The main finding — that QOL was not significantly improved — was to be expected in this population. Symptomatic women were discouraged from participation, and vasomotor symptoms were reported by only 12% of the participants. Furthermore, it is unlikely that many women who had bothersome menopausal symptoms would volunteer for a study in which they had a 50% chance of receiving placebo for a prolonged time. Symptom relief is the most relevant factor for improvement of QOL with hormone therapy; therefore, women without symptoms are not likely to experience large improvements in their QOL. Nevertheless, even this older population showed improvements in sleep, physical functioning, and pain. Thus, it is possible that there was an effect on the QOL, but that the study was not designed to capture this information.

The more important question of effect on QOL in symptomatic women was addressed by a subgroup analysis of 574 women ages 50 to 54 years who reported moderate to severe vasomotor symptoms at baseline. Women in the estrogen and progestin group demonstrated a significant improvement of vasomotor symptoms (p < 0.001) and sleep quality (p=0.02), as compared to placebo. Despite this, improvement in QOL was not observed. This contradicts previous well-designed prospective trials.2 There are several limitations in this study’s design that may explain the failure of this analysis to detect an improvement in QOL. First, the primary objectives of the WHI did not include evaluation of the effect on QOL. The study, and particularly the subgroup, may not have had the power to detect a meaningful effect.

Second, the main instrument used to evaluate QOL was the RAND-36.1 Although a good measure of health-related functioning, it was not designed to assess variables relevant to QOL in postmenopausal women.3 For example, important domains, such as sexual function, are not addressed. The authors attempted to evaluate this variable by asking a single question with a four-point response scale: very unsatisfied, a little unsatisfied, somewhat satisfied, and very satisfied. This approach is clearly inadequate as a method for assessing change in such a complex aspect of human function. Nevertheless, the data in this subgroup revealed an improvement in the estrogen and progestin group that had borderline statistical significance (p=0.06). Thus, the RAND-36 was not designed to assess the “sense of well-being,” particularly in the postmenopausal population. Validated instruments such as the Utian Quality of Life Scale (UQOL) are available for this purpose, and should be utilized in future studies.3

Another weakness of this study was the high rate of drop-ins. Many women randomized to placebo initiated hormones. Symptomatic women were most likely to do this, which may have introduced bias toward the null hypothesis, thereby decreasing the likelihood of detecting an improvement in QOL.

In summary, it is incorrect to conclude, on the basis of this study, that estrogen plus progestin therapy does not improve QOL in women with vasomotor symptoms. Previous randomized controlled trials have provided evidence to the contrary. Furthermore, even in asymptomatic women this conclusion is questionable, as the study was not designed to evaluate QOL in postmenopausal women.

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.

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.

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.