14 Menopause and osteoporosis
Menopause by definition is the time of cessation of menstruation. Women are said to be postmenopausal after 1 year of amenorrhoea. This occurs on average at 51.4 years1; in smokers, those with a hysterectomy and chronic disease, however, it occurs earlier.2 The perimenopause refers to those years leading up to and including the menopause. Premature menopause (that which occurs before the age of 40) occurs in up to 2.5% of women.3 It is usually iatrogenic, coming about as a result of bilateral oophorectomy, radiation or chemotherapy.
The current nomenclature used to describe stages of reproductive aging4 is described in Box 14.1 and shown in Figure 14.1.
BOX 14.1 Staging reproductive ageing
(short version of STRAW4 definitions)
From just after menarche (stage –5) cycles can be irregular for several years, but should then occur every 21 to 35 days for a number of years (stages –4 and –3). In the early menopausal transition (stage 2), the menstrual cycle remains regular but the length changes by 7 days or more (regular cycles are now every 24 instead of 31 days). The late menopausal transition (stage +1) is characterised by two or more skipped menstrual cycles and at least one intermenstrual interval of 60 days or more.4
Follicle-stimulating hormone (FSH) levels gradually increase throughout the menopausal transition, but the variability is high and an FSH level of 40 IU/L or more is not necessarily as predictive of the late menopausal transition as amenorrhoea of 60 days or more.5
The menopause commences when there are only a few thousand primordial follicles remaining in the ovary, an insufficient number to stimulate cyclical activity. Oestrogen levels fall in the course of about 5 years and this has a positive feedback on the pituitary, increasing the production of FSH and luteinising hormone (LH). Eventually the ovary produces only androstenedione (also produced by the adrenal glands), which is converted by peripheral fat into the weak oestrogen, oestrone.
The dominant feature of the early menopausal transition is cycle length variability of 7 days or more, with cycle irregularity marking for most women the approach of their final menstrual period. The time when a woman is most likely to experience menopausal symptoms is during the late menopausal transition when there is amenorrhoea of 60 days or more. An indicator of the approach of menopause (less than 20 cycles remaining) is a rise in cycle length to 42 days or greater.6 Bleeding patterns are most indicative sign of menopausal stage, not necessarily hot flushes.5
In women still experiencing menstrual bleeding, FSH levels measured on day 2 or day 3 after the onset of bleeding are considered increased when they exceed 10–12 IU/L, which is an indication of diminished ovarian response.7 FSH levels over 40 IU/L are indicative of the late menopausal transition.5 However, studies show that a single FSH determination alone poorly predicts menopausal status and cannot be used to predict final menstrual period.8 It has been common practice to consider ovarian failure highly likely when two measurements of FSH >30 IU/L are obtained at least 1 or 2 months apart. FSH should be measured when the woman is not taking either HT or hormonal contraception.
Despite the fact that all women pass through the menopause if they live long enough, the symptoms directly attributable to the menopausal transition are difficult to quantify because of confounding factors such as age, social class and education. One study9 found that vasomotor symptoms (hot flushes and night sweats), difficulty falling asleep, decreased sexual interest and vaginal dryness are all associated with menopause after controlling for the effects of age. Sexual satisfaction, however, was not related to menopausal status and symptoms often associated with menopause, such as cognitive difficulties, depression and irritability, were more strongly associated with social class and employment. Dennerstein et al10 found that from early to late perimenopause increasing numbers of women reported five or more symptoms (+14%), hot flushes (+27%), night sweats (+17%) and vaginal dryness (+17%). Breast soreness/tenderness decreased with the menopausal transition (–21%). Figure 14.2 (p 258) illustrates the association between hormone status and symptoms in the women they studied. A list of the common signs and symptoms associated with menopause is given in Box 14.2 (p 259).
(From Dennerstein et al10)
Another important point to note about menopausal symptoms is that, while a large proportion of women may experience menopausal symptoms, the proportion of women who experience the symptom as a problem is much less. For example, a British study11 found that 57% of women experienced hot flushes but only 22% said they were a problem, 66% reported sleep problems but only 33% said this was a problem. Interestingly, only 10% of women seek help from healthcare providers.12
For most women, symptoms are transient, with 30–50% of women improving within several months. Hot flushes usually last for 4–5 years and in some women may take longer to resolve. A recent meta-analysis has shown peak vasomotor symptom prevalence at 1 year after the final menstrual period, with 50% of women reporting symptoms after 4 years and 10% reporting symptoms as long as 12 years later13 (Fig 14.3).
Osteoporosis, urogenital atrophy, cardiovascular disease and stroke all increase in incidence in women after menopause. While twice as many women as men suffer from Alzheimer’s disease (the most common cause of dementia among the elderly), this may in part be due to longer life expectancy.14 Interestingly, limited clinical trial evidence suggests that HT does not improve symptoms or slow disease progression in Alzheimer’s disease and that it may actually increase dementia risk when initiated after age 64 years.15,16,17 Observational studies suggest that HT used by younger women around the time of menopause is associated with lower risk of Alzheimer’s disease. However, further research is needed to determine whether there might exist an early window during which HT effects on Alzheimer’s disease risk are beneficial rather than harmful.
First, it is important always to examine these patients, as their symptoms may in fact be due to a condition other than atrophic vaginitis. Treatment of atrophic vaginitis involves oestrogen replacement, either systemically or locally. An alternative if symptoms are not severe is the use of lubricant to assist sexual activity.
Oestrogen can be delivered transvaginally either through the use of creams, pessaries or a hormone-releasing ring. Initially, creams and pessaries should be used daily for about 2 weeks, but once symptoms improve the dosage can be reduced to once or twice a week. The advantages of creams and pessaries are that they are effective in treating symptoms and have fewer systemic effects, thereby lessening the risk of endometrial carcinoma. However, they involve vaginal manipulation and the twice-weekly dosage may lead to decrease of patient compliance. The transvaginal ring offers an alternative, as the ring can remain in the vagina and deliver a constant low dose of hormones. It can be easily removed and reinserted and can still be worn during sex.
CASE STUDY: ‘Should I take hormones if I have a family history of breast cancer?’
Marion was a 60-year-old woman who had been taking HT oestrogen (0.625 mg/day) for the last 20 years since having a bilateral oophorectomy and hysterectomy at the age of 40 for refractory endometriosis. She had been very happy taking the oestrogen replacement therapy (ET) all this time and had only once tried to come off it 10 years ago by tapering the dose slowly. At that time, however, she had had a severe recurrence of vasomotor symptoms with hot flushes occurring sometimes hourly and terrible night sweats. She had therefore recommenced her ET and not thought much more about it till she heard some press reports about the relationship between HT and breast cancer. Marion’s family history was of some concern. While there was no cardiovascular disease in the family, her sister had developed breast cancer in her late 30s. Marion had no risk factors for osteoporosis.
Today, she presented wanting to discontinue her ET. After taking a history, an examination was undertaken, which was normal. Marion’s case highlights some of the complexities of giving advice about ET or HT use. Given her family history, she is right to be cautious, but the oestrogen-only arm of the Women’s Health Initiative (WHI) study found no increased risk of breast cancer after 7 years of use compared to the oestrogen/progestogen arm of the study.18 The only two reasons to be on HT/ET are for the treatment of menopausal symptoms and the prevention of osteoporosis. While Marion is not at increased risk of the latter, some women continue to have hot flushes for many years after the menopause. In about 1 in 10 women who discontinue hormone therapy, the recurrence of menopausal symptoms is severe and persistent.19 Marion could try again to come off the ET; if this were not tolerated, other treatments for vasomotor symptoms could be offered such as a selective serotonin reuptake inhibitor (SSRI) (e.g. venlafaxine or paroxetine) or clonidine.
by pharmaceutical companies to prescribe HT as both a therapeutic and preventive agent, as the potential market for HT is enormous (all women over 45).
Despite this, it is interesting to note that less than 20% of population samples of postmenopausal women in the USA have ever had HT prescribed. In addition, less than 40% of women who commence HT are still using it 1 year later,20 and after 3 years that percentage drops further to 25%.21 The reasons for this poor compliance may be related to the side effects that women experience when they use HT, such as bloating, breast tenderness and withdrawal bleeds, or to the perceived risks, especially breast cancer.
Up until 2002, when the Women’s Health Initiative (WHI) study results were publicised,22 use of HT in postmenopausal women varied from <10% in the UK, to 30–40% in the US. Australia was slightly less than the US with 28% of postmenopausal women taking HT and 12–22% throughout Europe.23 In Australia, prescriptions for oestrogen/medroxyprogesterone acetate fixed-dose preparations dropped by 55.4% in the following 12 months; uptake of HT preparations decreased by about 30% in the same period and continued to fall at a lower rate following publication of the oestrogen-only (9%) and memory arms of the WHI (4%).24
What advice should general practitioners give patients seeking information about the pros and cons of HT?
In recent years, controversy has raged over the indications for HT and the risks and benefits of using HT in peri- and postmenopausal women. Much of this controversy stems from the undue fears and confusion that have resulted from the misinterpretation of clinical studies and the overrepresentation of risks arising from these studies,25 in particular:
In counselling women about HT, it is essential that GPs are skilled in representing risk accurately (Box 14.3). Common non-cancer risks and benefits are outlined in Table 14.1.
From North America Menopause society18)
|Consequences||Number of cases|
|Benefits (events prevented)|
|Harms (events caused)|
(From Nelson et al82)
The following is a summary of the NAMS position statement on HT18 and represents current guidelines on HT use.
HT should be used only after an individual assessment of the benefits and risks for that individual woman and confirmation of her treatment goals. This assessment will necessarily change with her age and the severity of her symptoms, but should always take into account her:
Dyspareunia (painful intercourse) that is caused by vaginal atrophy can be overcome by systemic ET/oestrogen & progestogen therapy (EPT) or local ET. However, these products are not recommended as the sole treatment for other problems of sexual functioning such as diminished libido.
In the presence of vaginal atrophy, local ET may benefit urge incontinence where there are symptoms of frequency and urgency in the absence of painful urination. If the latter is present, suspect a urinary tract infection and treat accordingly. Local ET may also reduce recurrent urinary tract infection.
HT reduces postmenopausal osteoporotic fractures, including hip fractures, even in women without osteoporosis. Extended use of HT is an option in women who have established reduction in bone mass regardless of menopausal symptoms, for prevention of further bone loss and/or reduction in osteoporotic fracture when alternate therapies are not appropriate or cause side effects, or when the benefit–risk ratio of the extended use of alternate therapies is unknown.
The variation noted between observational studies and randomised controlled trials examining the effects of HT on cardiovascular outcome is now understood to be due to the timing of initiation of HT in relation to age and proximity to menopause. Women who reach menopause at the typical age and who start HT within no more than 5 years of menopause are likely to gain some CHD protection, but, starting HT 10 or more years beyond menopause may increase risk. The absolute risks are rare, but nevertheless exist.
Fortunately, virtually all symptomatic women are in close proximity to menopause, so timing is not a real point of debate. The only reason for beginning systemic HT a long time after menopause would be for protection against osteoporosis, and in that context topics for discussion include risk, benefit and alternative bone-sparing therapies.
Another issue to consider, however, is the duration of therapy. For women in close proximity to menopause, the longer they remain on HT, the greater the protection. On the other hand, remaining on EPT for a long time adversely affects breast cancer risk.
While the incidence of haemorrhagic stroke is not an issue in relation to HT, the WHI EPT and ET trials demonstrated an increased risk of ischaemic stroke of 8 additional strokes per 10,000 women per year of EPT use and 11 additional strokes per 10,000 women per year of ET use when data from all the age groups in the entire cohort were analysed. Younger women in the WHI (aged 50–59 years at study entry) had no significant increase in risk of stroke. Even though the risk of stroke in older women is rare, this is a serious event, and women with risk factors for cardiovascular disease should usually not be considered for HT. Nor can HT be considered for younger women for stroke prevention.
The risk of VTE for all women starting HT is rare, but present. Growing evidence suggests that women with a prior history of VTE or women who possess factor V Leiden are at increased risk of VTE with HT use. Observational studies suggest that non-oral oestrogen (transdermal) use may be safer, as may lower doses of oral ET; however, there is no evidence as yet from randomised trials to support this.
DM is not a contraindication for HT. Limited evidence suggests that HT may actually reduce the incidence of DM in the order of 15 per 10,000 women per year of therapy, but this is not a reason in itself to prescribe. When prescribing oestrogen for a woman with DM, non-oral preparations may be preferred because of their reduced impact on raising triglycerides.
Unopposed oestrogen significantly increases the incidence of endometrial cancer in women with an intact uterus. This risk increases with duration of use and persists for some years after discontinuation. Women must always receive progestogen when being prescribed oestrogen with an intact uterus.
EPT use beyond 5 years is associated with increased breast cancer risk in the order of 4–6 additional invasive cancers per 10,000 women per year. It is unclear whether the risk differs between continuous and sequential use of progestogen. This absolute risk falls into the rare category. This risk needs careful explanation to women, and the decision to assume the risk is a personal one.
Evidence also suggests that EPT increases breast-cell proliferation, breast pain and mammographic density, negatively affecting the diagnostic interpretation of mammograms, which could lead to further, costly diagnostic tests, including biopsy.
Table 14.2 describes cancer risks and benefits associated with HT and may be helpful when counselling patients. Box 14.4 (p 264) contains the current recommendations of the National Breast and Ovarian Cancer Centre (NBOCC) regarding breast cancer risks and hormone therapy.28
While ET may enhance the sense of wellbeing, for postmenopausal women without clinical depression evidence is mixed concerning the effects of HT on mood. Progestogens may actually induce symptoms similar to premenstrual syndrome. There is no evidence to justify use of HT as an antidepressant.
HT cannot be recommended at any age for the sole purpose of preventing cognitive ageing or dementia. The WHIMS study16 showed an increase in dementia when HT was initiated in women over 65. Available data do not currently address whether HT used soon after the onset of menopause increases or decreases later dementia risk.29
Women <40 years of age experiencing premature menopause have a lower risk of breast cancer but an earlier risk of onset of osteoporosis and cardiovascular disease. There is inadequate data concerning this patient group in relation to HT. Existing data concerning women who reach menopause at the average age of 51 years should not be extrapolated to this younger patient group. However, the risk attributable to HT use by the younger women with premature menopause is likely to be smaller and the benefits potentially greater. Limited evidence favours these women being prescribed HT at least up to the typical age of menopause (51 years). Thereafter, the decision becomes the same as for all other women.
Oestrogens and progestogens share some common features and effects, as well as potentially different properties. Without randomised controlled trial (RCT) evidence, results obtained in clinical trials from one agent are likely to be generalised to others, even though there are likely to be differences within each family, based on factors such as relative potency of the compound, androgenicity, glucocorticoid effects, bioavailability and administration route.
Progestogen is indicated to safeguard the endometrium. Given the evidence suggesting that progestogen added to oestrogen increases breast cancer risk, cardiovascular risk and adverse symptoms, it would obviously be best to reduce exposure to the least amount necessary in order to protect the endometrium.
As with all medications, HT should be commenced using the lowest effective dose of oestrogen and corresponding low dose of progestogen to counter the adverse effects of systemic oestrogen on the uterus. Lower doses are better tolerated and may have a better benefit-risk profile than standard doses but have not been tested in long-term trials.
Observational evidence suggests that transdermal ET may be associated with a lower risk of DVT, but there is no evidence from RCTs. Local ET is preferred when treating solely vaginal symptoms. Systemic progestogen is required for endometrial protection from unopposed ET. Topical progestogen is not recommended. With the exceptions referred to above, the route of administration and selection of pill, patch, cream, gel, spray, vaginal tablet or ring is really a personal preference.
Research findings are inadequate to favour one regimen of dosing over another. There is insufficient evidence regarding endometrial safety to recommend as an alternative to standard EPT regimens the off-label use of: long-cycle regimens (14 days of progestogen every 2–6 months), vaginal administration of progestogen, the Mirena or low-dose oestrogen without progestogen. If any of these regimens are used, close surveillance is warranted. For a definition of the different EPT regimens, see Table 14.3.
|Cyclic||Day 1–25||Last 10–14 days of ET cycle|
|Cyclic combined||Day 1–25||Day 1–25|
|Continuous—sequential||Daily||10–14 days every month|
|Long cycle||Daily||14 days every 2–6 months|
|Continuous—pulsed||Daily||Repeated cycles of 3 days on and 3 days off|
(From North American Menopause Society18)
When started in close proximity to menopause, the only long-term risk (beyond 5 years) might be an increased risk of breast cancer. Women who have reasons to remain on HT must have regular and appropriate follow-up, including mammography. As stated by the North American Menopause Spciety (NAMS),18 provided that a woman is on the lowest effective dose, is well aware of the potential benefits and risks and has clinical supervision, extending HT use for individual treatment goals is acceptable under some circumstances for: