Menopause accelerates deaths from heart disease, and these can be prevented by hormone replacement therapy
Correspondent | Wednesday June 28, 2017 16:58
While egg death continue unabated, the speed with which eggs dye is reduced somewhat after birth such that at the time of the first period the girl child has only three hundred thousand to five hundred thousand eggs left. It is at this time during a female’s development that her ovaries begin to recruit some of the dying eggs for ovulation.
This period of egg recruitment marks the reproductive phase in the female, a period in which she will recruit and ovulate about 420 eggs. This recruitment of eggs is accompanied by a 40 year period in which the female body is bathed with female hormones, chief of which is oestrogen.
Oestrogen is the house keeper of the female body. It holds together the integrity of the female organs. Its presence at the start of the first menstruation is associated with padding of the female with fatty deposits that redefine the premenstrual female body to the typical female form.
It is oestrogen that helps develop and grow the female breast. Together with the other female hormone, progesterone, oestrogen is the means through which the female bone is replenished. The bone is constantly broken down and reformed. It is the duty of the female hormones to prevent excessive bone break down and to initiate formation of new bone.
Oestrogen is responsible for the growth of the female reproductive system, the growth of the vulva, vagina, cervix and the uterus is dependent on the presence of oestrogen. Oestrogen is responsible for the moisturisation of the female tract and keeping the external genitalia supple.
It is oestrogen that opens up the cervix and fills it with sperm-friendly mucous in the middle of the female cycle to allow for a possible pregnancy. Oestrogen helps keep the skin supple, a function well too often recognised immediately after the menopause.
Most important of all, oestrogen is the Teflon of the vascular system. The artery walls are kept smooth and spotless by the presence of oestrogen. It removes debris that get stuck on the arterial walls in the form of fatty deposits(cholesterol). The accumulation of cholesterol in the walls of your arteries lead to atheromatous plagues that cause narrowing of the blood vessels leading to hypertension, heart attacks and stroke.
Consequently the bathing of female tissues with oestrogen during the reproductive phase is critical to women’s survival, the withdrawal of which is associated with signs and symptoms of oestrogen withdrawal, recognised and known as the menopause. Menopause is the cessation of menses. On average, menopause happens at the age of 51.
At this point in time, a woman has less than one thousand eggs left in her ovaries. The number of eggs is insufficient to provide sufficient oestrogen to maintain the menstrual cycle and thus to sustain the house keeping role of oestrogen. The diagnosis of menopause can only be made in retrospect. A woman must have stopped having her periods for 12 months before a diagnosis of menopause can be made clinically.
About 3-5yrs before the menopause the menstrual cycle becomes irregular in timing and all too often becomes heavy. Initially the period becomes more frequent before it finally becomes more and more prolonged until a woman skips some months and ultimately a whole year.
It is during this transition that 60-80% of women develop hot flushes and sweating and mood swings due to lack of sleep (due to “waking up” at night during the menopausal heat wave – and yet unaware). Depression and anxiety are well recognised symptoms of the menopause.
Other signs and symptoms of the menopause such as sexual dysfunction, vaginal dryness, irritative bladder symptoms, degeneration of the skin, back pain due to degeneration of bone and increased propensity for fractures(osteoporosis), high cholesterol, heart attack and stroke, develop mostly after severe oestrogen withdrawal following establishment of the menopause.
While a lot of women would experience menopausal symptoms, about 15-30% would have very severe menopausal symptoms significant enough to interfere with their quality of life. In yet another 15% of women menopausal symptoms would persist without any hope of stopping. Due to declining oestrogen levels during the menopause and beyond, a woman’s cholesterol levels (which was previously used by her eggs to make oestrogen, progesterone and male hormones) eventually rise to dangerous levels.
The bad cholesterols called LDL and Triglycerides steadily rise, while the good cholesterol called HDL significantly takes a nose dive. The import of this finding is that cholesterol accumulates, start sticking to a woman’s arteries, gets taken up into the walls of the artery causing lumps and bumps of the artery walls (atheromatous plagues).
Atherosclerosis in turn leads to narrowing of the lumen of the vessels leading to high blood pressure and intermittent heart pain due to decreased blood supply at times of increased oxygen demand, such as during exercise. Further, after years of this carry-on, these fatty deposits become unstable and rupture, initiating clot formation within the blood vessels.
It is these clots that block heart arteries causing death of the heart muscle (heart attack) and death. When these clots, by chance are carried to the brain, they block the brain arteries causing brain attack, also called stroke. A study carried out by Tunstall-Pedoe and colleagues published in 1998 in the Lancet (figure 1), showed that deaths from blocked heart arteries are the same between men and women until the ages of 35-39 when men experience more deaths related to heart attacks. In women however deaths remained constant until the ages of 50-54, that is, until the menopause.
Following oestrogen withdrawal at the menopause women experienced deaths much the same way as men and eventually over took them. Not unexpectedly, in the same year researchers (Barret-Connor and Grady) found that giving oestrogen and progestogens to women in the menopause reduced deaths from heart disease by 30% and 34%, respectively. This was a higher order study called a meta-analysis in which high quality studies from 1980 to 1996 were aggregated to answer the question of benefit.
It is important to note that earlier similar high order quality studies in the early 1990’s had estimated that deaths from heart disease are reduced by 35-50% in hormone replacement therapy users, consistent with findings of meta-analysis of studies in the Barret-Connor and Grady study. In 2002 a very large study was published by the Americans called the Women’s Health Initiative. In this study they had randomized women into two groups. One group was given oestrogen.
These were women who had removed their womb. The other group who had a womb were given a combined HRT pill made of oestrogen and a progestogen called medroxyprogesterone acetate (MPA). The study had recruited women with ages ranging from 50-79. The study gave unexpected results. The protective effect of oestrogen on the heart was not confirmed by this study, although its benefit in preventing all fractures was upheld. Further the study confirmed what was known previously that oestrogen increases the risk of forming clots. Interestingly the study suggested that giving patients oestrogen increased the risk of stroke.
On the combined HRT group, the study confirmed what was already known that the combined HRT increased the risk of clots. However new findings suggested that it increased the risk of developing breast cancer and stroke. The absolute risk however was very small, suggesting that if you gave 10 000 women HRT 9 women may develop breast cancer, 9 may have a stroke, 9 may develop clots in the lung etc. Not surprisingly the results of the Women’s Health Initiative caused a lot of anxiety and discontinuation of HRT.
In 2009, a study by Islam (Menopause 2009;16:77) suggested that 60% of women had stopped taking HRT. The researchers noted a significant rise in women developing fractures. In 2013, it was suggested that about 45 000 women may have died as a result of avoiding HRT (Am J Public Health, POP July 18, 2013). In the USA between 1992 and 2006, 96% of USA counties registered improvement in deaths among men. During the same period deaths among women worsened in 43% of the USA counties.
These results together with other peripheral data suggested that something was wrong with the interpretation or design of the Women’s Health Initiative study(WHI), as deaths among women were on the increase after stopping HRT as expected. Granted the serious departure from well established knowledge about HRT as suggested by WHI, other researchers relooked at the same data used in the study. Hsia and colleagues were the first to draw blood (Arch Intern Med/Vol 166, Feb 13, 2006) and confirmed that the WHI suggested that oestrogen HRT did not confer benefit to users in the study as suggested by the initial authors.
However, they realised that most women recruited in the study were older (60-79)than women usually given HRT. They divided the oestrogen group into 3 groups, 50-59(which are the women usually given HRT), 60-69 and 70-79. The findings among the 50-59 years old confirmed what was known about Oestrogen HTR all along. The data suggested that if you gave women oestrogen-only HRT immediately after the menopause(that is within 10 years of their menopause) HRT reduced mortality from heart disease. They also found, that if you gave oestrogen-only HRT to older women (70-79) you increased death in this group from heart disease.
In the middle group (60-69) administration of HRT did not make any difference to deaths by heart disease. This analysis by Hsia and colleagues introduced a new concept in the prescription of HRT, called the window of opportunity. What the WHI taught us is that HRT must be started immediately after the menopause in order to be effective while taking it in the third decade after menopause caused more harm than good. These observations were consistent with established knowledge. The findings suggested that within 10 years of the menopause atheromatous plagues would not have yet formed within the arteries of women.
Giving Teflon estrogen HRT at this point is protective of the formation of the plagues. However, giving women oestrogen in their third decade from the menopause meant that when oestrogen start mobilizing and cleaning up the plaques that are already established at this time, it led to plaque rupture, clot formation and death. Therefore there exists a window of opportunity in menopausal women who are within 10 years of the menopause to prevent deaths from heart disease according to the WHI study. With the window of opportunity having been established by Hsia and colleagues, other researchers re-analysed the remaining data in the context of the window of opportunity. Rossouw and colleagues published their findings in 2007(Rossouw et al JAMA 2007;297:1465-1477). In their study they combined data from all women who were given HRT whether they were given oestrogen only or they were given a combined pill.
They wanted to know how the 3 groups (50-59, 60-69 and 70-79) performed with respect to stroke, heart disease and overall deaths. It was found that the younger women given HRT consistently had lower deaths from heart disease, stroke and an overall reduction in all cause mortality. Like the 2006 results by Hsia and colleagues, the results suggested no benefit to those between 60-69 yrs and increased deaths among older women given HRT. The researchers then split the data and re-analysed oestrogen HRT patients from the combined HRT patients. The results were exactly the same.
The findings by Rossouw and team firmly established the concept of the window of opportunity in the prescription of HRT. Not only did it confirm the findings by Hsia, but further showed that as expected giving HRT to younger patients was overall beneficial. In 2013, the original authors of the WHI published a follow up study of patients who were originally enrolled. After years of being followed up the only thing that remained significant after being given the combined HRT was increase in the risk of breast cancer. In the Oestrogen only group the only thing that remained significant was oestrogen risk to forming clots.
That oestrogen increased the risk of clots was a well known fact prior to WHI. What was surprising was why the combined HRT had a propensity towards increasing risk for breast cancer. A number of studies have been conducted to study this question. It has since been found that it was the progestin that was used in the study(MPA) that has increased risk to breast cancer.
It has been found that other progestins are safer for the breast such as micronized progesterone, digrogesterone, tissue selective oestrogen modulators such as duavive etc. The discrepancy in the findings of the WHI in relation to the established body of medical knowledge prior to its publication has finally been brought to book.
Through the women’s health initiative study, we learned that women benefit from HRT providing it is given within 10 years of the menopause. Secondly, that careful consideration should be made in our prescriptions of HRT to ensure that women are prescribed breast safe progestogens in the combined HRT preparations. All in all, if you are a woman who is within the window of opportunity HRT would benefit you by reducing deaths from all causes. The benefits associated with taking HRT far exceed potential risks associated with oestrogen withdrawal during the window of opportunity.
In prescribing for HRT your doctor would assess your risk for heart disease. If your risk is more than 10% you will not be suited for HRT. Other considerations your doctor would factor into your assessment would be existence or lack of other conditions such as breast cancer, smoking, hypertension, history of clots, stroke and the like, all of which may contraindicate HRT.
For women with premature menopause it is advisable to take HRT until the average age of the menopause at which time they would be further advised to continue with HRT according to the evidence we currently have, or they may choose to stop it at that point. HRT after all, is a personal choice, but the decision not to take it must be carefully balanced against potential harm brought on oneself by not taking it.
*Dr Vincent Molelekwa is an obstetrician, gynaecologist and fertility specialist (MB BCH BAO BMedSC DRCOG MRCPI MRCOG FRM)