Before menopause, women have a lower risk of cardiovascular disease than men. This has been well established in many studies across the world. On the assumption that female sex hormones are mainly responsible for this protective effect, hormone replacement therapy (HRT) has been tried in post- menopausal women. However, clinical trials have provided no evidence of net benefit and have revealed some harm in the form of an increased risk of blood clotting.
The major trial that deflated enthusiasm for HRT was the Heart and Estrogen/Progestin Replacement Study (HERS) , published in 1999. The trial, involving 2,763 women, was mounted with the high expectation that HRT will counter the risk of cardiovascular disease that begins to manifest in women after menopause. After 4.1 years of therapy with oestrogen and progestin, for secondary prevention of coronary heart disease in post-menopausal women who had a prior cardiovascular event, no benefit was noted. In the first year of therapy, a 52 per cent increase in fatal and non-fatal coronary events was noted in the group receiving HRT.
What about HRT for primary prevention of coronary disease, in post-menopausal women who have not had any manifest coronary disease? In 2002, the Women’s Health Initiative (WHI) published the results of a major trial in healthy women who had attained menopause. The trial was prematurely terminated due to adverse effects. A 29 per cent increase in adverse coronary events was observed in the hormonal therapy group, mostly manifesting early after initiation of therapy. There was also a 41 per cent increase in the risk of brain strokes with HRT in this trial.
These trials led to advice against the use of HRT for coronary prevention. Some later studies suggested that there is benefit if HRT is initiated very early after menopause rather than later. However, methodological issues have raised doubts about such studies. Pooling of data from all studies provides more robust evidence. This is what the US Preventive Services Task Force has been doing, through periodic reviews of evidence. Since 2002, USPTF recommendations have not favoured HRT. The last set of recommendations were provided in 2017.
For providing updated recommendations in 2022, investigators reviewed published data from 20 trials and 3 cohort studies with populations of 39,145 and 1,155,410 individuals, respectively, for inclusion in their review. The most recent recommendations, released on November 1, 2022, have further weighed against the use of HRT for prevention of chronic diseases in post-menopausal women. USPSTF presented 2 conclusions, from the latest review, labelled as those made with ‘moderate certainty’:
First, “use of combined estrogen and progestin for the primary prevention of chronic conditions in postmenopausal persons with an intact uterus has no net benefit.” Second, “the use of estrogen alone for the primary prevention of chronic conditions in postmenopausal persons who have had a hysterectomy has no net benefit.”
These recommendations are only related to the use of HRT for prevention of chronic conditions. The decision on whether to use HRT for relief of distressing post-menopausal symptoms has been left to the judgement of the treating physician. These recommendations also do not apply to persons who have had premature menopause or surgical menopause.
The Chairperson of the task force, Carol Mangione, was unequivocal in her summation. She stated “For people who have already gone through menopause, using hormone therapy is not an effective way to prevent chronic conditions because the potential harms, such as an increase in the risk of blood clots and stroke, cancel out any potential benefit.” She pointed out there are many other evidence-based recommendations on other ways by which women can stay healthy. Those ways include : not using tobacco; consuming healthy diets; regular physical activity; maintaining low risk profiles of blood pressure, blood sugar and blood fats, through natural methods and drugs when needed; having adequate sleep and reducing stress levels.
Even in pre-menopausal women, use of oral contraceptive pills has been associated with an increased risk of clotting in the blood vessels. However, the absolute risk is very low in most healthy young women. The risk is seen with combined contraceptive pills, which have both oestrogen and progesterone. The risk of thrombosis is greatly magnified if a person using oral contraceptive pills is also a smoker.
The recommendations of USPSTF are yet another reminder that a reductionist approach to medical management is flawed. There are many physiological mechanisms by which the blood vessels of women in the reproductive age group are better protected than men. A physiologically balanced hormonal profile is one of them. The profile of blood fats is also favourable to vascular health, with higher levels of HDL (“good”) cholesterol than in age-matched men. The pattern of body fat distribution too is different, with more fat around the hips (‘pear shaped’), compared to men who store more fat in the abdomen (‘apple shaped’). Abdominal fat deposition is associated with more inflammation, higher blood pressure and blood sugar, lower levels of HDL cholesterol, higher levels of triglycerides and inflammatory markers in the blood.
Evolutionary biology explains why nature resorts to many mechanisms by which the blood vessels of women are kept especially healthy in the child-bearing age. When a woman gets pregnant, she needs a healthy heart and blood vessels to transfer blood and nutrients to the growing child. This happens through the placental blood vessels, which connect the circulation of the mother to the foetus. After menopause, that protective purpose no longer exists. Women can and should maintain their blood vessels healthy after menopause through their own efforts, even though nature is no longer putting in an extra effort. Mechanically replacing female sex hormones does not mimic nature’s fine tuned balance. Irrespective of the reproductive function, longer and healthier lives of women will greatly benefit society through their many valuable contributions, including enlightened and empathetic leadership. They can achieve that, but not through HRT.