Hormone replacement therapy: recent advances
Hormone replacement therapy: recent advances |
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Department of Obstetrics and Gynaecology, Diana, Princess of Wales Hospital Northern Lincolnshire and Goole Hospitals NHS Trust, Scartho Road, Grimsby DN33 2BA
1Corresponding author
Key words: menopause, hot flushes, and hormones
Introduction
The last menstrual period is known as menopause, and it is part of the term climacteric which encompasses the years of progressive ovarian failure. There are many features of the menopause. By far the most common symptom for which menopausal women seek treatment is the hot flush. It is estimated that these episodes of flushing and perspiration will occur in more than 80 per cent of menopausal women, and will persist for a least one year. Hot flushes are most often described as heat starting in the face, neck, or chest – sometimes accompanied by reddening and sweating – and spreading. Night sweats, which sometimes necessitate a woman getting up during the night (to shower, change clothes, etc) can be a major cause of sleep deprivation. Other body systems are affected by menopausal changes. These changes have been previously
described1.
Hormonal management of the menopause
Hormone replacement therapy (HRT) was originally an oestrogen-only preparation, used orally as Bishop
(1938)2 first advocated for surgical menopause.There was a boom of HRT in the USA in the 1960s, when it was fashionable to prescribe oestrogen in order to maintain continued youth in the older women e.g. the concept of feminine
forever3. This changed dramatically in the 1970s when the complications of unopposed oestrogen replacement gradually became apparent
The total HRT market in the United Kingdom is currently valued around £146 m. and the market can be segmented into oestrogen only with a value of about £52.9m (approximately 36%) and combined products, which can be subdivided into sequential combined of £46.7m (32%) and continuous combined of £46.2m (32%) (Fig.1). The number of women in the United Kingdom choosing to use HRT is increasing with less than 15% of women aged 45-54yrs. in 1995 and 17% of women aged 40-65yrs. in 1997 (Fig 2).
HRT: routes of administration
HRT is available in several formulations for various routes of administration (table 1). Oral HRT comes from several sources and includes synthetic oestrogen, naturally derived oestrogen, or, in the case of one product, oestrogen from the urine of pregnant mares. Transdermal estradiol consists of patches worn on the skin and changed every few days or gels rubbed into the skin.
Vaginal administration includes pessaries, creams, and intravaginal rings. Oestrogen can also be administered as a nasal spray. Subcutaneous implants are biodegradable pellets that release oestrogen gradually. The key ingredients in the HRT are oestrogens and progestogens. Oral HRT is widely used but can cause nausea and may be associated with poor compliance. Transdermal therapy is effective against osteoporosis and has beneficial effects on lipid profiles, but is more expensive than oral treatment. Implants are the best method for administering testosterone to women and can be used in combination with oral, transdermal or implanted oestrogen. Implants are effective at preventing bone loss and have been shown to have a positive effect on libido. However strict control of oestradiol levels is required to prevent escalation.
Oestriol cream, pessaries and oestradiol 0.025mg tablets are administered vaginally whilst oestradiol rings can be used for local vaginal treatment only. Progestin intra-uterine contraceptive devices (IUCDs) are useful for women who are intolerant of progestin administered by other routes. They have been shown to be more effective than resection of
the endometrium in pre-menopausal women with bleeding problems.
Intranasal spray is now in clinical use. S21400 (Aerodiol) is a new aqueous nasal spray containing 17b-Oestradiol, conjugated to a novel polysaccharide excipient that allows for the aqueous solubility of the steroid hormone
4.
Benefits of HRT
HRT is recommended for a number of reasons: It can bring relief of the vasomotor symptoms as well as the depression, irritability, and sleep disturbances that often accompany the drop in oestrogen levels at menopause. Studies have shown that HRT has a beneficial impact on the psychological state of postmenopausal women, enhancing their sense of well being. Even in low doses it has been shown to relieve the effects of urogenital atrophy, and it may restore some of the collagen lost from the skin at menopause.
Alzheimer’s disease is a progressive degenerative brain disease that impairs memory, thinking and behaviour. The outstanding pathological feature of the disease is death and disappearance of nerve cells. This leads ultimately to extensive convolutional atrophy, especially in the frontal, parietal and medial temporal regions. Afflicted patients show signs of forgetfulness, word-finding difficulties, and problems performing complex tasks such as keeping accounts, cooking, and geographic disorientation. As the disease progresses, patients display an increase in language deterioration (such as empty speech) and difficulties doing even simple tasks.
Alzheimer’s disease (AD) occurs 2 to 3 times more often in women than in men. Several large longitudinal studies have indicated major reductions of AD risk in women who have ever used HRT, even if they only used it to treat symptoms during the menopausal transition. Studies are under way to determine if oestrogen can prevent or delay the onset of AD and enhance the effects of treatment. A significant association has been found between HRT and cognition, especially verbal memory. Oestrogen can minimise this risk. Various studies have indicated that the thinning of both dermal (inner) and epidermal (outer) skin, which occurs with age and after menopause, is reversed by HRT.
About 30% of a woman’s skin collagen, which is also associated with dermal thickness, is lost within the first 5 years after menopause. The loss of collagen and the decrease in production of glycosaminoglycans lead to reduced elasticity and, hence, increased extensibility, resulting in slackness and wrinkles. HRT has been shown to help prevent some of that loss5. The latter study indicated that HRT increases the water-holding capacity of skin; this may help protect against several forms of dermatoses. Finally, HRT may enhance levels of transforming growth factor beta 1, which positively affects the rate and quality of wound healing
5.
HRT increases bone density and reduces the rate of bone resorption and decreases the risk of osteoporotic fracture. Studies indicate that long-term HRT lowers the risk of fracture at numerous sites, including the wrist, hip, and vertebrae. The beneficial effect is seen in normal and osteoporotic women. Women with established disease may benefit from HRT to reduce fractures that result from further bone loss. The mode of action is to decrease the rate of bone resorption by inhibition of osteoclastic activity and corrects imbalance between resorption and bone formation at each bone-remodelling site.
Possible risks of HRT
The risks of HRT should always be interpreted in context. The lifetime risks of a fifty-year-old woman are shown in table 2. The various risks can be considered individually.
Breast Cancer
The fear of breast cancer is still an overwhelming issue with most women. The lifetime risk of breast cancer in the UK is 1 in 12. Data from prospective studies indicate that the use of HRT for five years or less does not increase the risk over that with never-use of HRT, but the risk increases with longer-term use. The International Cancer Research Federation (ICRF) data, published in 1997 was a large meta-analysis of the existing world literature
6. It allowed quantification of the risks more accurately, thereby enhancing patient counseling -table 3. The Women’s Health Initiative (WHI) data published last summer showed a slightly increased risk of breast cancer.
The Women’s Health Initiative (WHI) Study 7
This study published in JAMA in July 2002 amidst a blaze of publicity showed a slightly increased risk of breast cancer, which in fact hardly alters our perspective of this risk. In the UK, approach to management was largely unaffected since women had always been individually counseled and clinicians encouraged to construct an individual risk/benefit ratio for each case seen.
The whole trial consisted of 161,809 women aged 50-79. Recruitment was from 1993-1998. The primary outcome was designated as coronary heart disease and primary adverse outcome as invasive breast cancer.
The trial is a randomized controlled primary prevention trial planned for 8.5 years involving two arms, hysterectomised and unhysterectomised women. The latter group is randomized into
treatment group using 0.625mg conjugated equine oestrogens (CEO) and 2.5mg medroxy -progesterone acetate (MPA) and placebo group.
The continuous combined arm of the study was prematurely stopped based on health risks that exceeded health benefits over an average follow-up of 5.2 years. The result showed 29% increase in CHD (7 extra per 10,000 women), 41% increase in stroke (8 extra per 10,000 women,) 50% increase in venous thromboembolism (8 extra per 10,000 women) and breast cancer 26% increase (8 extra per 10,000 women). The latter risk statistically increased after 4 years, higher risk in those with prior use of HRT.
On the other hand, there was beneficial effect on colorectal cancer (6 fewer per 10,000 women) and osteoporotic fracture (5 fewer) with percent change of -37% and -33% respectively.
The conclusions from this trial are:
1. Continuous combined HRT should not be commenced for primary prevention of coronary heart disease.
2. Risk of breast cancer with the duration of use and risk of thromboembolism were confirmed. However there was no difference in overall mortality.
3. There was no class effect. Only one HRT regimen was tested, CEO and MPA and results do not necessarily apply to lower doses of these drugs or to other formulations of oral oestrogen and progestogens or to others administered by transdermal route.
HRT remains the most effective treatment for postmenopausal symptoms and similar trial involving 10,739 women using oestrogen (CEO) only has not been discontinued.
The European equivalent of WHI study is the Women’s International Study of Long Duration Oestrogen for Menopause (WISDOM) study to involve 16,000 women recruited from UK, Australia and New Zealand. It cost £10m to date and was due to be completed in 2016 recruited only 5,700 so far has also been discontinued by the MRC in October 2002 for scientific and practical reasons, following WHI study result publication.
Recent advances in HRT
Selective oE strogen Receptor Modulators (SERMs)
Engagement of the oestrogen receptors in breast and endometrium, leading to poor continuation of treatment due to vaginal bleeding and fear of breast cancer compromise the clinical utility of conventional HRT. The notion that it might be possible to create 'designer' oestrogens, possessing most or all of the good properties of oestrogens but few or none of the bad ones, has excited much interest and has inspired vigorous research efforts. This search for an ‘ideal’ oestrogen has led to the development of compounds with better pharmacological profiles than oestrogen. These are known as selective oestrogen-receptor modulators or SERMs (based on the American spelling of oestrogen). The ideal SERM would be effective in the treatment of osteoporosis, ischaemic heart disease and Alzheimer's disease, without adverse effects on the breast or uterus in terms of increasing cancer risk, and with no risk of inducing venous thromboembolism. The first compound in this new class of SERMs to gain approval for clinical use is raloxifene, which meets many of desirable criteria.
The advantages of SERMs include being non-hormonal, produce endometrial and breast protection and prevent osteoporosis. The disadvantage is the fact that they are not effective in reducing vasomotor symptoms and may in fact induce it initially.
Tibolone
Tibolone is a synthetic steroid that is structurally related to the 19-norethisterone derivative, such as norethynodrel and norethisterone. It has four features, which make it different from conventional HRT. These are
It is synthetic molecule
It has different activities at different tissues
It is a non-bleeding HRT
It has androgenic activity
As it is partly androgenic, progestogenic, and oestrogenic, it does not stimulate the endometrium to bleed in women at least 1 year past menopause. It apparently protects against osteoporosis, but there is no evidence of cardio- protection.
Intravaginal Ring
Until recently, intravaginal rings could not be prescribed for treating vasomotor symptoms, because they release insufficient oestrogen and could only be used to treat local symptoms. Menoring® is a novel intravaginal ring releasing estradiol acetate, which is rapidly hydrolysed to estradiol. Menoring delivers estradiol acetate at a rate equivalent to 50 _g per day; sufficient estradiol serum concentrations to achieve vasomotor symptom control are maintained for a 3-month therapy period.
In a recent double-blind, randomised, placebo-controlled trial, Menoring was observed to reduce vasomotor symptoms for 3 months with the same level of efficacy as 1 mg oral estradiol. Adverse-event rates were similar, and Menoring was found to be well tolerated by and highly acceptable to the women in the trial.
Conclusion
In conclusion, the number of postmenopausal women is growing globally. Initial use of and compliance with – HRT is low. Non-compliance is affected by lack of patient education, lack of education and communication by physician, difficulty with use of medication, and patient dissatisfaction with the products. Health professionals should adopt ‘best practice.’ This comprises clearly informing patients of the risks and benefits of treatment to enable informed choice; keeping good medical records and reviewing treatment at regular intervals. Many existing forms of HRT offer these benefits, and new forms are being developed continuously that will offer enhanced acceptability and, thus, increased compliance, resulting in more widespread benefit.
References
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