Management of menopause
Dr Safeera Hussainy
Menopause marks the end of a woman’s reproductive life, where eggs are no longer released by the ovary and oestrogen and progesterone production ceases. The word "menopause" refers to the last or final menstrual period (FMP) a woman experiences. Most women become menopausal naturally between 45 and 55 years, with the average age of onset at around 50 years. North American Menopause Society terminology explains the timing of menopause in a woman’s life and whether it is early, natural or induced:
Early menopause – natural or induced menopause that occurs well before the average age of natural menopause – at or under age 45.
Early postmenopause – the five-year time period after the FMP resulting from natural or induced menopause.
Induced menopause – permanent cessation of menstruation after bilateral oophorectomy (i.e. surgical menopause) or iatrogenic ablation of ovarian function (e.g. by chemotherapy or pelvic radiation therapy).
Natural/spontaneous menopause – the FMP, confirmed after 12 consecutive months of amenorrhoea with no obvious pathologic cause.
Perimenopause/menopause transition – the span of time when menstrual cycle and endocrine changes occur a few years before and 12 months after a FMP resulting from natural menopause.
Premature menopause – menopause reached at or under age 40, whether natural or induced.
Premature ovarian insufficiency – loss of ovarian function before age 40, leading to permanent or transient amenorrhoea (often described as premature ovarian insufficiency or premature menopause).
Contraception during perimenopause
The risk of pregnancy after the age of 50 is estimated to be less than one per cent but though less likely to occur, pregnancy is still possible and the pattern of fertility is less reliable, as women may ovulate twice in a cycle and up to three months before their FMP. Pharmacists should therefore advise women with perimenopause to keep using contraception for two years after their FMP if they experience menopause under the age of 50, and for one year after the FMP if aged 50 years or more.
As health risks associated with the oral contraceptive pill (OCP) increase with age, women taking the OCP should cease using it by the age of 51 and switch to a barrier method of contraception to minimise the risk of pregnancy.
Menopausal symptoms
Physical symptoms that women experience during menopause are due to the fluctuating and declining levels of the ovarian hormones, primarily oestrogen. Symptoms commonly reported by peri- and post-menopausal women include:
• Vasomotor – hot flushes, night sweats.
• Vaginal/sexual function – dryness, loss of libido, dyspareunia (painful sexual intercourse), atrophic vaginitis.
• Altered urinary health – urge incontinence, recurrent urinary tract infections.
• Weight gain – body mass index (BMI) peaks between ages 50 and 59; however, other factors may also contribute such as a decrease in energy expenditure and an increase in energy uptake coupled with a decrease in metabolic rate.
• Osteoporosis, aches and pains.
Approximately 60 per cent of women have mild menopausal symptoms for around five to eight years. Twenty percent of women have no symptoms at all while another 20 per cent are severely affected, with symptoms continuing into their 60s or later.
These physical symptoms can affect a woman’s quality of life and exacerbate the psychological symptoms of menopause such as mood changes, anxiety, forgetfulness, and difficulty concentrating or making decisions. Lower oestrogen levels are associated with lower levels of serotonin, a chemical that regulates mood, emotions and sleep. However, depression is not more common at menopause than at other stages of life.
Diagnosis
Doctors diagnose menopause based on a woman’s symptoms and changes in menstruation. When a woman has had her ovaries removed surgically (induced menopause) the diagnosis is obvious.
A symptom score sheet (available at www.menopause.org.au – information sheet number 26 under ‘consumers’) is a useful way to determine symptom severity on a scale of zero (none) to three (severe). This diagnostic tool categorises 20 symptoms into four groups - vasomotor, psychological, locomotor and urogenital – but not all of the symptoms listed are necessarily due to oestrogen deficiency.
A score of 15 or higher usually indicates an oestrogen deficiency intrusive enough to require treatment. Scores of 20–25 are common in symptomatic women, but with adequate treatment the score will fall to 10 or less in three to six months.
The score sheet should be used every three months or so to reassess the woman’s symptoms to determine any hormone replacement treatment (HRT) effectiveness. However, women are very variable in their tolerance of discomfort, with some tolerating quite severe symptoms before they will even consider taking HRT.
How risky is HRT?
Many women have abandoned HRT following concern over the findings of the Women’s Health Initiative (WHI) and Million Women studies that showed increased risk of cancers and heart disease in women taking HRT. The absolute risks (and benefits) of HRT reported in the WHI trial are shown in Table 1. These risks cannot be generalised to all menopausal women because:
1. The trial was conducted with postmenopausal women only.
2. The study only trialled one formulation of oestrogen (conjugated equine, 0.625mg daily), either alone or with one progestin (medroxyprogesterone acetate 2.5mg daily), and only one route of administration – oral.
3. Older women were studied (mean age 63 years), mostly more than 10 years beyond menopause and with more risk factors than women in Australia and younger women who typically use HRT, and largely without menopause-related symptoms.
Understanding risk
It is important for pharmacists to understand the difference between absolute and relative risk in order to interpret the findings of such studies and provide appropriate recommendations to women.
While risk means the chance of an event (disease/outcome) occurring, absolute risk is the actual or true risk of an event occurring over a time period, e.g. a patient has a one in 10 risk of developing stroke, which can also be expressed as a 10 per cent risk, or a 0.1 risk.
Relative risk is used to compare the risk in two different groups of people. All sorts of groups are compared in medical research to see if belonging to a group increases or decreases the risk of developing certain diseases. For example, smoker and non-smoker groups have been compared, and research has shown that smokers have a higher risk (2.5 times more) of developing heart disease compared to (relative to) non-smokers.
Most studies report relative risk or relative risk reduction, rather than absolute risk or absolute risk reduction, because the relative risk calculations tend to overestimate the extent that a treatment reduces the risk of an event. Absolute risk calculations more accurately illustrate how the treatment works.
This concept is illustrated by the following example:
If women have a two in 20 (10 per cent or 0.1) risk of developing a certain disease by the age of 60 years, and research shows that a new treatment reduces the relative risk of developing this disease by 50 per cent (the relative risk reduction), as 50 per cent of two is one, by having the new treatment the absolute risk of developing the disease is reduced from two in 20, to one in 20 (five per cent or 0.05).
Managing the risk
For some women using HRT any extra risk of illness will be unacceptable, but others may consider that the benefits of treatment outweigh the risks. Some questions women can ask themselves when considering HRT are:
How much do my symptoms affect my quality of life?
What could happen if I did nothing at all?
What are my treatment choices?
What are their risks and benefits? How reliable is the evidence for these risks and benefits? Are the findings of these studies relevant to me and my treatment?
Have I now got enough information to make a decision?
Issues that health professionals prescribing HRT should consider include:
Randomised controlled trials (RCTs) provide the highest level evidence, and evidence of association between HRT and disease from observational trials does not prove causation.
Absolute risk as well as relative risk should be considered when weighing risks and benefits for individual women.
Tailoring HRT to the individual can maximise its benefits and minimise its risks.
Re-analysis of the WHI trial findings on HRT and breast cancer show no increase in breast cancer for oestrogen-only therapy and no significant increase with combined therapy in the first seven years of use in women who had previously not taken HRT.
The International Menopause Society states that for women aged 50 to 59 years HRT remains first-line treatment for menopausal symptoms, and it reduces hot flushes by up to 90 per cent.
The benefit–risk ratio of HRT for an individual woman continually changes with her age and her menopause-related symptoms. Risk factors are related to a woman’s absolute risk of getting the disease to start with, her age, age at menopause, cause of menopause, time since menopause, severity of menopause, and prior use of any hormone, including type, route of administration dose, and medical conditions that emerged during treatment.
Menopause – A management algorithm by The Jean Hailes Foundation for women’s health (<www.managingmenopause.org.au/health-professionals/menopause-management-algorithm>) takes these risk factors into consideration in its treatment recommendations, and is a
useful tool for pharmacists to refer to. For interest, a combination of an oestrogen with an oestrogen agonist/antagonist is under investigation and may become an alternative to progestogen. Pharmacists should be aware that women considering HRT are urged to have a pre-treatment breast check and mammogram and that the decision to use HRT must be reviewed annually by the woman in consultation with her doctor.
Non-hormonal treatments
Excluding lifestyle changes, most non-hormonal treatments prescribed by doctors for menopausal symptoms are "off-label" and target vasomotor symptoms. Only clonidine has been approved for hot flushes. A summary of these is presented in Table 2.
Case study
Mrs Helen Kyriakos asks you about red clover (Promensil®) for menopausal symptoms – whether it is effective, and if it has any side effects. Helen, a 56-year-old woman with perimenopause, does not desire HRT. She has experienced vasomotor symptoms (hot flushes and light-headed feelings) for three months. She likes to walk and does Pilates classes at the local gym around three times a week. Helen’s bone density has been tested and is normal. She has gastro-oesophageal reflux disease and hyperlipidaemia, for which she takes pantoprozole 20mg daily and simvastatin 40mg daily.
Actions
You decide to do a quick search in The Cochrane Library for a RCT on red clover and/or other phytoestrogens. Typing ‘phytoestrogens’ in the search field yields the following results: two ‘Cochrane Reviews’, nine ‘Other Reviews’, 203 ‘Clinical Trials’, and one ‘Method Study’. Since you know that, when done well, systematic reviews of RCTs are the best source of evidence because they pool the results of various RCTs to answer one research question, you look first at the two Cochrane Reviews.
You peruse the abstract of one of the Cochrane Reviews: Lethaby A, Marjoribanks J, Kronenberg F, Roberts H, John E, Brown J. Phytoestrogens for vasomotor menopausal symptoms.
This review looked at the efficacy, safety and acceptability of phytoestogens for reducing hot flushes and night sweats in postmenopausal women. Thirty RCTs were assessed, and the findings from five trials on red clover extract were combined (that assessed daily frequency of hot flushes) and it was found that there was no statistically significant difference overall in the frequency of hot flushes between Promensil and placebo (weighted mean difference [WMD] = -0.6, 95 per cent Confidence Interval [CI] -1.8 to 0.6). The WMD means that on average, women who took Promensil experienced 0.6 fewer hot flushes on a daily basis than women who took placebo. The 95 per cent CI tells us that if the same trials were repeated 100 times, on 95 of those 100 occasions women who took Promensil would experience anywhere from 1.8 fewer hot flushes to 0.6 more hot flushes, daily. As this range (-1.8 to 0.6) includes 1.0, the point of no difference, the result is not statistically significant. Most trials had a strong placebo effect with a reduction in hot-flush frequency ranging from one per cent to 59 per cent with placebo. There was no evidence of harm with short-term use.
Wanting to know more about potential side effects, you then look at the nine other reviews and find the following relevant article:
Cochrane Database of Systematic Reviews 2007, Issue 4. Art. No.: CD001395. DOI: 10.102/14651858.CD001395.pub3. Temfer CB, Froese G, Heinze G, Bentz EK, Hefler LA, Huber JC. Side effects of phytoestrogens: a meta-analysis of randomized trials. American Journal of Medicine. 2009;122(10):939-946.e9. This review concluded that phytoestrogen supplementation has a safe side-effect profile in women, with moderately increased rates of gastrointestinal side effects when compared with placebo or not treatment. Supplementation over a period of two years was recommended; however, because the authors did not state how they assessed the validity of the 92 RCTs included in their review, the reliability of the findings is limited.
Recommendations
You explain to Helen that what you are about to recommend is based on the best available and current evidence from a high quality database.
As Helen is experiencing perimenopause, the findings of the Cochrane Systematic Review cannot be applied to her as the RCTs included in this review were conducted with postmenopausal women only.
However, there is no evidence for treating vasomotor symptoms with red clover in postmenopausal women. You explain this by saying that red clover was compared to dummy medication in five experiments, and on average women who took red clover experienced 0.6 fewer hot flushes on a daily basis than women who took the dummy medication. Though, this doesn’t seem like a big difference given that women typically have two to three hot flushes a day.
Informing Helen that there is no evidence to indicate that red clover use is harmful (no significant increases in rates of vaginal bleeding, endometrial cancer, breast cancer) is also important, and that at most, it may cause gastrointestinal side effects like abdominal pain. The decision to use red clover is ultimately hers and, before deciding, she should ask herself questions such as the impact that menopause is having on her quality of life. To help her with this you print a symptom score sheet and ask her to visit you or her doctor after doing the assessment to discuss further options (e.g. venlafaxine, gabapentin, clonidine) as listed in Menopause – A management algorithm. Recommending some lifestyle changes is also wise, like commencing aerobic exercise classes (e.g. weights) in the gym. Finally, recommend that Helen uses a barrier method of contraception if she is sexually active and refer her to the Australasian Menopausal Society website for information sheets that clearly explain risk associated with HRT and other menopause management options.
Conclusions
Understanding risk and other menopause terminology is important when reading literature and providing advice to women on management options in menopause. Women, pharmacists and other health professionals can use the various available tools, algorithms and information sheets that discuss the evidence behind treatment options and help to simplify management decisions.
Pharmacists can learn the valuable skill of doing fast yet effective searches in databases such as Cochrane to assist with patient care.
References available on request.
Dr Safeera Hussainy is a lecturer in the Centre for Medicine Use and Safety at the Faculty of Pharmacy and Pharmaceutical Sciences, Monash University.
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