HRT and the Change of Life

Menopause

An overview of the "Change of Life" or Climacteric, its cause and effects.
The "menopause" is the technical term for the first day of the last ever menstrual period. The "Climacteric" describes the whole time of life when a woman loses her fertility and ability to make oestrogen.  It was considered in the past as one of the “rungs of the ladder of life” which occurred every seven years  (Bar-mitzvah, key of the door). 


What is the Change of Life?

Mother Nature, a deity, evolution or whatever agency one believes has equipped the human male and female for different roles in life, so that the species can continue through the millennia. The female creates the body of the next generation within her womb and after the baby is born, nourishes it with milk and looks after it for many years before it is able to look after itself. In biological terms once the next generation is "fledged", the mother has no function. In social terms however she may continue to play a big role. The male on the other hand is designed for speed of running (narrow hips) and muscular power for short periods and long periods of rest and recuperation. This enables him to fulfil a role of protector, perhaps chasing away a sabre toothed tiger or as provider being a hunter, gatherer. These two roles are best served by a different metabolism and I shall mention differences later.


Why is there a change of life?

The female of the species is born with a certain number of primordial follicles in her ovaries, each of which may have the capacity to produce an egg. Surprisingly she has the highest number at about 6 months of intra-uterine life and by the time she is born has lost perhaps half of those. By puberty, perhaps another half has disappeared and during her menstrual life, several are chosen each month of which the best is selected to produce an egg and the others shrivel away. So by the time that she has reached 40 or 50 years of age, she really is scraping the barrel and using up her last primordial follicles, which eventually run out altogether. When the primordial follicle is producing an egg, it also produces the female hormones oestrogen and progesterone, which stimulate the body to behave in a female way.

Testosterone the male hormone is produced by the ovaries outside the follicles and this may be produced after the follicles have run out. Consequently if there is insufficient oestrogen to counteract it the small quantities of testosterone will encourage the female body to act in a masculine way. This may not be obvious for many years, as very low doses of testosterone lead to slow changes, but one can for example see in the very elderly, thinning of hair and a male pattern of baldness developing, whilst hair starts to grow more often on the chin. The change of life therefore is the time during which the woman is using her last primordial follicles which may be quite inefficient and lead to symptoms, through the time when she runs out completely and then changes from someone who was predominantly influenced through the hormone oestrogen to one who has a predominance of testosterone.

Is the change of life natural?

This is always a contentious question, for it depends upon what one considers the word natural to mean. One can contrast the state of oestrogen depletion which occurs in all women who live beyond the time that they have follicles in their ovaries with a surgical menopause or medical menopause when doctors through surgery or drugs cause the ovaries to be removed or to stop functioning. However if one considers natural to mean what would happen in the wild, the change of life is certainly not a natural occurrence.
Before the 19th century with its industrial revolution and general increase in wealth, its public health and consequent increase in lifespan, most women would not expect to live as long as 50 years of age. They would die from infections, malnutrition or problems associated with childbirth at probably around 35. Consequently for most of the time of the human race on this earth, women would tend to produce their children before the age of 35, if at all. What happened to them after that would have little bearing upon the future of the human race. How things have changed.


The Post-Menopausal Years

As the periods stop, because the woman runs out of these follicles and the follicles produce oestrogen, the post-menopausal years are characterised by a lack of this hormone. The effects of this are many and varied. The body in general is controlled by two mechanisms; there is the nervous system and the endocrine or hormonal system. The nervous system tends to be concerned with instantaneous sensations and responses, though there are parts of the nervous system which deal with internal functions which we don't recognise as they are happening. For example we only occasionally notice our heart beats (palpitations). The nerves travel between the brain and specific areas in the body. The hormones however travel around in the blood streams, they are chemicals which affect every cell in the body, but the effect on that cell may differ depending upon how the cell works.

For example, insulin has the function of enabling the fuel glucose to enter cells. If any cell cannot get its fuel it may not do whatever it is programmed to do efficiently. Consequently the dangerous problems of diabetes which is caused by lack of the hormone insulin are not purely related to sugar, but the malfunction of cells, most critically those in the lining of small blood vessels, supplying various organs of the body.

Thyroxin, produced by the thyroid gland in the neck, tends to make metabolism faster if there is an excess or slower if there is an insufficiency. Interestingly, extreme over activity or under activity of the thyroid gland can make the periods stop.

You will appreciate that if somebody becomes a diabetic due to under production of insulin, the correct levels of insulin are supplied to the body twice a day and if someone has an underactive thyroid gland they will usually take thyroxine tablets, so that their body works at the right speed. These therapies are continued for life.
Why then do we not apply oestrogen replacement therapy automatically and for life? This is a very complex question and the answer lies partly in misunderstanding, both among the public and amongst doctors, partly because there is a difference in the types of diseases suffered by men and women and partly because it is extremely difficult to design studies that give us the truth and also it is very difficult to interpret the results of these studies.


Misunderstandings

If a woman suffers a premature menopause, due to her ovaries running out of follicles say at 35, or if because of disease her ovaries are removed at that age, we would normally replace the missing oestrogen hormone. This enables her body to function as if the ovaries were functioning; it is not associated with any excess risk over and above the risk experienced by a woman who is menstruating. Indeed there is good evidence that between 35 and 50, the increase in risk of breast cancer for every year of HRT is less than the increased risk associated with normal menstruation for a year.

Once the woman is past the average age of the menopause (51), the comparison that is usually used changes. There is not really any good reason for this, other than the impossibility of finding large numbers of women menstruating into their 70s.

It would seem that if any of us lives long enough or gets fat enough we will become diabetic, so when life expectancy reaches that time, we will all suffer diabetes in old age. Nevertheless I am sure it will still be considered a disease. We do not compare the person having replacement hormones with the person bereft of the hormones, to assess risks, but compare them with the person who has the normal amount of circulating hormones.

However when considering oestrogen replacement therapy, we compare things with a woman with normal amounts of circulating hormones prior to the age of 51 and then after the age of 51, we choose a different comparator group and compare with a woman who has no circulating hormone calling that normal.

Research

Research is an attempt to find a way of understanding a whole situation by looking at a tiny proportion of it. Say that we have 55 million souls in this country of whom roughly half are female and so probably about 20 million will be in the menstrual years, or after them.  Our research therefore tries to draw conclusions about this 20 million population from samples of tens or hundreds.

The design of the study is therefore extremely important. Some sorts of study will be more likely to tell the truth than others. Our statisticians go to great lengths to try to avoid any bias or influence by either the patient or the researcher.

We therefore feel that the best studies are randomised, controlled, double blind crossover trials. These are extremely difficult to set up and to carry through and many studies cannot undertake this detail.

So in the second rank come other studies, recognised to be of good quality, but with some deficiency, with regard to the ultimate described above. Studies which follow groups of patients over many years are subject particularly to patient bias, in that certain patients will continue, but others will drop out and it may well be those that suffer that continue.  Those that get better could drop out or vice versa. Perhaps the lowest ranking in terms of influence that we might draw is the questionnaire. This really does little more than confirm that there is a question to answer.

Misunderstanding can arise when too much credence is put in a study with poor methodology, just because it is newer than a better study. There is also the problem of what we term publication bias. Firstly studies which produce "fashionable" results may be more likely to be published in the professional journals than those which challenge the accepted view.  Secondly dissemination in the public media; the newspapers and TV always seem to be full of bad news. Good news does not seem to be worthy of wide exposure, perhaps good news does not sell newspapers, or TV adverts.


What do we know about life around the menopause?

This time of life from maybe 10 years before to 10 years after the last period may be characterised by symptoms, the commonest of these are hot flushes and night sweats, though these will only affect about 75% of the women going through this time of life. There are many other symptoms that occur at this time, some of them are like hot flushes and sweats definitely associated with lack of oestrogen and cured by administration of the hormone, however there are many other things occurring at this time of life and symptoms may be due to other illnesses or be more to do with job or family relationships.

Every woman is unique, her symptoms are her own and therefore her need for oestrogen replacement or other treatments to correct her symptoms will be unique and should be discussed with her medical advisor. She may be particularly distressed about her periods becoming irregular and unpredictable; in this case after suitable investigation her specialist might recommend an oestrogen and progestogen cyclical preparation, with a fixed cycle to control the time of her bleed. However oestrogen might do little to correct the distress of her son's drug habit or her bosses bullying.

There is no symptom of poor bone density until a breakage occurs. However if we measure bone mineral density, we find that the time of rapid bone loss associated with the menopause, starts a couple of years before the last period and goes on for a couple of years after it. There is therefore some good sense to a policy of trying to start hormone replacement therapy before the end of the periods in order to prevent this bone loss.

Will I get fat?

HRT does NOT make you put on weight. We all tend to gain weight at this time of life and there is evidence that those taking HRT gain less weight, on average, than those who do not. If you had to diet when younger you may be able to eat more as your body becomes less efficient with falling oestrogen levels. When you start HRT, you may use food efficiently as before and need much less.


The Post-Menopausal years

After the ovaries have ceased oestrogen production entirely, no cell in the body has the complete set of proper instructions to function as it would function during the reproductive years. As we get older, many of our problems are due to wear and tear, but a woman may suffer many problems which are due to this disordered hormonal pattern.

The problem of which we know most is osteoporosis; this perhaps is because we can measure it better than other conditions. It is a condition of reduced bone mineral density, leading to brittle bones and fractures of bones.  Men and women increase their bone mineral density during childhood and their teenage years and then have a fairly constant mineral density during the childbearing years. Some will have higher density than others and men generally have higher density than women. Many factors will influence this of course including exercise, nutrition, pregnancy and so on. Then from approximately the age of 35 we see a decline in bone mineral density in both sexes. However women suffer a more rapid period of bone loss from a couple of years before their last period to a couple of years after. Whereupon they resume the normal slow decline seen in men. This means that having started on average from a lower density and after this period of rapid bone loss, they will suffer osteoporosis at an earlier age than men. This is why when you see veterans of the last 2 world wars you will see that the men are usually ramrod straight, but the women have often a curved back, known colloquially as the "Dowagers Hump". This is due to fractures of the spinal vertebral bodies due to osteoporosis. As I said above there is no symptom until fractures occur and although these fractures do not tend to be lethal, they can be very painful, even resulting in pain with every breath that one takes, though many can also be quite painless. Wrist fractures are more common in women "of a certain age" and the fracture that kills is that of the hip.

Hip fractures are twice as common as breast cancer (16% versus 8%) and as each condition kills about half of those suffering it, therefore kills twice as many women as breast cancer every year. There is a huge amount of research work which shows that replacing oestrogens can prevent this bone loss and prevent fractures. However once the bone has been allowed to become very deficient many of the bracing struts (trabeculae) within the bone structure will have been lost and building up the thickness of those remaining may not give quite as strong a bone as the mineral density would suggest and therefore not as much protection against fractures.
There are several other treatments which can reduce this bone loss or even increase bone mineral density (SERMs, bisphosphonates, etc.), which will be discussed in a section on osteoporosis. The thinking at present is that one should try to prevent the bone loss with a strategy combining various therapies at different times of life, perhaps starting with oestrogens and going through the SERMs to the bisphosphonates in later years.

 

Cardiovascular (heart) disease

It is not uncommon for men to suffer a heart attack in their 40s or early 50s but it is rare for a woman to suffer a heart attack until she is much older. It is not absolutely certain why this should be. The major thing that differentiates men and women is the hormonal status. Before that time of life, the woman has oestrogen which may protect her from heart disease and after that time oestrogen is lacking and so she can behave more like a man. There is some biological sense to this.

During her child bearing years a woman needs to carry cholesterol to her womb for its major purpose of building cell membranes. We all need some cholesterol circulating for repair of our own bodies, but a woman needs to make sure that it is delivered to the factory for the new baby without mishap. Consequently oestrogen encourages the body to package up the cholesterol in what are known as high density lipoproteins (HDL). One could consider this as lots of bubble pack, brown paper and string. As I mentioned above men and women have evolved for different roles in life.


How does this affect cholesterol metabolism?

Usually, muscles use glucose as their fuel form, but in the extreme muscular activity that men might undertake they will rapidly run out of glucose and need more fuel. Cholesterol is an appropriately sized molecule with the right characteristics; therefore when the adrenalin is up and testosterone is the predominant sex hormone, men will carry their cholesterol very badly or loosely packaged in the low density lipoproteins (LDL). One could envisage a single layer of cling film. This is so that the cholesterol travelling all the way around the body can be used by any muscle, as necessary, for fuel.

Heart attacks have become the scourge of the developed world, because we no longer live a natural lifestyle. Without these extremes of physical activity, when my adrenalin is up, I probably just depress the brake pedal in my car trusting to the power braking, the power steering and the ABS, to do all the work. However my body still prepares as if I was going to fight or run by loosely packaging my cholesterol, which can then "fall out of the bloodstream", into any damaged portion of the blood vessel wall forming plaques, hardening of the arteries and blockages.

The Women's Health Initiative (WHI) and Heart Disease

In the summer of 2002, the first part of the Women's Health Initiative Study was published, this was a large randomised controlled study set up by the National Institute of Health in the United States. It was designed to see whether HRT would prevent heart attacks in women.

Cleverly, they collected a group of women who would be highly likely to have heart attacks, about three quarters of them were obese by American standards and about three quarters of them smoked! Obesity and smoking are both strong indicators of high risk of heart attack. However many did not start their HRT at the time of the menopause, the average age of starting the study was 63 and one women started HRT at 80.

Obviously there was quite a possibility that some of them would have suffered hardening of the arteries (atherosclerosis) and some would be just about to have a heart attack. It was not a surprise therefore to find that in the first year of taking HRT there were more heart attacks amongst those taking the hormones than amongst those taking the placebo (dummy) tablet.

Over the next 5 years there were fewer and fewer heart attacks amongst treatment (HRT) group suggesting that protection was building up. However in year 5 those in the placebo group suffered practically no heart attacks, therefore even although there were fewer heart attacks in the treatment group than there had been the year before, it seemed very much more risky at five years to be taking HRT. This part of the study was stopped when this became apparent, earlier than the 8 years that had been envisaged.

The research workers concocted a "global index" of risk and benefit, which has not been validated by any other study and consisted of heart attacks, strokes, breast cancer and broken hips. This suggested that overall there was more harm to those in the HRT group than in the placebo group.

However, on the data of this study, if one looked at all cardio-vascular events, all cancers and all fractures there was more harm to the placebo group and protection in the HRT group.

The results were reported to the world's media in the "silly season" before the professionals were allowed to see them, which coupled with the selective reporting makes me very uncertain as to the motives behind the study. Worst of all, it was not made clear in the media that this was only half of the study. It was the arm which used oestrogen and progestogen HRT which is the appropriate therapy for women who retain their uterus.
The half of the study involving oestrogen only HRT for women after hysterectomy continued until this year (2004), when it was stopped not because of problems, or risks but because they felt they had sufficient data to analyse. There were initial fears of an increase in breast cancer risk, but now that the study group say that there is no overall increase risk in the oestrogen only HRT group, this seems to suggest that oestrogen actually protects women from breast cancer the longer it is taken. We await full disclosure of the data.

The difference is between the oestrogen and progestogen group and oestrogen only group in a similar population of women tends to point the finger at the progestogen used which was medroxyprogesterone acetate. This has been suggested by other studies in the past and now must deserve serious study from the profession.

The Million Women Study

A year ago the Million Women Study was also published to the media in the silly season. Although it sounds a very powerful study with such large numbers, it was in fact simply a questionnaire to women attending for breast screening. This screening is of course largely automatic, but may contain some women who are worried about lumps. It is, to my mind, the sort of study that should indicate the direction of research rather than formulate public policy.

For example, it too suggested that oestrogen and progestogen were dangerous in terms of breast cancer risk, but had not been set up to consider different types of progestogen. As conjugated equine oestrogens and medroxyprogesterone acetate was (prior to the WHI Study) one of the biggest sellers in this country, I suspect that the Million Women Study is heavily biased towards this progestogen, though we do not know.

The panic produced by the media over these two studies has made it very difficult to discover the truth. One big study in this country which might have helped was abandoned because understandably women would not take part and there seems little likelihood that several other very important studies will ever get off the ground.

Post-Menopausal Bleeding (PMB)

Bleeding more than six months after the menopause (the last menstrual period) is termed "Post-Menopausal Bleeding". It is vital that anyone who suffers this symptom consults their GP. They will normally be referred to a gynaecologist.


Why does this happen?

Any woman who retains her womb may bleed at any time. Bleeding from the endometrium (lining of the womb) may be because it is too thin or because it has grown thicker. Thinness is usually due to lack of oestrogen and may be safely left untreated or be treated with HRT. However, if the endometrium is thicker than one would expect, it is vital to have a sample examined microscopically. If cancer develops in the endometrium, it will tend to bleed before it has grown very much. If we find it at this early stage, it can be removed completely, and the patient cured. It is because of this success that we must trouble many women with bleeding from benign causes so that we are sure to find the few cancers early enough to cure.


How is a sample obtained?

Often, we can pass a thin tube through the cervix (neck of the womb) in the outpatient clinic. This tube is called a "Pipelle de Cornier" and the sample often referred to as a pipelle sample. It is rather like having a cervical smear with the sampler reaching about an inch farther beyond the cervix. A small sample of endometrium is sucked out of the womb by pulling a plunger inside the tube. It is equivalent, in sampling terms, to the old fashioned Dilatation and Curettage (D&C)which required an anaesthetic.
If we suspect a benign polyp, or there is difficulty in obtaining a pipelle sample, we would proceed to a formal Hysteroscopy to view the cavity of the womb and sample any endometrium that looks suspicious.


How long before a result is available?

The sample is sent to the pathology laboratory where it may take a week to process (Bank Holidays might extend this). I therefore suggest that you return to the outpatient clinic two weeks later.


What sort of Treatment is available?

If it is because of thin endometrium, hormone replacement therapy is the appropriate treatment.
If there is a polyp, removal of the polyp may be curative.
If there is benign hyperplasia (thickening), cyclical progestogen taken for two or three weeks out of four should produce a regular bleed and prevent further build-up. It could be administered with oestrogen in the form of an HRT preparation.
If the PMB is repeated, it is sometimes wise to perform an Hysterectomy in case a pathology is hidden from the sampler.

Cancer of the endometrium should be treated by hysterectomy and removal of the ovaries. The possibility of further therapy with drugs (chemotherapy) or with X-Rays (Radiotherapy) would be considered in our regular MultiDisciplinary Meetings (MDT) with pathologists and oncologists

HRT after Endometrial Ablation

What If I Have Periods After My Ablation?

If you have had periods following the procedure for endometrial ablation, these may become irregular in the years leading up to the menopause (the last ever period). Sometimes HRT will be recommended to control this irregularity and the preparation should be one containing oestrogen and progestogen in cyclical fashion so that it mimics a normal menstrual cycle. This will produce a monthly bleed. If you do not have irregularity of your periods but you have other symptoms suggesting that the amount of oestrogen in your body is falling (e.g. hot flushes), I would recommend the same sort of cyclical preparation. Although these cyclical regimens can be tailor made for individual patients with oestrogen and progestogen administered by different methods, it is usually easiest to use an off-the-shelf preparation with the appropriate doses built in to an easy to use formulation. This sort of ready-made regimen is available in tablet forms from many companies or in patch form.  These cyclical therapies control the bleeding to give a predictable pattern.  After a while it might be better to use a continuous therapy to produce no bleeds.


What If I Have No Periods After My Ablation?

If you have no periods following your endometrial ablation, it would appear that we have totally destroyed the lining of the womb (endometrium). Therefore, you would not, in theory, need the progestogen part of HRT which is designed to prevent overstimulation of the same endometrium. However, I would still recommend that an oestrogen and progestogen preparation be used. This is for two reasons: firstly, we cannot be 100% sure that there is not a small pocket of endometrium which could be over-stimulated by an oestrogen-only preparation. Secondly, it is important that everybody knows that the progestogen is required for a woman who has a womb and diluting this message may result in somebody getting dangerous treatment.
However, the preparation used does not need to be of the type that provokes periods. A combined continuous oestrogen and progestogen preparation would be entirely suitable. These preparations also are available as tablets or as patches.

HRT after Hysterectomy

What If I Was Using HRT Before My Hysterectomy?

Some surgeons would recommend that you stop your HRT preparation some weeks before an hysterectomy. However, that risks return of symptoms for little discernible benefit. It is accepted that deep vein thrombosis is a little more likely in somebody who is using HRT than in a post-menopausal woman who is not but the oestrogens of HRT probably do not confer as much risk as the oestrogens of a normal menstrual cycle. I therefore do not regard this as a necessity.


After your Hysterectomy

Once the womb has been removed and the lining of the womb within it, you do not need the progestogen. There would be no harm to continuing to use progestogen and so I would recommend continuing until the end of your current supplies. However, thereafter you have a free choice of how you have oestrogen-only HRT. Although there are possible theoretical advantages to some preparations, by far the greatest benefit is achieved by using them for a long time. Therefore it must be a preparation that you are happy with and I think that your choice is the paramount consideration.


Your choices are:

Sniffing up your nose
Rather like an asthma or hay fever inhaler, a metered dose of oestrogen is sniffed each day and absorbed through the nasal mucosa
Tablets
By far the commonest, (though probably not the best mimic of ovarian function) are tablets. 1 or 2 will be taken each day.
Gels
Oestrogen can be rubbed into the skin each day rather like a cosmetic. An appropriate dose is delivered from a metered dispenser or by sachets
Patches
A patch is worn continuously. Some need to be changed twice a week. Others will last for 7 days. Many of the tales of patches coming adrift in the night relate to the old-fashioned reservoir patches (often with the label TTS for "through the skin") rather than the more modern matrix patches (often carrying the letters MX).
Patches should be applied to an area of skin which is:

• Miss a pill
• Smoke
• Start a medication that interferes with the contraceptive . e.g. some antibiotics
• Become ill with vomiting or diarrhoea, which may impair absorption of the medicatio
n

Vaginal rings
The vagina is made of skin and so oestrogen can be absorbed through vaginal skin in the same way as the patch allows absorption through the outer skin. The reservoir of oestrogen is in the plastic ring which is worn continuously in the vagina and it is changed every 3 months. Most women can do this for themselves.
Implants
A tiny pellet is inserted under the skin, commonly in the thigh or buttock with local anaesthesia. It is usual to insert another every 6 months though some women are happy with a slightly larger dose and annual top-up. Testosterone implants are sometimes used also.
Are there any Risks?
The Women's Health Initiative (WHI) found no increase of any complications (even no increase in breast cancer) in women who had estrogen only therapy after hysterectomy.

HRT after Bilateral Salpingo-Oophorectomy

If your ovaries are removed at the time of hysterectomy, this effectively removes the factory for oestrogen production. If you are a young woman and used to fairly high levels of oestrogen, this may result in particularly unpleasant withdrawal symptoms unless you have HRT. If bilateral salpingo-oophorectomy is proposed, you should consider carefully your preferred mode of HRT before the operation so that you can start as quickly as possible (certainly within a couple of days) after the operation.

Your choices are the same as for anyone else who has had an hysterectomy and needs HRT. However, we would usually start at a low dose and work up to the required, but, in general in this circumstance I would recommend starting at a slightly higher dose, possibly reducing to low dose HRT after a little while.

If your ovaries have been removed some time before the time of a natural menopause (about 52), you can expect to suffer the problems of lack of estrogen (osteoporosis, skin ageing, increased abdominal girth, Alzheimer's etc. ) that much earlier than others.  Using HRT up to the age of the natural menopause confers no extra risk and indeed is probably safer than having normal ovarian function. 

The ovary also produces a little testosterone (the male hormone) and some woman may notice the loss of this. The commonest complaint is of a lack of interest in sex. Testosterone implants have been used for many years for this indication. Testosterone is now available in patch format or as a gel but these are both formulated for men and we do not yet have sufficient information to justify recommending them for women in most cases.

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