Counseling in menopausal women: How to address the benefits and risks of menopause hormone therapy. A FIGO position paper

Menopause marks the end of menstrual cyclicity and, depending on individual vulnerability, has several consequences related to gonadal steroid deprivation, especially if it is premature. Menopause may be more burdensome for some women than for others. Individual factors, such as personal history, socioeconomic status, ethnicity, and current health conditions, affect symptomatology and, thereby, the menopausal experience. In addition, some menopausal symptoms, such as severe hot flashes, sleep disorders, and depression, are markers of future health risks. Counseling is a fundamental part of health care in the peri‐ and postmenopause periods. It must include an assessment of the patient's symptoms, needs, desires, and risk profile to address the benefits and risks of menopausal hormone therapy (MHT) on an individual basis and promote a healthy lifestyle. Indeed, healthcare practitioners can and must protect the health and lives of mid‐life women by increasing awareness of menopausal symptoms and ensuring healthcare options, especially MHT. The type and duration of MHT should be tailored based on the patient's history, menopausal age, physical characteristics, and current health status so that the benefits always outweigh the risks. This FIGO position paper focuses on the benefits and risks of MHT on health domains, target organs, and systems, and on systemic and vaginal MHT regimens, to provide indications that can be used in the clinical practice for menopausal counseling. Moreover, it offers insights into what FIGO considers the mainstay for the healthcare management of women in peri‐ and postmenopause, worldwide.


| BACKG ROU N D
Menopause represents an opportunity for healthcare practitioners to comprehensively audit a woman's physical and psychological condition and to ensure due attention is given to any symptoms or risks she may present that could harm her future health.
With the increase in longevity and extensive research in recent decades, there has been a greater understanding of the impact and health implications that menopause has on women's lives.
Menopause marks the end of menstrual cyclicity and entails several consequences related to gonadal steroid deprivation.In most women, symptoms of menopause substantially affect their quality of life and arise at a time when they still occupy an essential role in the family and society.Early symptoms, such as hot flashes and sweats, mood swings, disturbed sleep, migraine, and poorer cognitive performance, are disruptive and may occur as early as a few years before the final menstrual period (FMP). 1 Late-onset manifestations, such as central body fat distribution, metabolic and cardiovascular consequences, urogenital atrophy and sexual dysfunction, osteoporosis, and an increased risk of disabling fractures, are frequently insidious. 1Moreover, menopause accelerates biological aging, especially if severely symptomatic. 2,3tural menopause, secondary to the physiological depletion of ovarian reserve, involves a transition from the reproductive to the post-reproductive phase, termed perimenopause, that may occur over several years. 4[7][8] Worldwide, most women experience their FMP between the ages of 45 and 55 years. 9Late-onset menopause, occurring after the age of 55 years, bears some health risks, such as an increase in estrogen-sensitive tumors such as breast cancer, as well as benefits, mainly a reduced cognitive decline and risk of CVD, [10][11][12] due to the more prolonged lifetime exposure to ovarian hormones. 11,12[13] Menopause may be more burdensome for some women than for others.In addition, individual factors, such as personal history, socioeconomic status, ethnicity, and current health conditions, especially obesity, affect the menopausal experience. 1 Vasomotor symptoms, the most disrupting manifestations affecting nearly 75% of women, may last an average of 7.4 years. 14,15e prevalence of vasomotor symptoms is still significant in older women.Indeed, 39% of women aged 65-69 years, 31% 70-74 years, and 24% aged 75-79 years still report hot flashes. 16[19] Women transitioning through menopause often experience problems with memory, concentration, and learning, 20 recently termed brain fog, 21 which causes considerable distress.3][24] However, most difficulties are limited to perimenopause. 20 menopause 6 and increases the risk of full-blown dementia, mainly if it occurs before the age of 45 years. 257][28] In addition, migraine frequency may also increase in susceptible women. 291][32] This phenomenon is accelerated in women who have had surgical menopause. 54][35] Together, these factors increase the risk of cardiovascular and cerebrovascular events, such as myocardial infarction and stroke, especially in women with premature ovarian insufficiency. 36 its early stages, menopause is commonly associated with decreased sexual libido 37 and, later on, vulvovaginal atrophy and dyspareunia, which can lead to sexual dysfunction 38,39 and interfere with social and psychological well-being.Genitourinary syndromes will also include dysuria and recurrent urinary tract infections. 38inary incontinence is probably related to weight gain and an increase in waist-to-hip ratio during this period of life. 40nopause is directly responsible for the never-ending decrease in bone mineral density, which is rapid within the first 3-5 years from the FMP. 41As a result, osteoporosis, initially in trabecular bone and then in cortical bone, increases the risk of fractures, which occur most frequently in the spine, hip, and wrist. 41In addition, sarcopenia and the loss of muscle tone that ensue after menopause are facilitating factors for fractures. 42althcare practitioners should also bear in mind that some symptoms of menopause are markers of future health risks.Severe vasomotor symptomatology and poor sleep quality are associated with an increased risk of CVD 43,44 and depression. 45Moreover, vasomotor symptoms, sleep disorders, and depression might increase the susceptibility to develop cognitive dysfunction. 46,47Severe hot flashes have also been associated with an increased risk of osteoporosis and bone fracture. 48ere may be an individual vulnerability, whereby some women have more symptoms and more significant morbidity related to the loss of exposure to estrogen.

| FI G O P OS ITI ON ON THE ISSUE
Healthcare practitioners can, and must, protect the health and lives of mid-life women by increasing awareness of the symptoms of menopause, providing healthcare options, namely menopausal hormone therapy (MHT), and promoting healthy lifestyle changes.
Modifications made before or during the menopausal transition have the most significant impact, even at an older age.
In women with bothersome symptoms of menopause, namely vasomotor and urogenital, and absence of contraindications (Box 2), MHT is the first line of treatment.However, MHT should be personalized based on the patient's history, chronological and menopausal age, physical characteristics, and current health status so that the benefits always outweigh the risks.
To obtain the most significant benefits, MHT should be started as soon as possible after menopausal symptoms appear and continued while the risk-benefit ratio is favorable.

| Longevity
[51] Women with premature menopause who start MHT before the age of 50 years achieve the most significant benefit in terms of longevity. 50

| Central nervous system
Vasomotor symptoms MHT effectively alleviates vasomotor symptoms, even at low doses. 52,53Estrogen-progestogen preparations and the bazedoxifene/conjugated estrogens (BZA/CE) combination are the most successful. 54Tibolone is also a valid option to provide relief from hot flashes. 55[54][55]

Sleep
7][58] All improvements in sleep domains correlate with a reduction in vasomotor symptoms, except for sleep latency and sleep efficiency, 56,57 demonstrating that the positive effect of EPT on subjective sleep cannot be fully explained by decreased bothersome vasomotor or depressive symptoms. 57The explanation may lie in additional underlying biological mechanisms for EPT-mediated improvements in self-reported sleep, such as a reduction in the hypothalamus-pituitary-adrenal axis sensitivity and reactivity. 57Progesterone alone is also beneficial for sleep. 59e BZA/CE combination favors sleep in postmenopausal women with moderate to severe vasomotor symptoms. 60

Cognition and mood
In women aged 75 years or older, a long duration of past MHT exposure, either with estrogen alone or with estrogen-progestogens, is positively associated with cognitive status, especially when MHT is started within 5 years from the FMP. 11deed, the notion of a "critical window" of MHT has arisen whereby MHT may improve cognition when started in the perimenopausal period but become deleterious if started too far from the FMP. 61e evidence suggests that the use of MHT, particularly in women who have had surgical menopause, especially when young, is protective against cognitive impairment. 61,62kewise, MHT is likely to be more efficacious on mood when started at a younger age.Furthermore, MHT and antidepressants seem to have a positive cumulative effect on clinical depression. 61 addition, in women who are APOE4 carriers and therefore at high risk for Alzheimer's disease, early MHT may represent an effective targeted strategy to mitigate their higher lifetime risk of Alzheimer's disease. 63,64rther investigation in this area is still warranted, as data from the literature are somewhat contradictory.Indeed, recent North European Finnish/Danish case-control studies, based on national registries, have pointed towards a relationship between MHT and the risk of developing Alzheimer's disease and/or late-onset dementia. 65,66wever, these studies have several essential biases.First, they are not randomized controlled trials.Second, the women were prescribed MHT because of vasomotor symptoms, often associated with sleep and mood disorders, which make them intrinsically more prone to developing cognitive dysfunction. 67,68Women with a predisposition for dementia may also have been prevalent in the Danish trial population as, during the study years, MHT was prescribed to prevent cognitive deterioration.Finally, in the Danish report, an increase in the risk of dementia was present for a duration of therapy as small as less than 1 year, suggesting the presence of confounding factors (alcohol, smoking, social isolation) that weaken the hypothesis of a direct causation.

Sexuality
In early postmenopause, transdermal estradiol-based treatment significantly improves overall female sexual function, whereas oral conjugated equine estrogens (CEE)-based treatment has less effect. 69Tibolone is the most effective therapy for restoring sexual function, including desire, sexual interest, and satisfaction, which may be attributed to its combined estrogenic and androgenic properties. 702][73] Moreover, it should be stopped if there is no response within 6 months of treatment. 69Women with premature and early surgically induced menopause are potential candidates for testosterone therapy because of their experience of abrupt loss of ovarian androgen and substantial prevalence of hypoactive sexual desire disorder. 72,74hydroepiandrosterone (DHEA) oral supplementation may be used in women with low sex drive associated with low levels of circulating dehydroepiandrosterone. 75,76 Prasterone (vaginal DHEA) may be used efficiently to improve all sexual domains in women with vulvovaginal atrophy and moderate to severe dyspareunia. 76,77

| Cardiovascular system
The effect of MHT differs according to age at initiation of MHT and time since menopause.
4][85][86][87] It is noteworthy that those benefits persist years after the cessation of MHT. 77,82[85][86][87] In the second decade after the FMP, estrogens have a fairly neutral effect, and therefore, women may still enjoy the benefits of MHT without fearing an increase in cardiovascular events. 83When more than 20 years have passed from the FMP, MHT should not be started as this could significantly increase cardiac thrombo-occlusive events due to a vascular disease that has developed over time. 83nerally speaking, lifetime cumulative estrogen exposure decreases the risk of ischemic and hemorrhagic stroke. 88This is in line with the finding that transdermal estrogens [89][90][91][92] and oral estradiol 92 tend to decrease the risk of stroke, whereas the use of oral CEE, at intermediate and high doses, increases the risk of ischemic stroke. 89me of oral CEE initiation from FMP may play a role, as the longer the time lapse from FMP, the higher the risk. 92ansdermal estrogens do not increase the risk of venous thromboembolism (VTE), [93][94][95] while oral estradiol, and particularly CEE, do. 94other critical determinant of thrombotic risk is the type of progestogens associated with estrogens used by women with an intact uterus.[95] Therefore, the use of transdermal estrogens and, where indicated, micronized progesterone or dydrogesterone should be preferred in women who have an increased baseline thrombotic risk. 96bolone does not increase the risk of VTE 94 but does increase the risk of stroke in women aged 60-85 years. 97Therefore, it should not be used in elderly women or those with stroke risk factors, such as hypertension, tobacco smoking, diabetes, and/or atrial fibrillation. 97e cardiovascular risk profile is acceptable for the BZD/CE combination. 98

| Endocrine system
Estrogen and EPT improve insulin resistance and lower progression to diabetes in postmenopausal women. 99,100The tissue-selective estrogen complex (BZD/CE) has neutral effects on glucose metabolism, 101 while tibolone reduces insulin sensitivity and should not be used in women with prediabetes or diabetes. 102

Breast
According to randomized clinical trials, CEE-only therapy is associated with a lower incidence and mortality of breast cancer incidence, 103 and estradiol-only therapy carries no risk for breast cancer. 104T in women with an intact uterus has a variable impact on the risk of breast cancer, depending on the type of progestogens used in combination with estrogens: medroxyprogesterone acetate (MPA), [103][104][105][106][107] norethisterone (NETA), [104][105][106] and levonorgestrel (LNG) [104][105][106] increase the risk of breast cancer, whereas dydrogesterone 101,104 and especially progesterone, 104,106 do not.
Due to their neutral effect on the risk of breast cancer, natural progesterone or its isomer, dydrogesterone, should be considered the first choice for endometrial protection in women with an intact uterus. 104,106,107ring CEE + MPA treatment, the risk of breast cancer increases with the duration of use, 105 but it drops substantially in the early post-treatment phase (within 2.7 years), although the relative risk remains higher than 1 through 5.5 years (median) of additional follow-up. 105,108vertheless, in the Finnish population, the risk of breast cancer mortality was reported to be reduced not only in women using estradiol-only therapy but also in those using estradiol-progestogen regimens (43% NETA, 30% MPA), especially in the age groups of 50-59 and 60-69 years. 109deed, neither unopposed estrogen nor estrogen-progestogen regimens used after surgical menopause or premature ovarian insufficiency are associated with an increased risk of young-onset breast cancer before the age of 50 years. 110bolone has a neutral effect on the risk of breast cancer only with a short duration of use (<5 years).Thereafter, the risk increases. 104,106However, in the Korean population, tibolone has been shown to lower the risk of breast cancer, both after short and long duration of use. 111though the literature is scant, BZA/CE appears to have a favorable breast-related safety profile as it does not increase mammographic breast density 111 and has been shown to have a neutral effect on the risk of breast cancer over follow-up periods of 5 and 7 years. 112,113erus Systemic estrogen-only therapy can cause endometrial hyperplasia or cancer in women with an intact uterus and should, therefore, always be combined with a progestogen. 114Continuous combined EPT is associated with a decreased risk of endometrial cancer, especially in obese women. 115,116bolone is associated with an increased risk of endometrial cancer, particularly for type 1 endometrial cancer and especially with a long duration of use (10+ years). 117ary Both estrogen-only and estrogen-progestogen hormone therapies are associated with an increased risk of serous and endometrioid ovarian cancer. 118Likewise, tibolone is associated with an increased risk of epithelial ovarian cancer overall, particularly serous ovarian cancer, especially with a long duration of use (10+ years). 117men with a history of endometriosis must be informed of the possibility of disease recurrence with MHT.In these women, even when subjected to hysterectomy, continuous combined preparations and tibolone should be considered instead of unopposed estrogens. 119Moreover, recent data suggest that in women with a history of endometriosis or de novo endometriosis, the risk of epithelial ovarian cancer appears to be increased after estrogen-only treatment, whereas EPT and tibolone therapy are neutral. 120ulva, vagina and urinary tract Estrogen, estrogen-progestogen, and tibolone therapy reduce bothersome symptoms of vulvovaginal atrophy. 121,122e effect of MHT on urinary symptoms depends on the type used.Systemic MHT may cause urinary incontinence 123 or worsen existing urinary symptoms, while vaginal estrogens improve dysuria, frequency, urge and stress incontinence, and recurrent urinary tract infections. 124reover, it is advisable to inform women with pre-existing pelvic organ prolapse that exposure to systemic estrogen-progestogen regimens might negatively affect this problem. 125ally administered ospemifene is an effective non-estrogen systemic treatment specifically for vulvovaginal atrophy with a good cardiovascular safety profile. 126,127

| Gastrointestinal system
Estrogen, estrogen-progestogen. and tibolone therapy lower the risk of colorectal cancer in women. 128,129

| MHT REG IMENS
When deciding to begin MHT, the route of delivery, dose, and type of estrogens or estrogen-progestogens should be carefully pondered based on a woman's characteristics (Table 1).

| Systemic MHT
In healthy, normal-weight early postmenopausal women (approximately 5-8 years from the FMP), the following regimens are generally suitable: oral estrogens or transdermal estradiol at medium doses combined with cyclic or continuous progestogens for endometrial protection; 130 tibolone at low to standard doses; 55 and tissue selective estrogen complex at the standard dose. 101 healthy late postmenopausal women, MHT may be continued but seldom begun, 86,87 with the following regimens: 130 low doses of transdermal estradiol 89,91 or low doses of oral estrogens, 89 associated with micronized progesterone or its isomer, dydrogesterone, administered continuously, where there is an indication for endometrial protection; 130 and low-dose tibolone. 55 overweight (body mass index [BMI, calculated as weight in kilograms divided by the square of height in meters] >25) early postmenopausal women (approximately 5-8 years from the FMP), the following regimen is generally suitable: transdermal estrogens 87,89 combined with cyclic or continuous progestogens. 130 women who have had surgical removal of the ovaries before the age of 50 years, the following regimens are generally suitable: medium to high doses of oral estrogens or transdermal estradiol, in combination with appropriate doses of progestogens, where indicated; 130 transcutaneous testosterone therapy may be necessary when hypoactive sexual desire disorder is diagnosed at a dose that achieves the normal premenopausal range of circulating testosterone levels. 71 women with primary ovarian insufficiency (POI) needing contraception, the following regimens are generally suitable for the first few years after diagnosis: low-dose estrogen-progestogen contraceptives; and estrogen associated with a levonorgestrel (LNG) intrauterine system. 75men transitioning through perimenopause with contraceptive needs may also use the abovementioned regimens.
In women with POI without contraceptive needs, the following may be used: medium to high doses of oral or transdermal estradiol, combined with appropriate doses of progestogens, where indicated. 130 women with symptoms of fatigue, depression, and/or a reduced sexual desire associated with low endogenous DHEA levels, supplemental DHEA may be considered at a starting dose of 10 mg/ day up to 25 mg/day alone or as an adjunct to systemic MHT. 75,76ble 1 lists standard systemic MHT regimes.

| Vaginal MHT
Vaginal estrogen therapy is the first-line treatment for the symptoms of vulvovaginal atrophy, such as dryness, dyspareunia, itching, and/ or burning. 131Moreover, it has been proven efficient in ameliorating dysuria, urinary frequency/urgency, and recurrent lower urinary tract infections. 132,1335][136] Moreover, it may be used alone, in which case there is no need for endometrial protection or in association with systemic MHT (Box 3).Prasterone (vaginal DHEA) treatment alleviates vulvovaginal atrophy, difficult lubrication, dyspareunia, and arousal. 76,77cause of their neutral effect on the risk of breast cancer and very low systemic absorption, both low-dose vaginal estrogens and prasterone may be considered an off-label treatment in women with breast cancer when symptoms of genitourinary menopausal persist after trials of non-hormonal interventions and quality of life is adversely affected. 137Box 3 lists standard vaginal MHT formulations.

| Compounded bioidentical hormone formulations
Bioidentical hormones have been defined as "substances that have the same chemical and molecular structure as hormones that are produced in the human body". 138However, this definition does not address the manufacturing, source, or delivery methods of the products and, therefore, may be misleading as it can cover both Food and Drug Administration (FDA)-approved formulations as well as

TA B L E 1 (Continued)
non-FDA-approved custom-compounded products that are prepared for an individual patient by a pharmacist in response to a licensed practitioner's prescription. 139mpounded bioidentical hormone products have often been promoted as a "safe"/"safer", "natural", and more effective alternative to manufactured FDA-approved hormone therapies to relieve symptoms of menopause. 138However, there is little or no scientific evidence to support the marketing myth of such a claim. 140deed, there are major concerns about compounded bioidentical hormone products that may consist of untested and unapproved combinations of multiple hormones and be used through nonstandard or untested routes of administration, such as subdermal implants, pellets, or troches. 141[142] Moreover, pharmacokinetic studies have reported that their bioavailability, bioactivity, and potency differ from batch to batch. 140The variable absorption of compounded estrogens and progesterone may lead to under-or overdosing, which could increase the risk of estrogen-stimulated cancers, especially endometrial cancers. 140Therefore, although there are some exceptions where compounded bioidentical hormone preparations may be acceptable, such as in cases of allergy to ingredients or dosages not available in FDA-approved products, 140,141 FIGO recommends the use of approved, regulated, and monitored bioidentical systemic and vaginal hormone therapies.

| FOLLOW-UP AND RE A SS E SS MENT
Regular reassessment of the woman's health status is mandatory.
Once optimal control of symptoms has been achieved, women should be checked annually, especially if they are on MHT.
Body weight and blood pressure should be monitored.Moreover, menopausal women must undergo timely screening for breast cancer by mammography, which hormone therapy does not interfere with. 143trasound examination of the endometrium in women on MHT, by any route, that reports bleeding is mandatory and may prompt hysteroscopic endometrial sampling if the thickness is over 4 mm. 144Recurrent bleeding should always be investigated by endometrial biopsy, whatever the endometrial thickness assessed by ultrasound. 144The monitoring of endometrial thickness in asymptomatic women is less specific and the ideal cutoff for invasive procedures has not been investigated thoroughly.Therefore, the need for further investigation should be based on the individual risk factors for endometrial cancer. 145,146T may be continued as long as women maintain their health status and contraindications do not develop.The benefits must always outweigh the risks. 130

| LIFE S T YLE
Well-tailored MHT should not preclude healthy lifestyle changes, which are the mainstay of primary prevention.
Moderate-intensity physical activity for 150-300 min per week or vigorous-intensity physical activity for 75-150 min per week is recommended to reduce cardiovascular and cancer morbidity and mortality in all adults. 147Breaking up prolonged sitting with standing or walking for 5 min every 20 min also has a positive impact on cardiovascular risks. 148gh-intensity exercise increases lumbar spine BMD. 149Although evidence on the effects of multicomponent exercise programs in postmenopausal and older women remains conflicting, combining resistance training using high-intensity loads and impact-aerobic activities may be the best strategy to enhance muscle and bone mass. 150[153][154][155] Maintaining alcohol consumption that meets public health recommendations and avoiding smoking are also key to reducing such risks. 156,157st but not least, engaging in leisure activities, such as visiting art exhibitions, reading, listening to music, singing, and painting, is positively associated with a lower risk of depression, dementia, and death by any cause.[160][161][162][163]

| SUMMARY OF KE Y P OINTS
• Post-reproductive health is a global priority as menopause comes at a time when women still occupy an essential role in the family and society.Counseling on the benefits and risks of MHT and lifestyle education is a must.
• Type and duration of MHT should be tailored based on patient history, menopausal age, physical characteristics, and current health status so that the benefits always outweigh the risks.
• Menopausal women should undergo regular reassessment of their health conditions, especially if they are on MHT.

| Longevity
• Women on MHT to relieve their symptoms of menopause will benefit from a significant increase in longevity.• who develop POI and start MHT before the age of 50 years achieve the most significant benefit in terms of longevity.

| Vasomotor symptoms
• Women experiencing menopausal vasomotor symptoms, with no contraindications for systemic hormone therapy, should be offered MHT to relieve their symptoms.

| Sleep
• Women with sleep disorders prescribed MHT to relieve their symptoms of menopause will benefit from a significant improvement in sleep.

| Cognition and mood
• Women who have had surgical menopause, especially when young, should be offered MHT to reduce their lifetime risk of cognitive impairment.
• Women who begin MHT close to the FMP to relieve their symptoms of menopause will benefit from a significant reduction in risk of cognitive deterioration.

| Sexuality
• Tibolone is the most effective therapy in terms of restoration of sexual function.
• In early postmenopause, transdermal estradiol-based treatment is associated with a significant improvement in overall female sexual function, whereas oral CEE-based therapy is less effective.
• Women with hypoactive sexual desire disorder, whose sexual function does not improve under MHT, can be offered a short trial of transdermal testosterone.

| Osteo-skeletal system
• Women on MHT to relieve their symptoms of menopause will benefit from a significant reduction in osteoporosis-related fracture risk, which persists well after the cessation of MHT.

| Cardiovascular system
• Women on MHT to relieve their symptoms of menopause will benefit from a significant reduction in the risk of CVD if it is begun within 10 years from the FMP.
• Transdermal estrogens and, where indicated, micronized progesterone or dydrogesterone should be the first choice MHT, especially in women with a baseline increased thromboembolic risk.

| Endocrine system
• Women with prediabetes or diabetes on estrogen or estrogenprogestogen MHT to relieve their symptoms of menopause will benefit from a significant improvement in metabolic compensation.
• Women with prediabetes or diabetes should not be offered tibolone to improve their symptoms of menopause.

| Breast
• Women with premature ovarian insufficiency on MHT will not increase their risk of young-onset breast cancer before the age of 50 years.
• Women on estrogen-only MHT to alleviate symptoms of menopause will not increase their risk of breast cancer.
• Women with an intact uterus should be offered natural progesterone or dydrogesterone for endometrial protection to avoid increasing their risk of breast cancer.
• Tibolone should be used for a short period of time (<5 years) to avoid increasing the risk of breast cancer.

| Uterus
• Women with an intact uterus on continuous combined estrogen-progestogen MHT to relieve their symptoms of menopause will benefit from a significant reduction in the risk of endometrial cancer.
• Women with an increased baseline risk for endometrial cancer due to individual factors should not be offered tibolone to relieve their symptoms of menopause.

| Ovary
• Women at risk of ovarian cancer must be informed that both estrogen-only and estrogen-progestogen hormone therapies, as well as tibolone treatment, increase the risk of epithelial ovarian cancer.
• Women with a history of endometriosis can be offered combined estrogen-progestogen or tibolone to relieve their symptoms of menopause.

| Gastrointestinal system
• Women on MHT to relieve their symptoms of menopause will benefit from a significant reduction in the risk of colorectal cancer.

BOX 2
ContraindicationsThese contraindications do not apply to transvaginal-based estrogen therapies, as the serum concentration of estrogen from this route is extremely low.