answer the question, whether individuals should be persuaded to live their whole lives in a state of chemical dependency, first upon contraceptive steroids and then on replacement therapy, depends upon your regard for the autonomy of the individual. If men would not live their lives this way, why should women? Even though all teenagers should by now be convinced that condoms should be their contraceptives of choice, British physicians have begun lobbying for the right to prescribe synthetic sex steroids to women under sixteen. The caponized woman is now the norm.

Natural vs. Synthetic Estrogenes

Our culture, which sees happiness as something you put in your mouth or inject into your body, no sooner suspected that estrogen, like serotonin, was a magic philter that would restore and maintain equilibrium, health and well-being, than it began clamoring for more and more of it. Synthetic versions were swiftly patented, manufactured and sold. Yet exogenous estrogen was no novelty, as women had been using it for years in the form of contraception, without noticing any euphoric effect. The pharmacologists who developed the so called hormone replacement therapy saw at once that synthetic estrogens did not produce the desired effects.

They went back to natural estrogen, a cumbersome and expensive product, harvested from the urine of pregnant mares. The mares are fitted with a collection cup attached to a hose and confined in a narrow stall for the entire eleven months of their pregnancy. As soon as possible after the birth of their foals, who are routinely slaughtered, the mares are re-impregnated and the urine-collection process begins again.

If the pharmaceutical companies were to get women hooked the best time was at menopause when they were in estrogen withdrawal and begging for a fix. At least that was what the researchers thought that hot flushes, joint pains, sleeplessness, etc., added up to. The new mixtures were the methadone rather than the heroin. For some reason the women did not stay hooked. The selling and the product design were relaunched time and again. Sub-dermal implants seemed to lose their effectiveness; women required bigger closes, the implants became ineffective more quickly, menopausal symptoms recurred at shortening intervals. The manufacturers of sex steroid preparations, like the manufacturers of cigarettes, had what they wanted, addiction, and they were just as unwilling to talk about it. An underground network of pushers w-as set up; women, all users themselves, held HRT parties, bring-and-buy sales and coffee mornings, to spread awareness so that women would ask their doctors to prescribe.

Women who take estrogen definitely tend to look younger than their years. Their skin remains smoother, moister, oilier and more flexible – in other words younger. That doesn’t mean you should take estrogen for cosmetic purposes alone. Younger-looking skin is just one of the magical consequences of HRT that researchers have been unable to substantiate; as far as laboratory investigations can establish, exogenous estrogen has no effect on the epidermis or supporting structures.

Hormones and Estrogen-Dependent Diseases

In an article in Brainwork J. Kinoshita speculated in the kind of way that inspires drug houses to finance the running of large-scale clinical trials, in this case of the effects of estrogen given in the post menopausal age on the incidence of Alzheimer’s disease. Elderly women are more prone than men to Alzheimer’s, but some physicians report anecdotally that those who receive estrogen do not develop the disease. Estrogen is said to enhance cognitive function. What this actually means is that some GPs think that some of their older female patients might not have developed Alzheimer’s because they were on replacement estrogen. They have no idea which ones these might be or whether they would ever have developed Alzheimer’s or whether some other factor such as non-exposure to environmental estrogen poisons might be involved.

Once a large-scale trial has been set up it has its own momentum. A positive correlation of smoking with incidence of Alzheimer’s has recently been observed. As for estrogen, it is said to have an effect on human cognitive function. But the only evidence is from short-term administration of estrogen to small mammals in the laboratory, animals not normally noted for intricacy of brain function.

Sex steroids can hardly be expected to be neutral in their effect on behavior, mood, cognitive function and so forth, especially if we consider that the pharmacologic versions of sex steroids are administered at much higher levels than those occurring naturally. We are also beginning to realize that there are reciprocal interactions between steroids and behavior. In other words, as hormones influence behavior, so behavior influences hormones. The more expert the endocrinologist, the more respect she/he has for the synergistic interactions of body chemicals; unfortunately most health practitioners have only an elementary understanding of endocrinology and are far too ready to believe in quick-fix remedies for perceived malfunction.

What is claimed for Alzheimer’s is also claimed for cancers, except those of the endometrium and breast, which are considered estrogen-dependent. The data are difficult to interpret. Women on replacement estrogen are three times as likely to develop endometrial cancer as women who are not, but opposing the estrogen with progestogens is thought to control the risk factor. British doctors believe that after stopping HRT women should continue to take progestogens for two years but American doctors have yet to be convinced of the usefulness of opposing estrogen at all. Women on HRT have twice the rate of breast cancer after nine years, and women on combined regimes are four times as likely to have breast cancer after six years. HRT used to be denied to women who have had a brush with the disease, but now HRT users may also take tamoxifen if the risk of breast cancer is considered significant. The constant crying up of HRT has the effect of making women who are denied the therapy feel hard done by, when the truth is that most women who could use replacement estrogen don’t. The latest cross-national study of HRT users in Europe calculated current users as only one-third of women actually going through menopause and no more than 13 per cent of post-menopausal women. About a quarter of post-menopausal women reported use at some time.

Still fortunes are to be made and professional clout to be accumulated by setting up large-scale cohort trials to track the incidence of the diseases of ageing in a post-menopausal population that faithfully persists in dosing itself with estrogen. The difficulty will be to find that population, because if current trends persist women will use HRT during the period of menopausal discomfort as a symptomatic treatment and then abandon it. The drug houses, who anticipated easy pickings as women remained on their product for the term of their unnatural lives, are perplexed. They want explanations of this poor compliance. They blame voices like my own crying in the wilderness, effortlessly overcoming the booming sound of their endless promotion of their product in the medical press, and the equally energetic distribution of free samples to GPs. The truth is that selling estrogen as a panacea was a miscalculation. Nobody knows better than women that biology offers no free lunches. In women with wombs and ovaries estrogen has got to be opposed by progestogens if uterine hyperplasia is not to result. This results in administration regimes that are onerous, especially when the adverse effects of exogenous progestogens, bloating, headaches, mood swings, etc., are taken into account. Then there is the question of monthly bleeding. Every year the drug houses present new methods of administration, tacitly admitting that they have not got the mixture right. There will be no definitive large-scale cohort trial of the prophylactic effects of post-menopausal estrogen because there are insufficient examples of long-term use of any single method.

Women and the Role of Estrogen

Estrogen seems to be as good for women as testosterone is bad for men. It makes women feel great and it doesn’t cost them anything.

Adult females make it themselves out of cholesterol converted by their gonads and their adrenal cortex first into progesterone, then into testosterone and then into estrogen. The ovaries carry on producing estrogen long after ovulation has ceased, more than twelve years in fact. The adrenal glands atop the kidneys produce estrone to boost it; all steroid hormones are lipophilic, that is, soluble in fats and easily diffused through membranes. They bind with intracellular receptor proteins and the resultant complex binds to DNA. The scale of effects of this process is as yet hardly glimpsed. What we know and are prepared to say is that ‘estrogen lifts our moods and gives us a feeling of well-being’. It probably does that by influencing some of the neuropeptide transmitters in the brain that regulate how we feel and think, probably oxytocin and vasopressin, together with the enkephalins and dynorphins, opioids produced in the brain.

Oxytocin is particularly interesting not only because it can be shown to have specific functions connected with arousal and orgasm in both males and females, but because neurons containing oxytocin receptors have been found in regions of the brain that suggest a role in bonding behavior. Such data might give the impression that personality is a simple bio-chemical cocktail and can be changed just by upping some part of the mixture. In fact the cocktail has some 4,000 elements that are continually being shaken and stirred; the overall and ultimate effects of adding a jigger of something new are unknowable.

The sex hormones estrogen and progesterone are closely related to anabolic steroids and, like them, affect mood and behavior. People suffering disruptions of their normal biochemical balance will report personality disturbances. The behavioral effects of added estrogen are difficult to quantify; estrogen will not increase libido, for example, as it exerts little action on the clitoris, but it does increase receptivity in that it controls the vaginal environment.

We know enough to know that sex steroids are powerful and that they have complex interactions with other substances, which would seem to be good reason not to introduce similar substances that would replicate or exaggerate or annihilate any part of the wonderfully intricate sequence. In the case of recreational drugs reasonable people are only too ready to accept the idea that interference is foolhardy; when it comes to exogenous estrogen, which is a drug like any other, we are suddenly undisturbed by the prospect of lifelong dependency. Estrogen is now being tried and found effective as a mood-altering substance; it has been used successfully as a symptomatic treatment for severe post-natal depression.