Menopause

Professor John Studd, DSc, MD, FRCOG

Hormone treatment for the menopause is now much more complex than simply giving oestrogens for hot flushes, sweats and vaginal dryness as there are many new developments to deal with specific problems and to improve acceptability and continuation therapy. There are many reasons why women do not continue with HRT, such as bleeding and fear of breast cancer but perhaps the most important is that they do not feel any better. It therefore seems a waste of time taking hormones to prevent a fractured hip at the age of 80 which may not occur anyway. Firstly, I think that we should avoid using Premarin which contains about 20 equine oestrogens that the human body has never seen before. It is true that it has worked well for about 50 years but we now have a better option, using oestradiol by tablet, patch, cream, implants, intravaginal application and even intranasal application. This is a human oestrogen found in men and women and can be measured by simple assays so that we can have a better understanding of absorption rates and response to treatment.

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When to Start

The traditional way of giving oestrogens for women after the menopause is to treat the characteristic climacteric symptoms with continuous oestrogens and the addition of cyclical progestogens for 10 or 12 days per month producing a withdrawal bleed or by continuous combined oestrogen/progestogen therapy with daily low dose progestogen as a non-bleed preparation.

However, there is often an indication to start therapy before the cessation of periods in women who have hormone responsive depression. This depression may be cyclical as in severe premenstrual depression or continuous with possible premenstrual exacerbations in the 2 or 3 years before the periods cease. It is very important to realise that climacteric depression is at its worst in these years when the woman is still having periods and therefore the association with a hormonal aetiology is not apparent. These women in fact do very well on a slightly higher dose of oestrogens, particularly in the form of patches, gels or implants with doses of 100 or even 200 mcgs of oestradiol patch twice weekly with cyclical oral progestogen is more effective than low dose oral therapy in this group of patients.

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When to Stop

There is a view that breast cancer may be increased in women having 10 years or more HRT. Although it must be stressed that there are more high quality publications showing no increased risk than publications showing a slight increase in risk. They do not get the same publicity in the Press. The apparent increase in the incidence of breast cancer may be an artefact but certainly there is now good evidence that the survival is better and that fewer oestrogen takers die of breast cancer than non-users. In spite of this, there remains the view, (which I do not subscribe to), that there should be a limit of 10 years. Perhaps this means that oestrogen therapy should be started at about the age of 60 when there will be maximum protection for osteoporosis, maximum cardiac protection with a lesser risk of breast cancer occurring in younger women. It is a reasonable point of view and at least it does reinforce the clear scientific fact that a 60 year old woman should not be neglected by denying her oestrogens because her older bones or even osteoporotic bones respond to oestrogens, even better than the skeleton of the younger postmenopausal woman.

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Testosterone

At last, doctors (and patients) are recognising the importance of testosterone. It is not of course a male hormone, as it is present in the normal young female in even higher concentration than oestradiol. But men, hopefully, have more testosterone on board than women. There is a female androgen deficiency syndrome (FADS) which occurs with failing ovaries and certainly after bilateral oophorectomy which manifests itself with loss of energy, loss of libido, tiredness, loss of self-confidence and headaches. These women respond very well to testosterone. Although testosterone is available in tablets, IM injections, patches and gels, these are not licensed for women and the only way in this country to deliver testosterone is by an implant. For convenience, it seems sensible to insert an oestradiol pellet at the same time as testosterone. The benefits of oestradiol and testosterone are particularly apparent in patients after hysterectomy and bilateral salpingo-oophorectomy because a) they need replacement of the missing ovarian androgens and b) HRT should be straightforward as there is no bleeding and no need for the cyclical progestogen with its PMS type side-effects. Our own data of 200 such patients shows a continuation rate of 96% at 5 years and 88% at 10 years. This brings us back to the initial statement about continuation rates because women feel better.

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Intranasal Oestradiol

The most recent development has been the appearance of intranasal oestrogen, Aerodiol, which is certainly as effective as oral oestradiol 2mgs or oestradiol patch 50mgs. It has an odd pharmacokinetic picture, as there is a massive peak of oestradiol of 4000 pmol/l at 30 minute (the normal range is 100 to 1400 pmol/l), which is reduced to normal postmenopausal values within 4 hours. I believe this may be a huge advantage, particularly in patients with hormone responsive depression, like postnatal depression, premenstrual depression and climacteric depression. However this hypothesis needs confirmation by clinical studies.

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Menopause and PMS Clinic
Wellington and Lister Hospital, London

A clinic dealing with gynaecological endocrinology was run at the Lister Hospital by Professor John Studd, DSc,MD,FRCOG. He was also a Consultant Gynaecologist at Chelsea & Westminster Hospital and started the first menopause clinic in Britain in 1970 and the first psycho-endocrine clinic in 1995. He is regarded internationally as an expert on menopause, osteoporosis, PMS and the hormonal aspects of depression in women. He is Vice-President of the National Osteoporosis Society.

Menopause

It is generally accepted that oestrogens abolish menopausal symptoms, increase bone density, reduce the incidence of heart attacks, strokes and Alzheimer's disease and improve sexuality. Oestrogen users also live about 1.5 years longer than non-users. If that is the case acceptance of oestrogen therapy should be simple but it is not. Only about 15% of women at risk take oestrogens and the vast majority abandon HRT within a year. This lack of continuity is due to a combination of things including breast cancer, fear of weight gain, reluctance to have periods or the PMS type symptoms that occur with cyclical progestogen (Table 1). Also many women taking low does oestrogens do not feel any better and are therefore reluctant to take long-term therapy to prevent a fracture at the age of 85 which may not occur anyway. There are many new formulations with using various routes of administration, various combinations which attempt to improve the well-being of menopausal women without side-effects or problems of bleeding. Thus therapy is becoming more complicated rather than more simple as we tailor treatment to the needs and response of the individual woman. It is for this reason that selective oestrogen receptor modulators (SERMs) have been introduced to improve patient acceptability but they produce flushes and sweats and other menopausal symptoms.

Oestrogen therapy for the over 60s is a very important area as these are often neglected in the belief that older osteoporotic bones do not respond to oestrogens. They do and they respond even better than the bones of younger postmenopausal women. In fact the lower the bone density the greater the increase with hormone therapy (Fig. 1). It is these women which value low dose oestrogens and no-bleeding regimens. There is a view disputed by many, that oestrogen therapy should only be on ten years' duration. If this is so it is possible that maximum cardiovascular and skeletal benefits with least side-effects would accrue by starting aged 60 rather than aged 50, but the 50 year old usually requires symptom relief during this decade.

Similarly, HRT for the peri-menopausal woman who is still having periods but suffering from depression, tiredness and loss of libido is another neglected area. These patients often have a long past history of hormone related depression i.e. postnatal depression or pre-menstrual depression. Such patients suffer their worst depression in the one or two years before their periods stop but often need oestrogens instead of, or as well as, anti-depressant therapy.

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Osteoporosis

Post-menopausal women have a substantial loss of collagen from the skin and the bone matrix which can be replaced with oestrogen therapy (Fig. 2). This has an obvious cosmetic and health effect upon the skin and will also increase the bone density in post-menopausal women. One in three women have a lifetime osteoporotic factor of the distal radius, proximal femur or the vertebral bodies of the spine. There is no doubt that the majority of these fractures can be prevented by simple measure such as HRT and that the effect is dose-dependant (Fig 3). Oestrogen therapy would also substantially increase the bone density of women with osteoporosis or who have had osteoporotic fractures. It is important to attempt oestrogen therapy as first-line therapy in combination with calcium and vitamin D and failing that it may be necessary to use bisphosphonates or the newer SERMs.

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PMS

Pre-menstrual syndrome is a very complex condition which is frequently difficult to treat. Mild PMS is very common and responds to many scientifically unproven treatments or to change of lifestyle and diet. There is also an impressive placebo response. Severe PMS is the sort that destroys careers and marriages is paradoxically easier to treat because the severity requires proven treatment administered by a medical practitioner. These treatments essentially rely on suppression of ovulation and thus removing the hormonal changes (whatever they are) of the ovarian cycle and hence removing the cyclical symptoms of PMS. The sort of treatments include use of moderately high dose oestradiol patches, (Fig 4) oestradiol implants, GnRH analogues with add-back HRT or even, if appropriate, total abdominal hysterectomy and bilateral salpingo-oophorectomy with hormone replacement therapy. The role of SSRIs anti-depressants should not be ignored, possibly in combination with transdermal oestrogen therapy.

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Hysterectomy and Depression

Menorrhagia, which requires a hysterectomy, is rarely a condition where the periods are merely heavy. They are often irregular, painful, associated with PMS, menstrual headaches, anaemia, exhaustion and depression. Every prospective study, there are now 13, looking at the effects of hysterectomy on depression in these sort of patients shows that this is usually helped by hysterectomy and efficient HRT (Fig 5). In spite of this, crusading journalist often write that hysterectomy causes depression, loss of sexuality, with great harm to the general health and marital relationship. Nothing could be further from the truth but it is essential to give hormones which adequately replace the missing ovarian hormones if oophorectomy has been performed which will usually be oestradiol and testosterone inserted as pellets into the wound at the time of closure.

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Psycho-endocrine

This part of the clinic recognises the association of hormonal changes, personality and environmental factors in the aetiology of many mood disorders in women. This has been investigated for more than 20 years by Mr. StuddÕs team who have shown in scientific trials that oestrogens are effective in peri-menopausal depression, pre-menstrual depression, post-natal depression (Table 2) as well as being valuable in the overall treatment of anorexia nervosa and chronic fatigue syndrome which are both often associated with low oestrogen levels and low bone density.

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The Clinic

The clinic will be able to measure the bone density by up-to-date Dexa technology, will be able to perform trans-vaginal pelvic ultrasound to assess endometrial thickness and uterine or ovarian pathology. Psychiatric advice and dietary/nutritional will be available if necessary.

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LEGENDS