CLIMACTERIC 2013;16:316–337

Updated 2013 International Menopause

Society recommendations on menopausal
hormone therapy and preventive
strategies for midlife health
T. J. de Villiers, A. Pines*, N. Panay†, M. Gambacciani‡, D. F. Archer**, R. J. Baber††, S. R. Davis‡‡,
A. A. Gompel***, V. W. Henderson†††, R. Langer‡‡‡, R. A. Lobo****, G. Plu-Bureau††††
and D. W. Sturdee‡‡‡‡, on behalf of the International Menopause Society

MediClinic Panorama and Department of Obstetrics and Gynecology, Stellenbosch University, Cape Town, South Africa;
*Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel; †Queen Charlotte’s & Chelsea Hospital, and Chelsea
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and Westminster Hospital, London, UK; ‡Department of Obstetrics and Gynecology, Pisa University Hospital, Pisa, Italy;
**Jones Institute, Eastern Virginia Medical School, Norfolk, VA, USA; ††Sydney Medical School, The University of Sydney, NSW,
Australia; ‡‡Department of Epidemiology and Preventive Medicine, School of Public Health and Preventive Medicine, Monash
University, Melbourne, Victoria, Australia; ***UF de Gynécologie, Université Paris Descartes, AP-HP, Hôtel-Dieu, Paris, France;
†††Departments of Health Research & Policy (Epidemiology) and of Neurology & Neurological Sciences, Stanford University,

Stanford, CA, USA; ‡‡‡Associate Dean for Clinical and Translational Research and Professor of Family Medicine-Las Vegas,
University of Nevada School of Medicine, Las Vegas, NV, USA; ****Department of Obstetrics and Gynecology, Columbia
University, New York, NY, USA; ††††Unité de Gynécologie Médicale, Hôtel Dieu, Paris, France; ‡‡‡‡Heart of England NHS
Foundation Trust, Solihull Hospital, Birmingham, UK
For personal use only.

INTRODUCTION including estrogens, progestogens and combined therapies.

The IMS is aware of the geographical variations related to
Ten years after the first results from the Women’s Health Ini- different priorities of medical care, different prevalence of dis-
tiative (WHI) trial were published, it seems that the atmo- eases, and country-specific attitudes of the public, the medical
sphere around the issue of menopausal hormone therapy community and health authorities toward menopause man-
(MHT) is increasingly evidence-based and more rational. The agement, different availability and licensing of products, all
pendulum has swung back from its peak negative sentiment, of which may impact on MHT. These Recommendations and
primarily as a result of acknowledging the importance of the the subsequent key messages therefore give a simple overview
age at initiation and the good safety profile of MHT in women that serves as a common platform on issues related to the
younger than 60 years. In November 2012, the International various aspects of hormone therapy, which could be easily
Menopause Society (IMS) organized a workshop with the par- adapted and modified according to local needs.
ticipation of representatives from The American Society for Key points derived from the 2013 Global Consensus (GC)
Reproductive Medicine, The Asia Pacific Menopause Federa- Statement and the Asia Pacific Menopause Federation Con-
tion, The Endocrine Society, The European Menopause and sensus (APMF C) will be highlighted where appropriate.
Andropause Society, The International Osteoporosis Founda-
tion, The North American Menopause Society and other
related medical associations, with the aim of reaching a global GOVERNING PRINCIPLES
consensus on the use of MHT and updating the 2011 IMS
recommendations. The Global Consensus Statement emerging Consideration of MHT should be part of an overall strategy
from this meeting was recently published simultaneously in including lifestyle recommendations regarding diet, exercise,
Climacteric and Maturitas and was endorsed by the above smoking cessation and safe levels of alcohol consumption for
societies in addition to the IMS. maintaining the health of peri- and postmenopausal women.
The 2013 update of the IMS Recommendations is similar MHT must be individualized and tailored according to
in structure and principle to the 2011 version but with addi- symptoms and the need for prevention, as well as personal
tional clinical data where needed. Throughout the Recom- and family history, results of relevant investigations, the
mendations, the term MHT has been used to cover therapies woman’s preferences and expectations.

Correspondence: Dr T. J. de Villiers, MediClinic Panorama, Parow 7500, Cape Town, South Africa

RECOMMENDATIONS
© 2013 International Menopause Society
DOI: 10.3109/13697137.2013.795683
 Updated IMS recommendations on menopausal hormone therapy de Villiers et al.

The risks and benefits of MHT differ for women during the women. However, long-term data on lower doses regarding
menopause transition compared to those for older women. fracture or cancer risks and cardiovascular implications are
MHT includes a wide range of hormonal products and still lacking.
routes of administration, with potentially different risks and
benefits. Thus, the term ‘class effect’ is confusing and inap-
propriate. However, evidence regarding differences in risks The dose and duration of MHT should be consistent
and benefits between different products is limited. with treatment goals, such as symptom relief, and
Women experiencing a spontaneous or iatrogenic meno- should be individualized. (GC)
pause before the age of 45 years and particularly before 40
years are at higher risk for cardiovascular disease and osteo- In general, progestogen should be added to systemic estro-
porosis and may be at increased risk of affective disorders and gen for all women with a uterus to prevent endometrial hyper-
dementia. MHT may reduce symptoms and preserve bone plasia and cancer.
density and is advised at least until the average age of
menopause.
Estrogen as a single systemic agent is appropriate in
women after hysterectomy otherwise addition of
In women with premature ovarian insufficiency, systemic
micronized progesterone/progestogen is required for
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MHT is recommended until the average age of the

endometrial protection. (GC)
natural menopause. (GC)

Micronized progesterone and some progestogens have

Counselling should convey the benefits and risks of MHT
specific beneficial effects that could justify their use besides
in clear and comprehensible terms, e.g. as absolute numbers
their expected actions on the endometrium, e.g. the well-
rather than, or in addition to, percentage changes from base-
documented blood pressure-lowering effect of drospirenone.
line expressed as a relative risk. This allows a woman and her
Progestogens are not alike with regard to potential adverse
physician to make a well-informed decision about MHT.
metabolic effects, cognitive effects or associated breast cancer
risk when combined with systemic estrogen therapy.
For personal use only.

The option of MHT is an individual decision in terms Low-dose vaginal estradiol and estriol administered for the
of quality of life and health priorities as well as personal relief of urogenital atrophy are systemically absorbed, but not
risk factors such as age, time since menopause and the at levels that stimulate the endometrium, and so concurrent
risk of venous thromboembolism, stroke, ischemic progestogen is not required.
heart disease and breast cancer. (GC) Direct delivery of progestogen to the endometrial cavity
from the vagina, or by an intrauterine system, does provide
endometrial protection and may cause less systemic progesto-
Written information about risks and benefits as well as deci- genic effects than other routes of administration.
sion aids may be useful. Androgen replacement should be reserved for women with
MHT should not be recommended without a clear indica- clinical signs and symptoms of androgen insufficiency, primar-
tion for its use, i.e. significant symptoms or physical effects of ily diminished sexual desire and arousal. Androgen replace-
estrogen deficiency. ment often has significant beneficial effects in women with
Women taking MHT should have at least an annual con- bilateral oophorectomy, pituitary insufficiency or adrenal
sultation to include a physical examination, update of medical insufficiency, particularly on health-related quality of life and
and family history, relevant laboratory and imaging investiga- sexual function.
tions, a discussion on lifestyle, and strategies to prevent or
reduce chronic disease. There is currently no indication for
increased mammographic or cervical smear screening. BENEFITS OF MHT
There are no reasons to place arbitrary limitations on the
duration of MHT. Data from the WHI trial and other studies General
generally support safe use for at least 5 years in healthy
women initiating treatment before age 60. Continued use MHT remains the most effective therapy for vasomotor symp-
beyond the 5-year window may be appropriate, based on a toms and urogenital atrophy.
woman’s individual risk profile.
Whether or not to continue therapy should be at the discre-
tion of the well-informed woman and her health professional, MHT is the most effective treatment for moderate to
dependent upon the specific goals and an objective estimation severe menopausal symptoms and is most beneficial
of ongoing individual benefits and risks. before the age of 60 years or within 10 years after
Lower doses of MHT than previously used may reduce menopause. (GC)
symptoms sufficiently and maintain quality of life for many

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 Updated IMS recommendations on menopausal hormone therapy de Villiers et al.

Other menopause-related complaints, including arthralgia has been shown to alleviate vasomotor symptoms, reduce
and muscle pains, depression, sleep disturbances and vaginal bone turnover rate and prevent bone loss.
atrophy, may improve during MHT. The administration of Raloxifene is also indicated for reduction in risk of invasive
individualized MHT (including androgenic preparations when breast cancer in postmenopausal women with osteoporosis,
appropriate) may improve both sexuality and overall quality but is associated with an increased risk of venous thromboem-
of life. bolism (VTE) similar to MHT.

Postmenopausal osteoporosis Cardiovascular disease

Cardiovascular disease is the principal cause of morbidity and

MHT is effective in preventing the acceleration of bone turn-
mortality in postmenopausal women. Major primary preven-
over and the bone loss associated with the menopause. MHT
tion measures are smoking cessation, weight loss, blood pres-
decreases the incidence of all osteoporosis-related fractures,
sure reduction, regular aerobic exercise and diabetes and lipid
including vertebral and hip fractures, even in women not at
control. MHT has the potential for improving the cardiovas-
high risk of fracture. In postmenopausal women at risk of
cular risk profile through its beneficial effects on vascular
fracture and younger than 60 years, or within 10 years of
function, cholesterol levels and glucose metabolism.
menopause, MHT can be considered as one of the first-line
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There is evidence that estrogen therapy may be cardiopro-

therapies for the prevention and treatment of osteoporosis-
tective if started around the time of menopause (often referred
related fractures.
to as the ‘window of opportunity’ concept).
MHT also reduces the risk of diabetes and, through improv-
MHT is an effective treatment for the prevention of ing insulin action in women with insulin resistance, it has
fracture in at-risk women before age 60 years or within positive effects on other related risk factors for cardiovascular
10 years after menopause. (GC) disease such as the lipid profile and metabolic syndrome.
In the WHI, younger women, 50–59 years, or  10 years
from the onset of menopause, had a trend to benefit for coro-
The initiation of MHT for the sole purpose of the preven- nary artery disease. In the estrogen trial, a composite coronary
For personal use only.

tion of fractures after the age of 60 years is currently not score was significantly reduced; at 10-year follow-up, there
recommended since the risk of long-term complications, e.g. was a significant reduction in coronary events, myocardial
breast cancer, outweighs the potential benefits. Therefore, the infarction and a reduction in mortality. In the estrogen–
continuation of MHT after the age of 60 years for the sole progestogen trial, the point estimate suggested a reduction in
purpose of the prevention of fractures should take into account risk, though not statistically significant.
the possible long-term benefits and risks of the specific dose Meta-analyses of randomized, controlled trials (RCTs),
and method of administration of MHT, compared to other including data from the WHI, have shown a significant reduc-
proven non-hormonal therapies. tion in coronary artery disease (CAD) as well as mortality in
The protective effect of MHT on bone mineral density women under the age of 60. A 10-year follow-up study of
declines after cessation of therapy at an unpredictable rate, younger women receiving CEE alone in the WHI confirmed
although some degree of fracture protection may remain after earlier findings of decreased coronary disease and mortality
cessation of MHT. If the patient is still considered at risk for in this group.
fracture after cessation of MHT, additional therapy with The recent Danish Osteoporosis Prevention Study (DOPS)
proven bone-sparing medication should be given. RCT studied younger women at the onset of menopause who
Evidence of the fracture-protective effect of MHT is limited received standard doses of estradiol and norethisterone in an
to standard dosages of conjugated equine estrogen (CEE) open-label fashion for 10 years and had 16 years of follow-up.
and medroxyprogesterone acetate (MPA), given by the There were significant reductions in mortality and in hospi-
oral route. talizations for myocardial infarction and congestive heart
Evidence for protection against loss of bone mineral density failure.
is available for lower than standard doses in oral (CEE and Two further RCTs evaluated the effects of MHT measuring
17β-estradiol) and transdermal (17β-estradiol) administration. intermediate end-points of carotid intima-media thickness and
Tibolone, a synthetic preparation metabolized to molecules coronary calcium. The Kronos Early Estrogen Prevention
that have affinity for the estrogen, progesterone and androgen Study (KEEPS) recently completed and did not show a differ-
receptors, has proven efficacy against vertebral and non- ence between CEE 0.45 mg, transdermal estradiol 0.05 mg
vertebral fractures. and placebo. These young healthy women had virtually no
The selective estrogen receptor modulators (SERMs), ralox- CAD and it is possible that there was insufficient progression
ifene and bazedoxifene, reduce the risk of vertebral fracture over 4 years to detect differences between the groups. Data
in postmenopausal women with or without prevalent verte- from the Early versus Late Intervention Trial with Estradiol
bral fractures. Bazedoxifene in addition prevents hip fracture (ELITE), which studied the effects of oral estradiol 1 mg
in at-risk patients. The combination of bazedoxifene and CEE and placebo in two groups of women, one  6 years from

318 Climacteric
 Updated IMS recommendations on menopausal hormone therapy de Villiers et al.

menopause and the other  10 years from menopause, will POTENTIAL SERIOUS ADVERSE
be analyzed in 2014. EFFECTS OF MHT
Given this information, in women less than 60 years old,
who are recently menopausal and with no evidence of cardio- Studies on the risks of MHT have mainly focused on breast
vascular disease, the initiation of estrogen-alone therapy and endometrial cancer, venous thromboembolic events
appears to reduce morbidity and mortality from coronary (pulmonary embolism or deep vein thrombosis), stroke and
heart disease. The combined estrogen–progestogen data are coronary artery events.
less robust but there is possibly a cardioprotective benefit in
this younger age group. Continuation of MHT beyond the
age of 60 years should be decided as a part of the overall Breast cancer
risk–benefit analysis, though few long-term RCT data exist
for women using MHT in this context. The incidence of breast cancer varies in different countries.
Therefore, currently available data may not be applicable
everywhere.
RCT and observational data provide strong evidence The degree of association between breast cancer and post-
that standard-dose estrogen-alone MHT decreases menopausal MHT remains controversial. The possible
coronary disease and all-cause mortality in women increased risk of breast cancer associated with MHT is small
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younger than 60 years of age and within 10 years of (less than 0.1% per annum, or an incidence of  1.0 per 1000
menopause. (GC) women per year of use), and lower than the increased risks
Data on estrogen–progestogen therapy in this popula- associated with common lifestyle factors such as reduced
tion show a similar trend but with less precision. (GC) physical activity, obesity and alcohol consumption.
Randomized controlled data from the WHI study demon-
MHT does not increase coronary events in healthy
strated no increased risk in first-time users of MHT during
women less than 60 years of age or within 10 years of
the 5–7 years since initiation of treatment. The WHI study
menopause. (GC)
also demonstrated that 7.1 years of treatment with unop-
posed CEE decreased the risk of breast cancer diagnosis and
Initiation of MHT in elderly women or those who are more mortality in hysterectomized women. However, the majority
For personal use only.

than 10 years postmenopause may be associated with increased of subjects in the WHI study were overweight or obese,
risk for coronary events, mainly in the first 2 years of use. which may have affected their basal breast cancer risk. This
Some data suggest that concomitant use of statins may miti- cannot reliably be extrapolated to younger and less obese
gate the risk of coronary events following initiation of MHT women.
in women over age 60. It is therefore not recommended to Several observational studies suggest that long-term admin-
initiate MHT beyond the age of 60 years solely for the pur- istration of unopposed estrogens alone can be associated with
pose of primary prevention of CAD. The implications for a small increase in the relative risk of breast cancer in leaner,
those who initiated MHT prior to the age of 60 are unclear. younger women, but lower than that associated with com-
bined treatment. For instance, the UK Million Women Study
(MWS), a large observational survey, raised concerns over the
Other benefits long-term safety of MHT from the perspective of breast can-
cer. However, a recent critique applied causal criteria, such as
Systemic MHT and especially local estrogen can correct estro- biases and biological plausibility, to assess the MWS findings.
gen deficiency changes in the urogenital tract and maintain The analysis highlighted several design flaws that would
vaginal health. potentially have skewed the findings.
A large European observational study suggested that
Local low-dose estrogen therapy is preferred for women micronized progesterone or dydrogesterone used in associa-
whose symptoms are limited to vaginal dryness or asso- tion with oral or percutaneous estradiol may be associated
ciated discomfort with intercourse. (GC) with a better risk profile for breast cancer than synthetic pro-
gestogens. A registry study from Finland also reported no
increase in risk with dydrogesterone after at least 5 years of
In additional to relief of vaginal symptoms, low-dose vagi- use compared to synthetic progestogens which were associ-
nal estrogen has also been shown to alleviate sensory urgency ated with a small increase in risk.
and reduce the frequency of urinary tract infections. In addition, no difference seems to exist in risk among oral
MHT also has benefits for connective tissue, skin, joints and and transdermal routes of estrogen administration. However,
intervertebral disks. Combined estrogen and progestogen there are not enough data from adequately powered clinical
therapy and tibolone have been shown to be associated with studies to fully evaluate possible differences in the incidence
a reduced risk of colon cancer. MHT initiated around the time of breast cancer using different types, doses and routes of
of menopause or in younger postmenopausal women is associ- estrogen, micronized progesterone, progestogens and andro-
ated with a reduced risk of Alzheimer’s disease. gen administration.

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 Updated IMS recommendations on menopausal hormone therapy de Villiers et al.

Baseline mammographic density is an independent risk spotting or bleeding compared to women not using any
factor for breast cancer risk. hormonal therapy.
Some MHT preparations increase mammographic density,
predominantly in women with high baseline breast density. Thromboembolism and cerebrovascular events
It is unclear whether the MHT-induced increase in
mammographic density correlates with increased breast The MHT-related risk for serious venous thromboembolic
cancer risk. events increases with age (although rare in low-risk women
The combined estrogen–progestogen therapy-related until age 60) and is also positively associated with obesity,
increase in mammographic density may impede the diagnostic smoking and thrombophilia.
interpretation of mammograms. Transdermal estrogen may avert some risk associated
The possible greater risk of breast cancer observed with with oral MHT by avoiding first-pass hepatic metabolism.
MHT may be partially decreased by selecting women with a Accordingly, transdermal therapy should be considered in
lower individual baseline risk (e.g. no baseline or treatment- higher-risk women.
induced increase in breast density) and by providing education The impact on the risk of a thromboembolic event may also
about preventive lifestyle measures (reducing body weight, be affected by the type and duration of progestogen. MPA
alcohol intake and increasing physical activity). may be associated with greater risk when used in oral therapy,
One caveat, however, is that MHT does not appear to as is the use of continuous combined regimens compared with
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increase the risk of breast cancer diagnosis in overweight or sequential regimens. In younger women, the absolute risk of
obese women whereas it does in women who are not VTE is small. In the WHI, in the 50–59-year-old group, the
overweight. excess risk was 11 additional cases per 10 000 women-years
Tibolone does not appear to be associated with an adverse for estrogen–progestogen therapy, and four additional cases
effect on mammographic density. Tibolone may convey a with estrogen alone; both far less than the risk of VTE in
lower breast cancer risk than estrogen–progestogen therapy normal pregnancy.
but increases the rate of recurrence in breast cancer RCTs do not demonstrate an increase in the risk of VTE
survivors. with tibolone but there does appear to be an increased risk of
stroke in women in their sixties.
The risk of stroke is correlated with age, but stroke is a rare
For personal use only.

The risk of breast cancer in women over 50 years

event before age 60. MHT further increases that risk, becom-
associated with MHT is a complex issue. (GC)
ing significant after the age of 60. The risk in younger women
The increased risk of breast cancer is primarily is of borderline significance; the 30% increased risk translates
associated with the addition of a progestogen to estrogen into a very small absolute risk. In the WHI study, the excess
therapy and related to the duration of use. (GC) risk was approximately one to two more cases per 10 000
The risk of breast cancer attributable to MHT is small women-years.
and the risk decreases after treatment is stopped. (GC) Observational findings from the large Nurses’ Health Study
showed significant findings of this magnitude even in younger
There is a lack of safety data supporting the use women, but the risk was not observed with lower oral doses
of MHT (estrogen therapy or estrogen–progestogen (CEE 0.3 mg).
therapy) in breast cancer survivors. (GC) In a large observational study from the UK, transdermal
estradiol at a dosage   50 μg did not increase the risk of
ischemic stroke, whereas risk was increased with higher doses
of transdermal estradiol and with oral estrogens. Low-dose
Endometrial cancer transdermal preparations therefore do not appear to be associ-
ated with increased risk for stroke, although absolute safety
Unopposed estrogen administration induces a dose-related can be difficult to judge when the event rate is low. Safety data
stimulation of the endometrium. Women with a uterus from studies of low-dose and ultra-low-dose regimens of
should have progestogen supplementation to counteract this estrogen and progestogen are encouraging, with fewer adverse
effect. Continuous combined estrogen–progestogen regimens events, but data from large prospective trials are awaited.
are associated with a lower incidence of endometrial hyper-
plasia and cancer than occurs in the normal population. The risk of venous thromboembolic events and ischemic
Direct intrauterine delivery systems may have advantages. stroke increases with oral MHT but the absolute risk is
Regimens containing low-/ultra-low-dose estrogen and pro- rare below age 60 years. (GC)
gestogen cause less endometrial stimulation and less bleed-
ing. Long-cycle regimens and long-term use of monthly Observational studies point to a lower risk with low-
sequential regimens do not provide optimal endometrial dose transdermal therapy. (GC)
protection. The incidence of venous thromboembolism with MHT
SERMs other than tamoxifen do not stimulate the endo- is very low among Asian women. (APMF C)
metrium and do not increase the incidence of endometrial

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 Updated IMS recommendations on menopausal hormone therapy de Villiers et al.

ALTERNATIVE TREATMENTS there are few risks when initiated and used within a few
years of menopause.
The efficacy and safety of complementary alternative medi- The WHI and other studies strongly suggest that it is the
cines for the alleviation of significant menopausal symptoms progestogen component of MHT that is more significant in
have not been demonstrated and further studies are required. any increase in breast cancer risk rather than the estrogen.
Selective serotonin reuptake inhibitors (SSRI), selective Thus, it seems prudent to minimize progestogen use where
noradrenaline reuptake inhibitors (SNRI) and gabapentin safely possible. Future research may clarify whether risks:
are effective in reducing vasomotor symptoms in short-term • are lower for one progestogen compared to another,
studies. Their long-term safety needs further evaluation. • vary according to cycle duration, and
An oral SERM (ospemifene) has recently received FDA • are reduced by SERMs that do not adversely affect the
regulatory approval for the treatment of moderate to severe breast but inhibit endometrial proliferation.
dyspareunia.
‘Customized bioidentical hormonal preparations’ have not There is increasing evidence that non-oral routes of estrogen
been adequately evaluated for dosage or efficacy in studies, have little or no increased risk of VTE and would be the regi-
and their purity and risks are unknown. mens of choice in women with thromboembolic risk factors,
if MHT were considered appropriate.
There is mounting evidence from laboratory, animal, obser-
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The use of custom compounded bioidentical hormone vational studies and RCTs that there is a probable therapeutic
therapy is not recommended. (GC) window of benefit for long-term cardioprotection and possibly
for aspects of long-term neuroprotection if MHT is prescribed
in midlife for vasomotor symptoms.
The measurement of hormone levels in the saliva has not
Women can have the option of MHT for as long as they
been proven to be useful.
derive symptomatic benefit and are aware of the risks for their
regimen and personal circumstances. They can try without
RESEARCH MHT every few years, but menopausal symptoms in some
women can last for many years and should be treated with
There is urgent need for further research especially into the the lowest effective dose.
For personal use only.

risks and benefits of lower doses, regimens and routes of It is very unlikely that large, long-term RCTs, like the WHI
administration of MHT and into late-life cognitive effects of which finished prematurely, will ever be funded or be practi-
midlife MHT use. cally possible in the future. Therefore, clinicians in any field
must treat or not treat on the balance of the available data.
Such data for the foreseeable future have and will come from
CONCLUSION smaller randomized trials such as DOPS or studies using sur-
rogate end-points for long-term morbidities such as KEEPS
MHT is not a standard regimen given to a standard woman. and ELITE. Data from large, long-term cohort studies (e.g.
The benefits and risks vary greatly in individual circumstances, Nurses’ Health Study) or from systematic reviews of the
but research over the last decade has helped to show that risks quality literature are also very useful.
can be minimized and benefits maximized with selection of The excessive conservatism engendered by the presentation
the optimal regimen at the optimal time. to the media of the first results of the WHI in 2002 has dis-
The safety of MHT largely depends on age. Healthy advantaged many women over more than a decade who have
women younger than 60 years should not be unduly con- unnecessarily suffered severe menopausal symptoms and who
cerned about the safety profile of MHT where there are may have missed the potential therapeutic window to reduce
indications for its use. New data and re-analyses of older their future cardiovascular, fracture and dementia risk. These
studies by women’s age show that, for most women, there IMS evidence-based recommendations are intended to encour-
is potential benefit for MHT given for a clear indication and age better care of all women in mid-life.

KEY MESSAGES

EXERCISE IN THE MENOPAUSE • The benefits of exercise far overweigh possible adverse
consequences: the more, the better, but too much may
• Regular exercise reduces cardiovascular and total mortality. cause harm.
• Better metabolic profile, balance, muscle strength, cogni- • Optimal exercise prescription is at least 150 minutes of
tion and quality of life are observed in physically active moderate-intensity exercise per week. Two additional
persons. Heart events, stroke, fractures and breast and weekly sessions of resistance exercise may provide fur-
colon cancers are significantly less frequent. ther benefit. However, the recommended intensity of

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 Updated IMS recommendations on menopausal hormone therapy de Villiers et al.

aerobic activity should take into account the older adult’s • Use of systemic MHT does not seem to prevent urinary
aerobic fitness. incontinence and is not preferable to low-dose local estro-
gens in the management of urogenital atrophy or recurrent
lower urinary tract infections.
HEALTHY LIFESTYLE • After lifestyle changes and bladder retraining, anti-
muscarinic drugs combined with local estrogens constitute
• Obesity (body mass index  30 kg/m2) affects over 20% first-line treatment in postmenopausal women with symp-
of the population in many parts of the world and is becom- toms suggestive of an overactive bladder.
ing an increasing problem in the lower socioeconomic sec- • All women complaining of stress urinary incontinence will
tors and also among children. It can be associated with benefit from pelvic floor muscle training in the first instance.
insulin resistance and thus increases not only a woman’s Duloxetine may work synergistically with conservative
risk of cardiovascular disease and diabetes, but also therapy. However, some women will ultimately undergo
increases the risk for breast, colon and endometrial cancers surgery, and retropubic and trans-obturator tapes are the
and is associated with higher rates of depression and most popular procedures.
sexual dysfunction. • There is currently no role for systemic estrogen therapy in
• Weight loss of only 5–10% is sufficient to improve many women with pure stress urinary incontinence.
of the abnormalities associated with the insulin resistance
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syndrome.
• The basic components of a healthy diet are: several serv-
OSTEOPOROSIS
ings/day of fruits and vegetables, whole grain fibers, fish
twice per week, and low total fat (but the use of olive oil General guidelines
is recommended). Consumption of salt should be limited
and the daily amount of alcohol should not exceed 30 g The disease
for men and 20 g for women.
• Smoking should be prohibited.
• Osteoporosis is a systemic skeletal disease of diminished
• Lifestyle modifications include socializing and being phys-
bone strength that results in fractures when falling from
ically/mentally active.
one’s own body height. Bone strength is determined by
For personal use only.

• The public health approach to lifestyle promotion requires

a combination of bone density and microarchitectural
a multidisciplinary approach, starting from schools
integrity.
through to work places, involving the food and advertis-
• Postmenopausal osteoporosis can be caused by the failure
ing industry, as well as medical insurers and health
to attain peak bone density or accelerated bone loss after
authorities. A new paradigm in doctor–patient relations
menopause.
is required, where the doctor becomes more of an advisor
• Although skeletal health is a function of genetic predispo-
and the patient has to take the responsibility for his/her
sition, it can be modified by lifestyle factors such as diet,
own health.
weight-bearing exercise and the avoidance of bone-toxic
substances.
• Hip fracture is responsible for a large proportion of the
UROGYNECOLOGY financial burden of osteoporosis to health-care systems but
other osteoporosis-related fractures, particularly vertebral
• Symptoms such as vaginal dryness, soreness, dyspareunia, fractures, cause considerable morbidity which can be
urinary frequency, nocturia and urgency are extremely long-standing.
common in postmenopausal women. Incontinence in
women increases in prevalence with age. Overall, 25% of
women report urinary incontinence of which 7% consider Diagnosis and assessment
it to be significant; 50% of women complain of stress
incontinence, 11% urge incontinence and 36% mixed • The diagnosis of osteoporosis is based on assessment of
incontinence. bone mineral density by dual X-ray absorptiometry
• However, there is a wide variation in symptoms and signs (DXA), expressed as the T-score, or the presence of fragility
of urogenital aging. fractures.
• The loss of lubrication and hormonal changes may lead to • Bone mineral density assessment is not a cost-effective
sexual dysfunction. Treatment of this condition improves population screening tool but is best applied on a selective
quality of life, not only for the woman but also for her basis, based on age and other risk factors including a fam-
partner. ily history of fractures, history of amenorrhea, corticoster-
• Urogenital symptoms respond well to estrogens. Long- oids, etc.
term treatment is often required as symptoms can recur • The 10-year probability of fracture in an individual can be
on cessation of therapy. Systemic risks have not been estimated using a model that integrates various risk factors
identified with local low-potency/low-dose estrogens. for fracture, such as the FRAX model developed through

322 Climacteric
 Updated IMS recommendations on menopausal hormone therapy de Villiers et al.

the World Health Organization, which is available online • Low-dose tibolone (1.25 mg/day) is effective in reducing
at www.sheffield.ac.uk/FRAX/. vertebral and non-vertebral fractures.
• An appropriate assessment of prevalent fractures and
secondary causes of osteoporosis should precede any ther-
apeutic decisions. Calcium and vitamin D

Treatment • Postmenopausal women need a dietary reference intake

(DRI) of 1000–1500 mg of elemental calcium.
• The goal of management in osteoporosis is the prevention • Calcium supplementation should be restricted to bridge
of fracture. Choice of therapy should be based on a the shortfall between dietary intake and the DRI and
balance of effectiveness, risk and cost. to patients being treated for high fracture risk. Routine
• Intervention thresholds for therapy can be based on 10-year dietary calcium supplementation cannot be justified in
fracture probability and will be country-specific. terms of efficacy and health economics.
• Alternatively, treatment can be given to all patients with a • Excessive calcium supplementation in addition to adequate
fragility fracture or a T-score of  2.5 (osteoporosis), or
or high dietary calcium may be associated with increased
a T-score of  1.0  2.5 (osteopenia) and additional cardiovascular risk.
risk factors, as a large proportion of fractures occur in • The DRI for vitamin D is 800–1000 IU in the postmeno-
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individuals with osteopenia. pausal period.

• Monitoring of therapy by serial DXA should be inter- • As the major source of vitamin D is dependent on sunlight
preted with caution and take into account the site moni- exposure, the need for supplementation will vary. Measur-
tored, time interval, drug-specific expectations and the ing the blood 25-hydroxyvitamin D level may be helpful
value of least significant change as calculated for the in selected individuals.
specific device and operator. • Vitamin D supplementation has been shown independently
• The monitoring of treatment by biochemical markers of to lower the risk of fracture and of falling in elderly
bone turnover is presently not recommended in routine patients.
clinical practice.
• The cost-effectiveness of treatments to prevent osteoporotic
For personal use only.

fracture will be highest where they are used in women who Bisphosphonates
have increased fracture risk. The relevant fracture risk thresh-
old will be specific to the individual health-care system. • The bisphosphonates are potent inhibitors of bone
resorption and decrease the rate of bone turnover, with
proven efficacy in the prevention of vertebral and hip
Menopausal hormone therapy fractures.
• A drug-free holiday may be considered after 3–5 years of
• MHT decreases bone turnover and the incidence of all bisphosphonate therapy in patients with a good response
osteoporosis-related fractures, including vertebral and hip of bone mineral density to treatment, without prevalent
fractures. fractures.
• MHT can be considered as one of the first-line therapies • Bisphosphonates have benefits in some cancers and may
for the prevention and treatment of osteoporosis-related prevent bone metastases from breast cancer.
fractures in women below 60 years. • Bisphosphonate-related osteonecrosis of the jaw is a rare
• The initiation of MHT for the sole purpose of the pre- complication when dosages as recommended for fracture
vention of fractures after the age of 60 years is not prevention are used.
recommended. • An association has been suggested between atypical femur
• The protective effect of MHT on bone mineral density shaft fractures and over-suppression of bone turnover
declines after cessation of therapy at an unpredictable in patients exposed to bisphosphonates for longer than
rate. 3–5 years.
• Data for protection against loss of bone density is avail-
able for low doses of oral (CEE and 17β-estradiol) and
transdermal (17β-estradiol) administration. SERMs

• The SERMs, raloxifene and bazedoxifene, reduce vertebral

Other therapies fractures in postmenopausal women with or without
prevalent vertebral fractures.
Tibolone • Bazedoxifene prevents hip fracture in at-risk patients.
• Bazedoxifene and CEE have been shown to reduce bone
• Standard-dose tibolone (2.5 mg/day) has proven efficacy turnover rate and prevent bone loss whilst also alleviating
against postmenopausal osteoporosis. vasomotor symptoms.

Climacteric 323
 Updated IMS recommendations on menopausal hormone therapy de Villiers et al.

Parathyroid hormone CARDIOVASCULAR SYSTEM

• Parathyroid hormone (PTH) produces a significant reduc- Gender-specific characteristics of atherosclerosis

tion in the risk of vertebral and non-vertebral fractures in menopausal women
by stimulation of bone formation. There is no indication
that combining PTH with a bone resorption inhibitor has • The clinical course of cardiovascular disease has gender-
any additional benefit to giving either drug alone. Prior specific characteristics.
treatment with a bisphosphonate blunts the effect of • Risk factors for CAD increase at the time of menopause
subsequent PTH. due to the potential effects of ovarian failure on cardio-
• PTH is given as a daily subcutaneous injection for a vascular function, blood pressure and various metabolic
maximum of 18 months. Use is limited by high cost. parameters (glucose tolerance, lipid profile).
• Arterial hypertension, high triglyceride level and especially
Strontium ranelate diabetes negate the gender advantage of women compared
to men in cardiovascular event rates.
• Given in a daily oral dose, strontium ranelate significantly • Preventative strategies should be focused in women on
reduces the risk of vertebral and non-vertebral fractures in reducing blood pressure and controlling weight and insulin
osteoporotic and osteopenic patients, irrespective of the resistance
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presence of a fracture or age. The mode of action of stron- • Women may have angina with non-obstructed coronary
tium ranelate involves stimulation of bone formation as arteries but, when they develop an infarct, their prognosis
well as inhibition of resorption. is significantly worse than that of men.
• Accordingly, it is imperative to evaluate symptoms
Denosumab despite the lower positive predictive value of angina in
women.
• A human monoclonal antibody to the receptor activator
of nuclear factor-kappa B ligand (RANKL), at a dose of
60 mg subcutaneously 6-monthly, significantly reduces the
MHT and coronary artery disease
risk of vertebral, non-vertebral and hip fractures. As with
For personal use only.

• Estrogen induces beneficial effects on various CAD meta-

other biological therapies, denosumab may have adverse
bolic risk factors.
immunological effects.
• MHT is associated with a lower risk of new-onset type
2 diabetes.
SKIN, CARTILAGE AND OTHER • The majority of preclinical data and observational studies
CONNECTIVE TISSUES support the potential benefits of MHT in reducing risk
of CAD.
Skin, the carotid artery and intervertebral discs • Previous observational data on the protective effects of
MHT were based on studies in younger women.
• Estrogen protects connective tissue metabolism in the • Age of initiation, near to the time of menopause, is a
whole body. critical factor in determining whether MHT reduces or
• After the menopause, there is loss of connective tissue in increases CAD risk.
the dermis of the skin which in some cases is reversed with • RCTs in women with established CAD have shown that
estrogen therapy. there is no coronary benefit of MHT in these women.
• Similar changes in connective tissue are observed at the • Certain hormonal regimens and progestogen types may be
arterial media layer. important in determining the potential CAD benefit in
• Intervertebral discs become thinner after the menopause younger women, as has been shown with estrogen alone;
and this may be prevented by estrogen therapy. however, there are no comparative trials.
• Overall, data strongly suggest a coronary benefit with
estrogen alone, and possibly with estrogen and progestogen
Articulated joints and the menopause in young women at onset of menopause.

• The marked predominance of polyarticular osteoarthritis in

women and, in particular, the marked increase of osteoar- MHT and stroke
thritis in women after the menopause suggest that female
sex steroids are important for cartilage homeostasis. • Although both CAD and stroke are arterial vascular dis-
• Timely initiation of estrogen/SERM treatment can effec- eases, the effects of postmenopausal hormones on these
tively prevent both bone and cartilage loss accompany- common conditions are not necessarily similar.
ing the menopause, involving both direct and indirect • Hypertension and body mass index significantly increase
mechanisms. the risk of ischemic stroke.

324 Climacteric
 Updated IMS recommendations on menopausal hormone therapy de Villiers et al.

• Oral estrogen therapy and estrogen–progestogen therapy • The liver-derived pro-inflammatory effects of estrogen may
increase the risk of ischemic stroke by about one-third in be avoided by non-oral administration of 17β-estradiol.
relatively healthy postmenopausal women. • There is limited evidence that different progestogens mod-
• Low-dose tibolone (1.25 mg) increases the risk of stroke ulate liver and vascular inflammatory effects.
in women over 60 years.
• The excess absolute risk of MHT is expected to be lower
among women below the age of 60 years, because stroke BRAIN
incidence is lower in this younger age group.
• In the Nurses’ Health Study, the risk of stroke was not General
increased with lower oral doses of MHT (CEE 0.3 mg.)
• Low-dose transdermal estradiol (below 50 μg) does not • During development and adulthood, the human brain
increase the risk of stroke. is a target for estrogens and other gonadal steroid hor-
• Evidence from basic science studies reaffirms the neuronal mones. Estrogens influence neural function and neuro-
protective effects of estrogen in the setting of experimental logical disease directly, through effects on neurons and
infarction. glia, and indirectly, through effects on oxidative stress,
• Based on findings from a single, well-designed clinical trial inflammation, the cerebral vasculature and the immune
of postmenopausal women with a history of ischemic system.
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stroke or transient ischemic attack, estrogen therapy • With menopause, the cessation of ovarian production of
should not be prescribed for the secondary prevention of estrogens and progesterone has the potential to influence
stroke. processes in the central nervous system relevant to neuro-
• Data on progestogen use versus unopposed estrogen use logical and psychiatric disorders. Within the brain, how-
have not been consistent. ever, some neurons remain capable of synthesizing small
amounts of estradiol.
• Many women note cognitive and emotional symptoms at
COAGULATION times that are associated with changes in circulating levels
of gonadal steroids. It has been more difficult, however,
VTE safety to demonstrate consistent cognitive and affective effects
For personal use only.

of MHT.
• VTE is one of the major adverse events during use of oral
MHT and SERMs.
• The risk increases with estrogen dose, age and body mass Cognition and cognitive aging
index and is greater during the first years of therapy.
• Consistent observational data suggest that the risk of • For midlife women, observational evidence indicates no
VTE is not increased with transdermal therapy using persisting effects of the natural menopause on memory or
17β-estradiol, unless high doses are used. other cognitive functions. During the menopausal transi-
• Some progestogens, e.g. MPA, nor-pregnane derivatives tion, however, some women experience transient prob-
and continuous combined regimens, may be associated lems, the magnitude of which is usually small.
with greater risk of VTE in oral MHT users. • Limited evidence from short-term clinical trials in midlife
• In younger women, the absolute risk of VTE is small. women suggests that MHT has no substantial cognitive
• The incidence of VTE is less frequent among Asian effect after natural menopause. This needs clarification
women. from further research.
• Population screening for thrombophilia is not indicated • For older women without cognitive impairment, there is
prior to MHT use. convincing clinical trial evidence that MHT started in the
• Selective screening may be indicated on the basis of late postmenopause has no substantial impact on cognitive
personal and familial history. abilities.
• Smoking should be strongly discouraged in women using • For surgically menopausal women, limited evidence from
any estrogen-containing products small clinical trials suggests that estrogen therapy could be
of short-term cognitive benefit when initiated at the time
of oophorectomy.
Arterial disease safety • The long-term cognitive consequences of MHT initiated
during the menopausal transition or early postmenopause
• Oral MHT induces both pro-inflammatory (liver biomark- are unknown. There remains an urgent need for further
ers) and anti-inflammatory (vascular biomarkers) effects. research in this area.
Modification of inflammation in either direction can be • For healthy postmenopausal women, there is clinical trial
good or bad for arterial disease depending upon the indi- evidence that isoflavone supplements in a daily dose com-
vidual status of inflammation in the vascular wall, poten- parable to that consumed in traditional Asian diets have
tially related to age and time after menopause. no overall effect on cognition.

Climacteric 325
 Updated IMS recommendations on menopausal hormone therapy de Villiers et al.

Alzheimer’s disease • Multiple sclerosis symptoms may be influenced by hormo-

nal status. It is not known whether MHT affects multiple
• For women with dementia due to Alzheimer’s disease, lim- sclerosis symptoms or progression.
ited clinical trial evidence indicates that MHT does not
improve dementia symptoms or slow disease progression.
• Limited clinical trial evidence indicates that MHT increases ONCOLOGY
all-cause dementia risk when initiated in the late postmen-
opause. For women aged 65–79 years, the excess risk of MHT and breast cancer
dementia attributed to hormone use is about 1.2 per 1000
women-years for estrogen therapy and 2.3 per 1000 • The incidence of breast cancer varies in different countries.
women-years for estrogen–progestogen therapy. In this age • The possible increased risk of breast cancer associated with
group, MHT risk may be higher for women with lower MHT is small.
cognitive function at baseline. • The WHI study demonstrated no increased risk in first-
• Observational evidence implies that MHT used by younger time users of MHT and decreased risk of breast cancer
women around the time of menopause is associated with diagnosis and mortality in hysterectomized women using
lower risk of Alzheimer’s disease. Findings from several unopposed CEE.
observational studies support the concept of a therapeutic • Unopposed estrogens can be associated with a small
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window, suggesting that MHT initiation and use in midlife increase in relative risk of breast cancer in leaner, younger
may be beneficial, with respect to Alzheimer’s risk, whereas women.
starting MHT in later life is harmful. • Micronized progesterone or dydrogesterone used with
• The long-term cognitive consequences of MHT initiated estradiol may be associated with a better risk profile for
during the menopausal transition or early postmenopause breast cancer than synthetic progestogens.
are largely unknown. • More data are required to evaluate the incidence of breast
• There remains a need for further research in this area. cancer using different types, doses, routes of estrogen,
progesterone, progestogens and androgens.
• Baseline mammographic density correlates with breast
Depression cancer risk, but this is independent of breast cancer asso-
For personal use only.

ciation with MHT.

• The prevalences of depressive symptoms are similar before • The combined MHT-related increase in mammographic
and after the menopause. However, depression risk may density may impede interpretation of mammograms.
be increased during the menopausal transition and the
early postmenopause.
• Limited clinical trial evidence suggests no effect of estrogen Endometrial safety, bleeding, MHT
therapy on depression in the late postmenopause. and endometrium
• Accumulating clinical trial evidence suggests that short-
term estrogen therapy significantly benefits depression dur- • Unopposed estrogen therapy is associated with a duration
ing the menopausal transition. and dose-related increase in risk of endometrial hyperpla-
• Large studies should be conducted to further evaluate the sia and cancer.
potential benefits of estrogen both as monotherapy and as • This increased risk persists for many years after cessation
adjunctive treatment for the management of depression in of therapy.
the menopause transition. • Progestogen prevents the endometrial proliferation of
estrogen.
• Endometrial protection requires an adequate dose and
Other neurological disorders duration of progestogen.
• Long-term use of sequential combined MHT regimens may
• Potential effects of MHT on the incidence or symptoms of increase the risk of endometrial hyperplasia and cancer,
Parkinson’s disease are largely unknown. particularly the long-cycle regimens.
• Based on evidence from a single, small clinical trial, com- • Continuous combined regimens are associated with a
bined MHT may increase seizure frequency in postmeno- lower risk of endometrial cancer than in the untreated
pausal women with epilepsy. population.
• Progesterone therapy before the menopause has no sub- • In the WHI and Million Women Study, there was no dif-
stantial effect on seizure frequency. It is not known whether ference in risk of endometrial cancer with continuous com-
this finding generalizes to postmenopausal women with bined regimens.
epilepsy. • New lower-dose regimens cause less endometrial stimula-
• Headache prevalence is lower after menopause than before. tion and less bleeding.
Limited observational evidence suggests that current MHT • Intrauterine delivery of progestogen is a logical route
is positively associated with increased headache frequency. of administration and provides effective endometrial

326 Climacteric
 Updated IMS recommendations on menopausal hormone therapy de Villiers et al.

suppression, but outpatient insertion may be problematic • The risk of death from lung cancer was also higher for
in postmenopausal women. MHT users and this increase was greatest amongst those
• Data from RCTs on the effect of tibolone on the who were smokers.
endometrium suggest a similar effect to continuous com- • In women aged 50–59 years, no increased risk of lung
bined regimens. cancer was observed.
• Tamoxifen has an estrogenic effect on the endometrium
whereas raloxifene and other modern SERMs have no
apparent effect.
Colorectal cancer
• Following treatment for endometrial cancer, the use of
MHT is not generally recommended, although there are • The majority of observational studies show a reduced risk
few data. of colorectal cancer amongst users of oral MHT.
• Obesity increases the risk of developing endometrial • Three meta-analyses have reported a reduced risk of color-
pathology. ectal cancer with MHT use with benefit persisting for
4 years after cessation of therapy. A typical effect
was relative risk (RR) 0.80 (95% confidence interval (CI)
0.74–0.86) for ever-users and 0.66 (95% CI 0.59–0.74)
MHT and cancers other than breast for current users.
• The LIFT study demonstrated that tibolone was associated
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Ovarian cancer with a reduced risk of colon cancer in women aged 60–79
years.
• Premenopausal use of the combined oral contraceptive pill • Results from the WHI randomized trial of estrogen-only
is associated with a reduced risk of developing ovarian therapy showed no effect of estrogen-only therapy on risk
cancer. of colorectal cancer.
• The WHI study is the only RCT to examine MHT and • In the WHI RCT of estrogen–progestogen therapy,
ovarian cancer risk. In women receiving combined MHT, colorectal cancer risk was reduced (RR 0.56; 95%
there was no significant increase in risk. CI 0.38–0.81). This effect was predominantly for local
• Several case–control and population studies suggest a sig- disease and, where spread had occurred, there was more
For personal use only.

nificant increase in risk, but the effect of duration or type node involvement and a more advanced stage at diagnosis
of therapy varied among the studies. In one large-scale amongst users of MHT.
trial, the increased risk rapidly returned to normal within • MHT should not be used solely for the prevention of
2 years of cessation, consistent with a promoter rather colorectal cancer.
than inducer effect. • There are no data for an effect of non-oral MHT on risk
• In summary, long-term, estrogen-only therapy may be of colorectal cancer.
associated with a small attributable risk of ovarian cancer
of 0.7 per 1000 women per 5 years of use, whilst either a Cervical cancer
significantly smaller, or no, increased risk is seen with com-
bined estrogen plus progestogen therapy.
• Long-term cohort studies have shown no increased risk of
cervical cancer with MHT use.
• In the WHI RCT, there was no increase in risk of cervical
Lung cancer cancer with MHT use.

• Lung cancer incidence in women continues to increase,

mainly due to smoking, and lung cancer is the largest con- Upper gastrointestinal tract cancer
tributor to cancer mortality in women.
• Large observational studies have reported a protective • Gastric and esophageal cancers are predominantly a dis-
effect of hormonal contraception and MHT on lung cancer ease of men. The reason for this is unclear and no hormo-
risk. nal mechanism has been found.
• In the WHI RCT of estrogen-only therapy, there was no • A nested case–control study showed a reduction in
increase in the risk of non-small cell lung cancer in users stomach cancer for users of MHT (RR 0.48; 95% CI
of MHT compared to placebo. 0.29–0.79) but no effect on esophageal cancer.
• In the WHI RCT of combined estrogen–progestogen ther- • Oral MHT is known to affect gall bladder function and
apy, there was an overall non-significant trend towards an observational studies have reported an increased incidence
increase in risk of non-small cell lung cancer. of cholecystectomy amongst users of MHT.
• The increased risk became significant only in women aged • The only report of gall bladder cancer and MHT comes
60–69 years where the absolute attributable risk was 1.8 from a small case–control study which found an increased
extra cases of lung cancer per 1000 women taking MHT risk associated with MHT use and with duration of use
for 5 years. (RR 3.2; 95% CI 1.1–9.3).

Climacteric 327
 Updated IMS recommendations on menopausal hormone therapy de Villiers et al.

ATTITUDES TO SEXUALITY AND QUALITY satisfaction, desire, arousal, pleasure and orgasm in
OF LIFE IN THE MENOPAUSE surgically postmenopausal women on estrogen, naturally
postmenopausal women on estrogen–progestogen therapy,
Clinical evaluation/diagnosis postmenopausal women on no hormone therapy and
premenopausal women in their late reproductive years.
• Healthy status represents a major determinant of quality • Before considering androgen therapy, factors such as dys-
of life, particularly in elderly people, but sexuality is an pareunia, depression, medication side-effects, relationship
important factor at all ages as well. issues and other health problems need to be identified and
• A complex interplay of biological, psychological and managed.
socio-relational factors determines women’s sexual health. • Androgenic side-effects are dose-related and avoidable
This may negatively affect the entire sexual response cycle, with the use of appropriate formulations and dose.
inducing significant changes in desire, arousal, orgasm and • There is no evidence from large, placebo-controlled
satisfaction at menopause and beyond. RCTs that transdermal testosterone in appropriate doses
• Both age and declining sex hormones have detrimental results in adverse metabolic effects or effects on the
effects on sexual functioning, with a significant increase in endometrium.
vaginal dryness/dyspareunia and a significant decrease in • Available data do not indicate an increase in risk of breast
desire and sexual responsiveness. cancer with transdermal testosterone; no large study with
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• The partner’s general and sexual health and the relation- this outcome has yet been published.
ship itself may significantly contribute to the relevance of • Oral DHEA does not improve sexual function, well-being
sexual symptoms in postmenopausal women. or metabolic health in postmenopausal women.
• Reduced libido is the most common sexual complaint • Oral DHEA may improve health-related quality of life and
experienced by women and the proportion increases with depression in women with adrenal insufficiency.
age. However, there are age-related changes in sexually • The role of vaginal DHEA administration for improving
related personal distress, which are especially evident in sexual function in postmenopausal women requires con-
surgically menopausal women. These women are at firmation.
increased risk for hypoactive sexual desire disorder. • Preliminary data support the need for research to clarify
• Women may not be willing to initiate a conversation on the role of testosterone for prevention of bone and muscle
For personal use only.

sexual interest, behavior and activity themselves, but they loss, maintenance of cognitive performance and cardiovas-
usually appreciate being questioned by doctors. cular effects.
• Validated tools (self-administered questionnaires/daily dia-
ries and event logs/semi-structured interviews) may be used
properly to diagnose sexual symptoms and to gain infor- Non-hormonal approaches to the management
mation on sexual constructs and relationships; sex steroid of menopausal symptoms
assays are not generally helpful.
• An accurate sexual history and a focused clinical evalua- Non-pharmacological and lifestyle interventions
tion may help clinicians in the management of sexual
symptoms that are causing significant distress.
• High-quality data from studies of non-pharmacological
• Vaginal atrophy should be always diagnosed and appro-
and lifestyle interventions for vasomotor symptoms have
priately treated.
been limited.
• Hormonal and non-hormonal treatments and/or psycho-
• Meditation, relaxation, controlled breathing and cognitive
sexual strategies should be individualized and tailored
behavior therapy show promise in managing hot flushes,
according to a woman’s history and current needs.
but adequately powered randomized trials are still
needed.
Androgen therapy in the postmenopause • There is little evidence that dietary modifications or exer-
cise improve hot flushes but they may improve mood and
• Androgen levels decline with age prior to the menopause quality of life.
such that by menopause most women have half the level • Regular exercise, weight reduction, and avoiding triggers
of circulating testosterone and pre-androgens, androstene- to hot flushes (such as caffeine or direct heat) may help to
dione and dehydroepiandrosterone (DHEA) that they had minimize hot flushes or their impact.
in their twenties. • Randomized trials of acupuncture have not consistently
• The consequences of the decline in androgens in women shown a beneficial effect in reducing vasomotor symptoms
with age need to be better understood.
• The primary indication for testosterone is for the treatment Complementary therapies for vasomotor symptoms
of desire, arousal and orgasmic disorder.
• Several large, placebo-controlled RCTs have consistently • High-quality studies to date have not consistently sup-
show benefits of continuous testosterone for sexual ported the efficacy of complementary or over-the-counter

328 Climacteric
 Updated IMS recommendations on menopausal hormone therapy de Villiers et al.

therapies in reducing severity or frequency of hot flushes • There have been very few head-to-head studies of
or night sweats. non-hormonal agents.
• Black cohosh and soy products are not superior to placebo • Currently, the only preparation which has demonstrated
in the treatment of hot flushes. equivalent efficacy to estrogen is gabapentin. Gabapentin
(300 mg three times per day) was equivalent to low-dose
So-called ‘bioidentical’ or ‘natural’ hormones estrogen (0.5 mg CEE or a 25 μg estradiol patch) for
vasomotor symptoms.
• No other agents have been directly compared with estro-
• Such labelling and advertising has no sound scientific basis
gen for the reduction of vasomotor symptoms.
to delineate them from many current forms of registered
• Venlafaxine, desvenlafaxine, fluoxetine, paroxetine and
MHT.
citalopram have all been shown in RCTs to reduce vaso-
• Estradiol, estrone or estriol, whether pharmaceutically
motor symptoms. A recent head-to-head study found that
produced or compounded as a ‘bioidentical’ product, are
venlafaxine (37.5 mg per day increasing to 75 mg con-
synthesized usually from the vegetable yam and are identi-
trolled release) was equally effective but better tolerated
cal to ovarian estrogens.
than gabapentin (300 mg once per day increasing to
• Other so-called ‘natural’ but synthesized human hormones
300 mg three times per day) in breast cancer patients.
that can be mixed into untested ‘bioidentical’ concoctions
Both products reduced the frequency and severity of
can be progesterone, testosterone, DHEA, thyroxine,
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hot flushes (by 66%) but side-effects were greater with

growth hormone and melatonin.
gabapentin.
• These hormones are usually administered in troches (buc-
• In breast cancer patients, the SNRI venlafaxine was equally
cal lozenges) or transdermal creams, compounded by local
as effective as clonidine in reducing vasomotor symptoms
chemists on the prescription of medical practitioners, in
but clonidine was better tolerated. Efficacy up to 12 weeks
combinations and doses that have never been tested in
has been demonstrated for these agents.
published quality clinical trials.
• In general, these non-hormonal agents reduce hot flushes
• There are inadequate quality data to show the long-term
by 50–60%. This level of reduction appears to be accept-
safety or efficacy of any of these products.
able to many women who wish to avoid hormones.
• Endometrial cancer has been associated with estrogen-
• For those with mild/moderate hot flushes, it is reasonable
containing bioidentical hormones. If used in the bioidenti-
For personal use only.

to start with clonidine treatment. For moderate to severe

cal mixture at all, the progesterone used may not inhibit
hot flushes, or, when clonidine fails or is not available,
estrogen-induced endometrial hyperplasia.
consider venlafaxine or gabapentin. These agents may act
• Hormonal assay of saliva is sometimes claimed as a way
by different mechanisms, so, if one fails or is not well
of assessing hormonal need and of titrating the com-
tolerated, the other can be tried. If these are not effective,
pounded ‘natural’ hormones. There are no data to show
consider paroxetine, but avoid in those on tamoxifen.
that salivary hormonal assay can reliably achieve these
Citalopram can be considered in tamoxifen users.
aims.
• A key consideration in breast cancer patients using non-
• Bioidentical hormones are extensively marketed direct to
hormonal agents is concomitant tamoxifen use. Agents
the public on the internet and in other media, often with
which inhibit the enzyme CY2D6 can affect tamoxifen
unproven and unlikely claims such as they have no
metabolism and may reduce the efficacy of tamoxifen in
side-effects, are safe, will help you lose weight and are
preventing new breast cancers or their recurrence. Agents
anti-aging.
which interact with the cytochrome P450 system include
• Locally compounded ‘bioidentical’ hormones are not sub-
paroxetine, fluoxetine and buproprion and these should
ject to the scrutiny of pharmaceutical regulatory bodies in
not be used in conjunction with tamoxifen for the treat-
many countries and the manufacturers can avoid having to
ment of depression or vasomotor symptoms. If antide-
test their products for quality control, safety and efficacy.
pressants are to be used with tamoxifen, venlafaxine,
• These unproven products and the associated inaccurate
desvenlafaxine, citalopram and escitalopram appear to
saliva tests are usually promoted for commercial gain and
be safe.
are much more expensive than proven registered pharma-
• Sudden cessation of a SNRI or SSRI may cause withdrawal
ceutical hormone therapies.
symptoms and they should be discontinued gradually by
• All main-stream scientific, clinical and regulatory bodies
reducing the dose over 2 weeks.
in women’s health advise against the prescription and use
of these hormones.
• The prescriber is at risk of future medico-legal claims.
POSTMENOPAUSAL VAGINAL ATROPHY

Pharmacological agents for vasomotor symptoms • Vaginal atrophy becomes clinically apparent 4–5 years
after the menopause and objective changes as well as
• The mechanisms underlying vasomotor symptoms are still subjective complaints are present in 25–50% of all post-
not well understood. menopausal women.

Climacteric 329
 Updated IMS recommendations on menopausal hormone therapy de Villiers et al.

• Postmenopausal women have a poor understanding of • A SERM/estrogen combination (CEE/bazedoxifene),

vaginal atrophy and it is often considered a taboo subject. developed to treat menopausal symptoms and osteoporo-
• It is essential that health-care attendants routinely engage in sis, has completed phase III trials and is seeking regulatory
open and sensitive discussion with postmenopausal women approval.
about their urogenital health to ensure that symptomatic • Approval of a dose-appropriate androgenic formulation
atrophy is detected early and managed appropriately. for women for desire/arousal/orgasmic disorder is needed
• Treatment should be started early and before irrevocable to abrogate the need for physicians prescribing com-
atrophic changes have occurred. pounded testosterone or modifying doses of testosterone
• Treatment needs to be continued to maintain the benefits. formulated for men.
• All local estrogen preparations are effective and patient
preference will usually determine the treatment used.
Route of administration
• All currently available topical estrogens are absorbed, the
extent depending on dose and formulation.
• Non-oral estradiol and progestogens avoid the first-pass
• Additional progestogen is not indicated when appropriate
metabolism and therefore have the potential for less stimu-
low-dose, local estrogen is used although long-term data
lation of the liver proteins and a neutral metabolic profile.
(more than 1 year) are lacking.
• The risk of VTE and stroke is less with transdermal than
• If estrogen is ineffective or undesired, vaginal lubricants
with oral estradiol.
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and moisturizers can relieve symptoms due to dryness.

• First uterine pass of vaginal delivery of progestogens leads
• There are few data on the use of vaginal estrogens in
to adequate local concentrations and good endometrial
women with gynecological hormone-responsive cancers so
protection, but with very low systemic progestogen levels.
they should be used with discretion.
• The combination of non-oral administration of estradiol
• Use of local estrogen in women on tamoxifen or aromatase
and direct intrauterine delivery of progestogen or vaginal
inhibitors needs careful counselling and discussion with
ring delivery of progesterone may improve compliance.
the patient and the oncology team.
Long-term, good-quality studies are still needed.
• Estriol and testosterone preparations may be an option for
such patients but more studies are needed.
INFLUENCE OF METHODOLOGY AND
For personal use only.

EPIDEMIOLOGY ON PERCEPTION OF MHT

NEW HORMONAL THERAPIES
AND REGIMENS • There is a hierarchy of scientific evidence which should be
taken into account when drawing conclusions from any
Newly approved medications scientific investigation. In general (from the highest stand-
ard or level of evidence to the lowest), the standards of
• Low- and ultra-low-dose oral and transdermal prepara- evidence are replicated findings from high-quality RCTs,
tions appear to maintain benefits for symptom relief and RCTs, cohort studies, case–control studies, case series and
osteoporosis while minimizing side-effects and risks. case reports, and, lastly, expert opinion. However, RCTs
• A number of new SERMs have been approved by regula- and observational studies must be interpreted with
tory agencies for indications related to osteoporosis. caution, particularly with reference to MHT.
• Ospemifene, an oral SERM, has received FDA approval • Observational studies (e.g. Nurses’ Health Study) are pri-
for the treatment of moderate to severe dyspareunia. marily used for hypothesis development and do not pro-
• The IMS recommendations on management of vaginal vide strong evidence of causality. Inherent biases in many
atrophy have highlighted the excellent benefit/risk ratio of observational studies of MHT typically include: selection
estrogenic and non-hormonal vaginal preparations. bias – healthier women prescribed MHT; recall bias – less
• An ultra-low-dose 10 μg estradiol vaginal tablet has received healthy women may not accurately recall prior hormone
regulatory approval and is now available globally. usage; prevention bias – monitoring and treating more
• A new injectable monoclonal antibody, targeting RANK intensively in women prescribed MHT; compliance bias –
ligand (denosumab) is available for the prevention of frac- patients with greater adherence (even to placebo) have
tures in postmenopausal women with osteoporosis and better outcomes; survivor bias – MHT may be stopped due
high fracture risk. to illness; prevalence-incidence bias – early adverse effects
of MHT may not be observed if the user dies before
becoming part of cohort.
Late-stage products • RCTs (e.g. the WHI) are primarily used for hypothesis
testing, to prove or disprove cause and effect. They can
• Clinical studies are ongoing into the possible use of vaginal be downgraded in their level of evidence due to factors
DHEA for atrophy and low libido. such as: poor compliance and large dropout rate, loss of
• Studies of SSRI and SNRIs are ongoing for treatment of blinding, and non-generalizability (lack of adequate
vasomotor symptoms. representation of the applicable group of women). It has

330 Climacteric
 Updated IMS recommendations on menopausal hormone therapy de Villiers et al.

been argued that the WHI should be downgraded to a level also influence clinical decision-making, particularly by
of evidence equivalent to that of a well-conducted obser- those less familiar with the primary data being reported
vational cohort study, primarily due to loss of blinding. by the media. Each new news report is often treated as if
• The World Health Organization Council for International it were the most important and of the highest quality, often
Organizations of Medical Sciences (CIOMS) classifies the to the exclusion of other scientific evidence. For example,
frequency of drug reactions, which would include the the initial results of the WHI estrogen–progestogen arm
impact of MHT or estrogen therapy, as: received enormous media coverage – more than 400 news-
paper stories and 2500 television-radio stories in the US
Very common  1/10 ( 10%)
alone, yet subsequent WHI reports have received much less
Common (frequent)  1/100 and  1/10
press coverage, leading to the impression that surgically
( 1% and  10%)
menopausal women on estrogen without progestogen have
Uncommon (infrequent)  1/1000 and  1/100
similar risks as noted in the initial reports.
( 0.1% and  1%)
• The press more often focuses on negative outcomes (i.e.
Rare  1/10 000 and  1/1000
breast cancer) than on positive findings such as fracture
( 0.01% and  0.1%)
reduction or cardiovascular disease reductions in younger
Very rare  1/10 000 ( 0.01%)
women. Media coverage sometimes includes superficial
However, these frequencies do not necessarily correspond and uncritical evaluations.
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to statistical significance. Rare findings in large RCTs and • However, most journalists write well-balanced accurate
observational studies may be statistically significant articles given the correct information. It is important that
because of the large sample size, but may be of minor health professionals present the facts to the media in a
clinical importance in their application to a particular professional, clear, unbiased way so that accurate report-
patient in the clinical setting. Failure to provide a clinical ing can take place.
context is often a problem in understanding and interpret- • Media coverage has done a good job of telling women what
ing study outcomes. to be concerned about if they are using MHT, but a poor
job of providing the information women need to determine
• Future guidelines from the IMS will include the levels of
whether the latest findings apply to them. It is important
evidence and grade of recommendations based on the
that health professionals provide this information for
For personal use only.

available data.
women to individualize the benefits and risks of MHT.
• There is a general distrust of large organizations and par-
INFLUENCE OF THE MEDIA AND ticularly of research done by the pharmaceutical industry
PERCEPTION OF MHT despite conformance to regulatory agencies, both in North
America (the Food and Drug Administration; Health Can-
• The mass media has a tremendous influence over what the ada) and in other countries of the world (e.g. European
public ‘knows’ about MHT. Media-driven perceptions Medicines Agency).

ACTION POINTS

How should we optimize the impact of the Global Consensus • Pharma industry: Effective communication with pharma
Statement and the Updated 2013 Recommendations? These industry to help reverse negative commercial decisions on
six action points are suggested: MHT products and encourage research and development
of new regimens.
• Health Departments and Regulators: Immediate discussions to
• Menopausal women: Improve access to information for
encourage a change of policy to a more lenient stance on MHT
given new favorable data in younger menopausal women, e.g. women about menopause, treatment of menopausal symp-
removal of the ‘black box’ warning for women  60 years. toms, health promotion, and disease prevention, thus
• Prescribers: Expansion of clinical education and training in empowering women to optimize their quality of life and
menopause, particularly in primary care, to increase confidence future health.
in management of the menopause and health promotion. • MHT: Planning of future research programs to seek clari-
• Media: Positive engagement of the media to increase fication of the differences in action and risk profiles of
awareness of menopause issues and to highlight new data various MHT regimens – the term ‘class effect’ is outdated
on MHT. and misleading where MHT is concerned.

Climacteric 331
 Updated IMS recommendations on menopausal hormone therapy de Villiers et al.

Conflict of interest The authors report no associations or GmbH, Bayer Pharma AG, Besins Healthcare, Novo
fi nancial relationships with any pharmaceutical company, Nordisk, Pfi zer Inc., Shionogi Inc. and Teva.
other than consultative agreements, honoraria for lecturing 2011 Updated IMS Recommendations Authors: D. W. Sturdee
at scientific meetings, and research support. Details of all and A. Pines on behalf of the International Menopause Society
disclosures have been updated and are on file in the IMS Writing Group. Writing Group: D. F. Archer, R. J. Baber,
Secretariat. D. Barlow, M. H. Birkhäuser, M. Brincat, L. Cardozo,
T. J. de Villiers, M. Gambacciani, A. A. Gompel, V. W. Henderson,
C. Kluft, R. A. Lobo, A. H. MacLennan, J. Marsden,
Source of funding The IMS Workshop in November R. E. Nappi, N. Panay, J. H. Pickar, D. Robinson, J. Simon,
2012 was supported by unrestricted grants from Abbott R. L. Sitruk-Ware and J. C. Stevenson.

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