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Gail A Greendale, Nancy P Lee, Edgar R Arriola Menopause is diagnosed after 12 months of amenorrhoea resulting from the permanent cessation of ovarian function.
The mean age at menopause is 51 years. The perimenopause, a time of changing ovarian function, precedes the finalmenses by several years. The physiology and clinical manifestations of this transition to menopause are not wellunderstood; however, some symptoms, such as hot flashes, certainly begin in the perimenopause. Causalassociations between menopause and several symptoms and diseases are proposed. The evidence for theseassociations varies and is reviewed. Hormone replacement therapy can be directed at symptom relief or at preventionor treatment of chronic diseases. Doses and routes of hormone replacement therapy vary by indication. Complicationsof hormone replacment therapy depend on the regimen used. Knowing the expected vaginal bleeding pattern for eachhormone replacement therapy regimen is important, since unexpected bleeding may signal endometrial hyperplasia.
Postmenopausal hormone therapy is a complex intervention that produces positive and negative specific healtheffects. Overall, based on observational studies, postmenopausal women who use hormones have a 30–50% lower all-cause mortality rate than those who do not use hormones. It is important to recognise that the value that individualwomen place on various health outcomes associated with hormone replacement therapy may differ. Thus, thedecision to use hormone replacement therapy should be made jointly by each woman and her health-care provider,after careful consideration of possible benefits, risks, and her personal preferences.
menstrual cycle that may occur in perimenopause, some women have classic postmenopausal symptoms, for M e n o p a u s e—The menopause is the permanent cessation example, hot flashes (we do not use the term flushes of menstruation due to loss of ovarian follicular function.
because not all women flush as part of their hot flash Clinically, menopause is diagnosed after 12 months of experience). Furthermore, indicators of risk for chronic amenorrhoea, so the time of the final menses is disease, such as lipid profiles, may become less favourable during the perimenopause. Therefore, we describe perimenopause and postmenopausal presentations of P e r i m e n o p a u s e—Although a discrete point in time (the symptoms and changes in risk factors for chronic disease.
final menses) is designated as the beginning of thepostmenopausal period, the transition to postmenopausal status is not abrupt. Current theory holds that theperimenopause, a period of changing ovarian function, precedes the final menses by between 2 and 8 years. The The unequivocal, temporal relation between hot flashes physiology and clinical presentations of perimenopause and the menopause transition justifies this designation as are not well understood, but one model proposes that it a definite perimenopausal and postmenopausal symptom.
occurs in stages. Early perimenopause occurs when the Hot flashes are a sensation of warmth, frequently neurohormonal systems that govern ovulation begin to accompanied by skin flushing and perspiration. A chill may follow as core body temperature drops. Hot flashes vary: they can be occasional or frequent, or last from perimenopause may be characterised by irregular seconds to an hour, and are characterised by mild warmth menstrual cycles, particularly by short cycles intermingled to profuse sweating. Some women perceive hot flashes as with longer time between menstruation.
a minor nuisance, whereas in other women this symptom During perimenopause, concentrations of follicle- disrupts work, sleep, or daily activities.
stimulating hormone (FSH) may be raised to the Hot flashes commonly start during perimenopause.
postmenopause range during some cycles, but return to McKinlay and colleagues2 reported that 58% of women premenopausal concentrations during subsequent cycles.
i n their study had hot flashes in the 2 years around Gonadotropins and oestrogen may also be high during the t h e i r final menses. The proportion of women who report transition to menopause.1 Thus, high concentrations of hot flashes may be as great as 80% in western countries,3 FSH should not be used to diagnose menopause in but as low as 10% in some East Asian countries.4 T h e menstruating women. In addition to such variability in causes of this variation are not known. Hot flashesdiminish spontaneously as time from menopause Although there is some evidence that hot flashes Division of Geriatrics, School of Medicine (Prof G A Greendale MD) r e s u l t in adverse biological consequences, for example, and Department of Pharmaceutical Services (N P Lee, E R Arriola),Center for Health Sciences, University of California, Los Angeles, h y p e r t r i g l y c e r i d a e m i a ,5 flashes and negative metabolic profiles requires furtherstudy. The major reason to treat hot flashes continues to Correspondence to: Dr Gail A Greendale, Division of Geriatrics,University of California, Los Angeles, 2339 PVUB, Box 951687, be their effect on the woman’s comfort and ability to THE LANCET • Vol 353 • February 13, 1999 Panel 1: Vaginal oestrogen preparations and indices to assess safety Oestradiol tablet (Vagifem) Each table contains 25 ug oestradiol 1 tablet twice weekly Low serum concentrations of E1 and E2.
Progestagin challenge, endometrial ultrasoundand in some cases endometrial biopsy.
Progestagin challenge, endometrial ultrasound and in some cases endometrial biopsy.
No change in SHBG or other liver markers.
0·5 mg oestriol twice weekly Low serum concentrations of E1 and E2. No change in SHBG or other liver markers.
Endometrial biopsy.
E1=oestrine; E2=17␤-oestradiol; E3=oestriol. SHBG=sex hormone binding globulin.
*Although E1 and E2 concentrations are unaffected by low-dose oestriol, E3 concentrations increase.
Treatment of hot flashes—Oestrogens diminish hot genitourinary response to usual systemic oestrogen flashes, and there is a dose-dependent relation between regimens, vaginal therapy may be added rather than an oestrogen dose and suppression of hot flashes. To achieve increase of the systemic dose. Some examples of vaginally satisfactory control of this symptom, women with severe administered oestrogens are shown in panel 1. The or frequent flashes may require higher than standard availability of the vaginal oestrogen preparations varies by oestrogen doses (see menopause treatments). For example, in a woman who continues to have hot flashesafter the start of 0·625 mg conjugated equine oestrogens daily, the dose can be increased to 1·25 daily. Higher than Although there is no definite causal link between urinary standard doses of oestrogen should be reduced if possible tract infection and menopause, physiological changes that to keep to a minimum potential long-term risks.
occur after the menopause may lead to increased Alternatives to oestrogen for treatment of hot flashes susceptibility to such infection. These changes include include methyldopa, clonidine, medroxyprogesterone increased vaginal pH and an alteration in the vaginal flora acetate, and megestrol acetate. Of these, megestrol to predominantly gram-negative organisms.
acetate (20 mg twice daily) is most effective, and Treatment of urinary tract infection—One 8-month produces a 71% reduction in the frequence of hot flashes.
intervention with vaginal oestriol in women with recurrent Moderate reductions in hot-flash frequency (about 20%) urinary tract infection resulted in 0·5 episodes of infection have been obtained with oral or transdermal clonidine; per patient-year in the treated group, compared with 5·9 however, adverse effects such as dry mouth, constipation, episodes per patient-year in the controls.1 2 C o r r e s p o n d i n g local skin irritation, and drowsiness limit its usefulness.
improvements in risk factors (pH, bacterial flora) forurinary tract infection were seen.1 2 Some studies report an association between menopause and increased prevalence of urinary incontinence, whereas In clinical samples, women who present with symptoms others do not.6 , 7 Postmenopausal changes in the urinary of dyspareunia, vaginal dryness, itching, and irritation tract that may account for irritative voiding symptoms frequently have signs of vaginal atrophy on physical (frequency and urgency) and incontinence include: examination. These signs can include epithelial pallor, atrophy of the bladder trigone; decreased sensitivity of petechiae, friability, and absence of rugae. Signs ␣-adrenergic receptors of the bladder neck and urethral consistent with atrophy may be present on examination in sphincter; and thinning of the urethral mucosa.
the absence of symptoms; coversely, women may have Use of oestrogens for stress and urge urinary symptoms but no atrophy. The maturation index, a incontinence have mixed results. Individual studies have measurement of vaginal parabasal (least mature), reported up to a 50% reduction in stress urinary intermediate, and superficial (most mature), cells shifts incontinence with combination ␣ agonist and oestrogen towards less mature cell types after menopause. In small studies, however, an immature maturation index has not incontinence with oestrogen use.9 However, Frantl and correlated with symptoms.1 3 Thus, the syndrome known c o l l e a g u e s1 0 showed no symptomatic benefit of oestrogens as atrophic vaginitis is ill-defined and can include for stress or urge urinary incontinence.1 0 A meta-analysis symptoms only; symptoms and signs; or signs on concluded that oestrogens had only a small effect on urinary incontinence.1 1 The reliability of this summaryestimate is limited by small and heterogenous samples, Treatment of vaginal atrophy—Usual systemic doses of varied forms of incontinence, and use of different oestrogen can be used for therapy of vaginal atrophy, oestrogens. In the face of such conflicting results, many atrophic symtoms, or both. As with urinary tract clinicians use a trial treatment of oestrogen for stress and infection, additional vaginal therapy (hormonal or non- hormonal) is sometimes required for women who don o t respond adequately to systemic oestrogen; this Treatment of urinary incontinence—Oral oestrogens can o p t i o n is preferable to an increase in the systemic dose.
be used for urinary incontinence. Alternatively, local For women who cannot or do not wish to use systemic therapy with oestrogen vaginal creams, tablets, and rings oestrogen, vaginal atrophy can be treated with vaginal can be used. For a woman who has an incomplete moisturisers (proprietary names include Astroglide, THE LANCET • Vol 353 • February 13, 1999 hormone is fairly safe, low-dose testosterone may be tried Panel 2: Some testosterone preparations used in women whose main sexual complaint is diminished for diminished sexual function in postmenopausal arousal. Some testosterone compounds and doses are Several longitudinal population-based studies report no Esterified oestrogens/ 0·625–1·25 mg Alopecia, acne, hirsutism, association between the menopause transition and d e p r e s s i o n .2 3 By contrast, one Canadian cohort study did show high rates of depressive symptoms among menopausal women: 51% of women screened positive on the Centers for Epidemiologic Studies Depression Scale at least once during 3 years of observation, but high scores were related to poor perceived health and not to the menopause per se.2 4 Two other cohorts, from the perimenopausal depression, mostly in women who had had a history of depression. These studies lend support to a vulnerability theory—women who have previously had affective disorders may be at increased risk of *Increase risk of long durations of use or high doses virilisation.
m o o d disturbance during the menopausal transition.
B y contrast, women who present for care at menopause clinics have rates of clinical depression as high as 45%.2 7 (Replens) decreases vaginal pH and reduces symptoms of Oestrogen treatment of mood disturbance—The effect of oestrogens and oestrogen/progestagen combinations onmood and wellbeing in women without clinical depression is unsettled. Some studies showed improvements and The prevalence of sexual activity in one US sample1 1 o f others no benefit.2 3 There are few placebo-controlled 875 women was 70% among those aged 45–54 years and studies of monotherapy with oestrogen for clinical 60% among those aged 55–64 years,1 5 which is similar to depression. In a post-hoc analysis of a large clinical trial, the prevalence reported in community-based surveys from Europe and the USA.1 6 , 1 7 Although studies are limited by augmented the patients’ response to fluoxitene. Oestrogen cross-sectional design, narrow definitions of sexual should not be relied on to treat menopausal women with behaviour (usually frequency of intercourse), and clinically significant signs of major depression; these incomplete control for the multiple determinants of women should be assessed and treated with standard sexuality, there seems to be a trend toward declining frequency of sexual intercourse and decreased sexualdesire with increasing age. Whether part of the age-relatedreduction in sexual behaviour is related to menopause per se is uncertain, but there is reason to believe that some menopause-related symptoms interfere with sexuality. For An aetiological relation between menopause and example, vaginal atrophy can lead to vaginal dryness and increased risk of cardiac disease is corroborated by a friability which causes dyspareunia, and in some women higher age-adjusted rate of this disease among women who have had an ooporechtomy than among those who Hormone therapy for sexual complaints—There is no have not, and by the finding that postmenopausal women controversy about treatment of overt dyspareunia in a have a two-fold higher risk of developing the disease than postmenopausal women with vaginal atrophy. However, premenopausal women, after adjustment for age.
whether diminished sexual desire, arousal, orgasm, or In longitudinal studies that have accounted for satisfaction benefit from oestrogen treatment is not ageing and the menopause transition, age-adjusted known. Since oestrogen improves the integrity of vaginal concentrations of lipids and lipoproteins become less tissue, beneficial effects on sensation, vasocongestion, and favourable after the menopause.2 9 Scores of intervention vaginal secretions may occur, leading to enhanced arousal.
studies reported beneficial effects of various oestrogens The role of testosterone for sexual dysfunction, o n lipid indices. When oestrogens are combined with particularly for decreased desire, is uncertain. Findings progestagens, some degree of mitigation of the lipid that testosterone improves sexual desire come from benefit is seen, depending on the dose and type of studies of women who have oophorectomy and received high doses of testosterone.1 9 , 2 0 Whether such findings can Progestins Intervention Trial,3 1 with the longest follow-up be applied to naturally menopausal women is debatable and the advisability and safety of the very high replacement therapy, conjugated equine oestrogens testosterone doses used have been questioned.2 1 M o r e produced the greatest increase in HDL. Combination commonly, a trial of low-dose oral methyltestosterone treatment with conjugated equine oestrogens and cyclical (1·25–5 mg daily) is used for postmenopausal women micronised progesterone resulted in slightly less increase who report low sexual desire. One study2 2 of 5 mg in HDL, compared with conjugated equine oestrogen methyltestosterone (together with conjugated equine alone. This combination regimen (2·5 mg daily or oestrogens) showed an increase in self-stimulation but cyclically) produced the third highest increase in HDL n o t in self-reported arousal. Nonetheless, because this THE LANCET • Vol 353 • February 13, 1999 Adverse changes in other factors that mediate the risk of discrepancies partly arise from inexact definitions of coronary heart disease, such as insulin resistance, increased perimenopause and early menopause and inprecision thrombotic tendency, and less favourable haemodynamic i n some measurements of bone mineral density and profiles, may also lead to increased cardiac risk with the b o n e markers. Evidence for varying rates of bone loss menopause. However, menopause-associated longitudinal after menopause3 8 raises the question of whether there is a patterns of these risk indicators await detailed description.
subset of women who lose bone substantially more rapidly After adjustment for age and body-mass index, menopause than others, and whether this group can be identified. If alone does not cause increased blood pressure.3 2 I n so, such women might be targeted for screening and normotensive women, unopposed oestrogen or combined counselling about osteoporosis prevention, and might also hormone therapy does not raise blood pressure.3 1 S i m i l a r l y , require unique therapeutic interventions. Although the blood pressure does not increase as a result of hormone postmenopausal rapid bone loss raise important research Hormone therapy and events from coronary heart issues, it is too early to define a distinctive clinical d i s e a s e—Observational studies of the relation between approach for these theoretical subgroups of women.
unopposed postmenopausal use of oestrogen and risk of Hormone therapy and osteoporotic fracture—A few events from coronary heart disease consistently show small-scale randomised trials showed a reduction in risk lower rates of events among postmenopausal women of fracture as a result of use of oestrogen or oestrogen w h o use oestrogen than among non-users. Meta-analyses estimate that the relative risk of coronary heart disease in prevention of fractures and postmenopausal use of users versus non-users of oestrogen is about 6 for ever- hormones comes from observational studies. Cohort users and 0·5 for current users.3 4 , 3 5 There have been only studies are, of course, open to bias that may overestimate a few cohort studies of the effects of oestrogen in the protective effect of hormone therapy on osteoporosis.
combination with a progestagen, but the magnitude of Despite this bias, the large number of cohort studies that protection against coronary heart disease seems to be consistently report fracture prevention, the evidence of similar to that found with oestrogen alone.3 6 D e s p i t e strong effects, and the biological plausibility of this effect controlling for known confounders, these observational all point to a protective effect of hormone therapy studies are limited by a degree of residual selection bias.
o n fracture. Grady and colleagues’ meta-analysis4 1 o f However, the magnitude, consistency, and biological observational studies in which most women used plausibility of protection against coronary heart disease unopposed oestrogen calculated a summary risk estimate associated with use of postmenopausal hormones suggest of hip fracture of 0·50 among current users and 0·75 in ever-users of oestrogen. Later cohort studies, in The apparent cardioprotection by oestrogen evident in w h i c h women who used oestrogen plus progestagen these observational studies led to a recently completed, combinations are well represented, report similar degrees large randomised trial, in which continuous combined of protection against fracture risk as a result of conjugated equine oestrogen plus medroxyprogesterone acetate or placebo was given to about 2700 women with The time at which hormone therapy must be initiated pre-existing coronary disease.3 7 At the average follow-up in order to protect against osteoporotic fracture is not duration of 4 years, no overall effect of the intervention known. The Study of Osteoporotic Fractures4 3 s h o w e d was found for coronary heart disease events. However, a that only women whose use of hormones started within complex temporal pattern emerged. Compared with 5 years of the menopause had a reduced risk of hip placebo, the intervention group had significantly more f r a c t u r e ;4 1 former users, even those who used oestrogen coronary heart disease events in the first year of the trial, for longer than 10 years and began it soon after and fewer events during years 4 and 5. Based on these menopause, were not protected against hip fractures.
results, institution of hormone treatment for secondary However, in the Rancho Bernardo cohort,4 4 the bone prevention of coronary heart disease is not recommended, mineral density of current users who started treatment but it may be appropriate for women already receiving after age 60 years was similar to that of women who treatment to continue. Questions related to the safety of institution of hormone treatment in women with possible Hormone therapy and bone mineral density— M o s t subclinical coronary heart disease remain unanswered at studies of the effects of oestrogen or oestrogen plus progestagen on bone mineral density in postmenopausalwomen have lasted 1–2 years and showed increases in h i p and spine bone mineral density of 1–4%. The PEPI A causal relation between menopause and osteoporosis is s t u d y4 5 showed no significant differences in the percentage postulated based on the higher rates of osteoporotic change in bone mineral density as a function of added fractures in postmenopausal than in premenopausal progestagen use. In that study, 3 years of treatment with women, loss of bone mineral density after menopause, oestrogen or oestrogen plus progestagen produced preservation of bone mineral density as a result of use of a n increase in bone mineral density of 3·5–5·0% at the hormone therapy after the menopause, and evidence spine and 1·7% at the hip. Trials that have used more (mainly from cohort studies) that postmenopausal androgenic progestagens (for example, norethisterone) hormone users have fewer fractures than non-users.
reported greater gains in bone mineral density at the spine The timing of onset of bone loss in relation to menopausal status, bone mineral density, and bone Epidemiological studies continue to show possible turnover markers (serum and urine indicators of bone associations between menopause, hormone therapy, and the occurrence of various chronic diseases and THE LANCET • Vol 353 • February 13, 1999 oestrogen by injection causes wide variation in Panel 3: Some oestrogens and doses associated with concentrations and therefore is a suboptimum method of administration. Oestradiol implants are crystalline 1 7 -␤ oestradiol pellets that are inserted subcutaneously into the anterior abdominal wall or buttock. If there are side-effects, pellets are difficult to remove and because Micronised 17-␤ oestradiol valerate (Climaval) implants may continue to release oestradiol for a long 17-␤ oestradiol transdermal patch (Estraderm) time after insertion, progestagen therapy should be maintained until bleeding stops (which may take ୑3 years). Percutaneous gel or cream preparations are convenient and perhaps particularly well suited to *Doses are the lowest oestrogen doses that prevent bone loss in randomised trials.
women who live in tropical climates and want to use a conditions—for example, arthritis, cognitive decline and transdermal route. High moisture in such climates makes Alzheimer’s disease, tooth loss and periodontal disease, local skin irritation from patches troublesome. The major skin atrophy, cataract formation, ovarian cancer, and limitation of oestrogen gels and creams is variability in the amount applied, so metered dose-measurement systemswere developed to standardise the amount used.
Reactions at the application site occur in about 10% and5% of women who use reservoir (alcohol-based) and Hormone therapy for postmenopausal women can target matrix (oestrogen in adhesive) patches, respectively.
symptoms or prevention of chronic diseases. Therefore, it Avoidance of moisture and rotating sites keeps to a is important to establish each patient’s treatment goals, minimum patch-related local skin reactions.
because therapy directed at some symptoms, such as hot Vaginal oestrogens—Some oestrogens that are applied flashes, can be short term, whereas treatment of a chronic vaginally are listed in panel 1. The absence of endometrial indication, such as osteoporosis prevention, is usually life- hyperplasia with some vaginal preparations has been long. Because many women are concerned about the shown by endometrial ultrasound or biopsy. Other potential long-term risks of hormone replacement therapy, the distinction between short-term, and long- concentrations of circulating oestrogens or have no effect term goals is central to the discussion of the benefits and on salient liver proteins. However, as a safety indicator, serum concentrations must be interpreted with caution: Doses and routes of hormone replacement therapy vary some conjugated oestrogens (such as Premarin) contain by indication. Some commonly prescribed doses and multiple compounds that are not tested in serum as regimens of postmenopausal systemic oestrogens and estrone or oestradiol. Two older vaginal preparations, progestagens are shown in panels 3 and 4; these are conjugated equine oestrogens vaginal cream and 17-␤ judged standard because the oestrogen doses are oestradiol vaginal cream, are not shown in panel 1 since associated with preservation of bone mineral density and, there are no comprehensive data on safety available for in the case of combined hormone therapy, the added low-dose applications of these products. Whether the progestagen regimen prevents endometrial hyperplasia. As effects of vaginal preparations, including those that do not noted earlier in the above sections on treatment, higher lead to endometrial hyperplasia are local is not known.
doses of oestrogen are sometimes warranted (for example, For example, Estring produces concentrations of in recalcitrant hot flashes). By contrast, in some oestradiol that are greater than baseline concentrations, conditions, topical therapy can keep to a minimum reported to preserve bone density.4 8 Thus, one should notassume that low serum hormone concentrations or absence of endometrial hyperplasia are proof of the absence of any other systemic effect.
transdermally, intradermally (by patch, skin cream, orpellet), vaginally, and by injection. Commonly used oestrogens are summarised in panel 3; doses shown are Progestagens are used to prevent endometrial hyperplasia the lowest doses reported to prevent bone loss in in women with a uterus. There is no need to prescribe a randomised clinical trials of at least 1 year’s duration.
progestagen if a woman has had a hysterectomy.
Non-oral administration of oestrogen avoids first-pass Commonly used progestagens are summarised in panel 4; liver metabolism and can be particularly useful, for doses and durations shown are those for which protection example, for women with significant liver function from endometrial hyperplasia has been shown.
abnormalities or high triglycerides. Non-oral routes Progestagens used for hormone replacement therapy include intramuscular injection, implantation, vaginal can be devided into subgroups: the C-21 derivatives cream, skin creams or gels, and patches. Intramuscular Panel 4: Progestagens used for prevention of endometrial hyperplasia in combination hormone therapy Medroxyprogesterone acetate (Provera; Cycrin; Amen; Curretab) Micronised progesterone (Prometrium; Utrogestan) Norethisterone (Micronor; NorQD; Aygestin; Primolut; Nor) *Degree of hyperplasia protection achieved varies by dose. †Limited data.
THE LANCET • Vol 353 • February 13, 1999 dydrogesterone); C-19 derivatives of nortestosterone ( 1 0 mg) regions. In PEPI4 4 study at 3 years, ten cases of (norethisterone); and natural progesterone and similar cystic or more advanced hyperplasia were distributed compounds. When appropriate doses and durations are among the continuous (2·5 mg) and cyclic (10 mg used, these progestagens prevent endometrial hyperplasia, but differ in their relative metabolic and androgenic effects.
medroxyprogesterone) regimens; this overall 3-year rate Medroxyprogesterone acetate is minimally androgenic but did not differ from that with placebo. This finding does counteract the rise in HDL produced by unopposed confirms the safety of 2·5 mg medroxyprogesterone oestrogen therapy.3 1 Oral micronised progesterone does not acetate daily; the main reason to use the 5·0 mg daily mitigate against oestrogen-induced HDL increases.3 1 dose is to reduce bleeding. Similarly, the 3-year safety of Dydrogesterone has no androgenic and oestrogenic activity the 10 mg cyclical monthly regimen is well established;4 4 and when 10–20 mg is used cyclically with 2 mg oral 17-␤ the documented safety of 5 mg medroxyprogesterone oestradiol daily, it does not antagonise the beneficial effects acetate cycled monthly is limited to 1 year.5 4 of oestrogen on lipids. Although various clinical trials that Ferenczy and Gelfand5 5 assessed the safety of cyclic 10 use metabolic risk factors as outcome measures report that mg dydrogesterone, in combination with 2 mg oral 17-␤ some progestagens mitigate against oestrogen-induced oestradiol daily in a 1-year study among 188 benefits, observational studies have not confirmed a postmenopausal women and found no endometrial measurable difference in clinical outcomes3 5 or metabolic h y p e r p l a s i a .5 5 The same result was reported in a smaller 2-year study of this regimen in 27 women.5 6 There have Investigational methods to deliver progestagens locally been no reports of the minimum continuous dose of include an intrauterine device5 0 and vaginal gel. Suhonen and colleagues’ study5 0 in 45 women reported no endometrial hyperplasia after 3 years of using a In the PEPI trial,4 5 during 3 years, 120 women with an levonorgestrel-releasing intrauterine device in conjunction intact uterus were randomly assigned cyclic micronised with various oestrogens. However, such devices do not progesterone (200 mg) plus daily conjugated equine have only a local effect. When combined with oestrogen oestrogen (0·625 mg). Five women developed cystic they produce changes in lipids similar to that of 1 mg hyperplasia and only 1 developed atypical hyperplasia; this rate did not differ signifcantly from that in the bioadhesive vaginal gel (Crinone) is also under placebo group. The safety of a daily dose of 100 mg investigation for use in hormone replacement therapy and micronised progesterone with regard to endometrial was recently licensed in the UK. One 3-month trial hyperplasia has not been tested widely. In one 12-month reported that this low-dose sustained-release formulation uncontrolled study in 40 women, there was a 3% rate of simple hyperplasia.5 7 Gillet and colleagues5 8 found that a postmenopausal women receiving oestrogen.5 2 25-day regimen of 100 mg oral micronised progesteroneand 1·5 mg percutaneous 17-␤ oestradiol resulted in no Oestrogen and progestagen regimens hyperplasia in 78 women after six cycles of treatment.
From pooled data, the recommended dose for cyclic administration of oestrogen. This regimen augments therapy with norethistrone is 0·7–1 mg. Some of the compliance and avoids breakthrough of symptoms.
earliest continuous combined studies on hormone Progestagens can be prescribed on a monthly cycle, replacement therapy were done with norethisterone.
continuously, or four times per year (quarterly regimens).
dose-ranging studies biopsy samples taken at Some commonly used progestagens for postmenopausal 6 m o n t h s showed complete endometrial atrophy with therapy are shown in panel 4. When the monthly cycled norethisterone 0·35–5 mg daily when used in conjunction regimen is used, the easiest way to prescribe the with conjugated equine oestrogens (0·625–1·25 mg) or progestagen is on calendar days 1–12 each month. This oestradiol implants (50 mg). Biopsy samples in a regimen allows women to remember which days to use the hormone and also simplifies reporting the bleeding 0 · 3 5 m g i n conjunction with conjugated equine oestrogen pattern. When used cyclically, progestagens should be prescribed for at least 10 days each month; with newer regimens the progestagen component is given for 12 days.
Longer durations of progestagen therapy is associated Bleeding patterns and need for endometrial monitoring with reduced risk of endometrial cancer.5 3 Q u a r t e r l y Understanding the expected bleeding patterns for each progestagen regimens are not widely used. Although type of regimen is critical to their use, since bleeding initial studies reported that this regimen was safe, a long- patterns are markers of endometrial safety. Bleeding that term study was stopped early because of an unacceptably differs from the expected pattern may signal endometrial high rate of hyperplasia. Various combinations of hyperplasia, and warrants investigation. With a monthly oestrogen plus progestagen are commercially available.
cycled regimen of progestagen, 70–90% of women will Doses to prevent endometrial hyperplasia—In one large have vaginal bleeding (the absence of bleeding is not a problem). With this regimen, bleeding should start oestrogen (0·625 mg) combined with continuous sometime after the ninth day of progestagen use.
( 2 · 5 – 5 · 0 mg) or cyclic (5–10 mg on days 15–28) Endometrial assessment is recommended if bleeding medroxyprogesterone acetate resulted in a low rate of starts before this time or if there is a change in duration or endometrial hyperplasia (୏1%) at 1 year.5 4 In that study, intensity of blood flow compared with what is usual for cystic hyperplasia occurred rarely with the lower doses of medroxyprogesterone acetate (2·5 mg daily or 5·0 mg With continuous progestagen regimens, bleeding is cyclically), and no hyperplasia occurred at 12 months light to moderate in amount but its timing is erratic and with the higher-dose continuous (5·0 mg) or cyclic unpredictable. After 12 months of continuous combined THE LANCET • Vol 353 • February 13, 1999 hormone therapy, bleeding stops in about 90% of women.
women taking combined hormone treatment, since about Older women who have not been taking hormones since half will have an endometrial thickness greater than menopause may have less vaginal bleeding than younger 5 mm, which requires follow-up biopsy.6 2 women during the first year of continuous combinedtherapy, probably because their endometrium is already atrophic. Since older women who have not menstruated Although the efficacy of testosterone for improved sexual for many years may find resumption of bleeding difficult, function is not well-established, the safety of a low-dose a continuous combined regimen may be better suited to testosterone makes a trial of therapy acceptable. An them. With continuous combined hormone replacement androgen therapy carries the risks of virilisation (alopecia, therapy, endometrial assessment is recommended during acne, hirsutism, and deepening of voice). Serious hepatic the first year only if bleeding is heavy or extended; toxicity (for example, liver dysfunction, peliosis hepatis) t h i s subjective judgment is often difficult to make.
Endometrial assessment is also advised if bleeding methyltestosterones. Virilisation is generally reversible continues to occur after 12 months of use.
and depends on dose and duration, with frequency Women with an intact uterus sometimes choose increasing at dosages of methyltestosterone of 10 mg daily therapy with unopposed oestrogen. The longest study of or greater or long duration of use. At 2 years, about a third of women taking 1·25 mg methyltestosterone report oestrogen) showed that 62% of women developed hyperplasia after 3 years of treatment, about half of whom methyltestosterone (1·25 mg) is lipid neutral when given had complex hyperplasia or atypia.5 9 Thus, baseline and with standard doses of oestrogen.6 4 When 2·5 mg annual endometrial biopsy samples are required when this methyltestosterone is used with oestrogen, the oestrogen- dose of unopposed oestrogen is used. Any vaginal endometrial biopsy. In a 2-year study of 0·3 mg esterified Contraindications and precautions with hormone oestrogens given in an unopposed manner, Notelovitz and colleagues found a rate of hyperplasia of only 1·7%, which Absolute contraindications to hormone replacement was similar to that in the control women. However therapy include undiagnosed vaginal bleeding, breast or Cushing and colleagues case-control study6 1 showed that endometrial cancer, and active deep vein thrombosis.
the odds of developing endometrial cancer were five-fold Some other conditions warrant careful consideration, but higher in women taking 0·3 mg unopposed conjugated do not preclude hormone use. Most gynaecological equine oestrogen daily, compared with unexposed oncologists judge hormone use to be acceptable after women. Thus, low-dose unopposed oestrogen is not cured stage I endometrial cancer.6 5 Studies of women given unopposed oestrogen after low-grade stage I Methods of endometrial monitoring—Because of the high endometrial cancer reported no evidence of cancer rate of hyperplasia, women taking unopposed oestrogen progression related to hormone use. A weak association require routine endometrial surveillance. Measurement of between melanoma and hormone therapy has been endometrial thickness (double layer) by means of vaginal reported; use of hormone therapy after a diagnosis of ultrasound is not an efficient strategy for safety melanoma remains controversial. The safety of hormone surveillance in women taking unopposed oestrogen. The specificity of ultrasound for hyperplasia detection (with controversial; available evidence does not assure safety or a 5 mm cut-point) in women taking conjugated equineoestrogen alone is only 10%; even when simple prove toxic effects. Uterine leiomyoma may grow slightly hyperplasia is excluded from the analysis, the positive with hormone therapy but in general do not pose a major predictive value for an endometrial thickness of 5 mm or obstacle to hormone use. The hepatic and biliary effects greater in these women is only 12% for cystic or a more of oral oestrogens raise concerns about their use in serious hyperplasia.6 2 An increase of the double-layer cut- women with hypertriglyceridaemia, liver disease, and point to 9 mm or greater increases the positive predictive previous gallbladder disease (with an intact gallbladder).
value of serious endometrial findings to 15%. Thus, with Women with these conditions should be monitored unopposed oestrogen, the endometrial lining thickens in most women. The negative predictive value of a 5 mm administration may be a safer approach. Case-control endometrial measurement in women who use unopposed studies show that oral oestrogens increase the risk of conjugated equine oestrogen is 100%; but the occurrence deep-vein thrombosis by about 2–3 times. A large of a measurement this thin is extremely rare.6 1 S c r e e n i n g observational study6 6 showed that the risk increased by ultrasound before performing an oestrogen-only similarly with transdermal oestrogen. This increase in risk surveillance biopsy would exclude few women from a must be considered in the context of the population baseline risk of deep-vein thrombosis in women aged Routine surveillance of the endometrial lining is not 45–64 years, about one per 10 000 women per year.
warranted in women who use combination hormonereplacement therapy. If a woman’s bleeding pattern Complications of hormone replacement therapy differs from what is expected with the regimen used, Endometrial hyperplasia is a proven consequence of investigation is needed. Should this assesment include an unopposed oestrogen use. Atypical hyperplasia is an endometrial biopsy, or is ultrasound alone adequate? An important risk factor for the development of endometrial endometrial double layer thickness of less than 5 mm has cancer. Thus, the observed increase in endometrial cancer a negative predictive value of 99% for any degree of with use of unopposed oestrogen (without endometrial surveillance) is believed to result from induction of predictive value, ultrasound is an inefficient way to assess hyperplasia which proceeds to cancer. Endometrial THE LANCET • Vol 353 • February 13, 1999 hyperplasia can be prevented by use of appropriate doses Cignarelli M, Cicinelli E, Corso M, et al. Biophysical and endocrine- of progestagens and by careful attention to bleeding metabolic changes during menopausal hot flashes: increase in plasmafree fatty acid and norepinephrine levels. Gynecol Obstet Invest 1 9 8 9 ; 2 7 : 3 4 – 3 7 .
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Hinton P, Tweddell AL, Mayne C. Oral and intravaginal estrogens the Nurses Study6 8 found a 30% increase in risk of breast alone and in combination with alpha adrenergic stimulation in genuine cancer among current oestrogen users and a 45% increase stress incontinence. Int Urogynecol J 1990; 1 : 8 0 – 8 6 .
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THE LANCET • Vol 353 • February 13, 1999

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