2016 IMS Recommendations on womens midlife health and

2016 IMS Recommendations on women’s midlife health and menopause hormone therapy The IMS Writing Group 2016 IMS Recommendations. Climacteric 2016; 19: 109– 50

2016 IMS Recommendations on women’s midlife health and menopause hormone therapy Methodology • Major databases were searched and information drawn from International consensus statements published by bodies including IMS, EMAS and NAMS • This guideline was produced by a body of experts not exclusively confined to the IMS • Particular attention was paid to publications from 2013 onwards • The definitions of evidence used are detailed in Governance advice No. 1 of The Royal College of Obstetricians and Gynaecologists • Definitions of levels of evidence and grades of recommendations used in this guideline are set out in the next slide • Where possible, recommendations are based on and linked to the evidence that supports them • Where good evidence is lacking but advice is given based on extensive experience, this is annotated as good practice points 2016 IMS Recommendations. Climacteric 2016; 19: 109– 50

Levels of evidence and Grades of recommendations Classification of evidence levels 1++ High-quality meta-analyses, systematic reviews of RCTs or RCTs with very low risk of bias 1+ Well-conducted meta-analyses, systematic reviews of RCTs or RCTs with a low risk of bias 1 - As above but with a high risk of bias 2++ High-quality systematic reviews of case– control studies with a very low risk of confounding and high probability of causality 2+ As above with only moderate probability of causality 2 - Case–control or cohort studies with a high risk of confounding and significant risk on noncausality 3 Non-analytical studies, e. g. case reports 4 Expert opinion A At least one meta-analysis, systematic review or RCT rated 1++ and directly applicable to the population; OR a systematic review of RCTs or body of evidence consisting principally of studies rated as 1+ directly applicable to the target population, and demonstrating overall consistency of results B A body of evidence including studies rated as 2++ directly applicable to the target population, and demonstrating overall consistency of results; OR extrapolated evidence from studies rated 1++ or 1+ C A body of evidence including studies rated as 2++ directly applicable to the target population, and demonstrating consistency of results; OR extrapolated evidence from studies rated 2++ D Evidence level 3 or 4; OR extrapolated evidence from studies rated as 2+ 2016 IMS Recommendations. Climacteric 2016; 19: 109– 50

IMS governing principles on MHT • Menopausal hormone therapy (MHT) remains the most effective therapy for vasomotor symptoms and urogenital atrophy • Other menopause-related complaints such as mood swings, joint and muscle pains and sleep disturbance may improve with MHT • The administration of individualized MHT (including androgenic preparations, when appropriate) may improve both sexuality and quality of life • Consideration of MHT should be part of an overall strategy including lifestyle recommendations regarding diet, exercise, smoking cessation and safe levels of alcohol consumption for maintaining the health of peri- and postmenopausal women • MHT must be individualized and tailored according to symptoms, the need for prevention, personal and family history, results of investigations and each woman’s preferences and expectations • The risks and benefits of MHT differ with age and years since the last menstrual period 2016 IMS Recommendations. Climacteric 2016; 19: 109– 50

IMS governing principles on MHT • Women experiencing a spontaneous or iatrogenic menopause before age 45 and particularly before age 40 are at higher risk of cardiovascular disease and osteoporosis. In these women, in the absence of contraindications, MHT is advised at least until the average of menopause • Counseling on MHT should convey risks and benefits in clear and comprehensible terms, ideally expressed as absolute risk in real numbers • MHT should not be recommended without a clear indication for its use • Women taking MHT should have at least an annual medical consultation • There are no reasons to place a mandatory limit on the duration of MHT • Dose and duration of MHT should be consistent with treatment goals • Whether or not to continue should be decided at the discretion of the well -informed woman and her health professional 2016 IMS Recommendations. Climacteric 2016; 19: 109– 50

Diagnosis of menopause • Menopause is defined as the final/last menstrual period • Menopause is a retrospective clinical diagnosis as the final menstrual period can only be defined if followed by 12 months amenorrhea • Menopause is a natural and inevitable event that happens on average at age 51 in white Caucasians, with ethnic and regional variations • Menopause before age 40 is considered to be premature • Accurate staging of reproductive aging is important from a clinical and research perspective • The gold-standard criteria for staging of reproductive aging were defined by the Stages of Reproductive Aging Workshop + 10 (STRAW + 10) [see next slide] 2016 IMS Recommendations. Climacteric 2016; 19: 109– 50

The Stages of Reproductive Aging in women • Current data indicate STRAW + 10 criteria apply to most but not all women • Criteria cannot be used in PCOS or POI, nor after endometrial ablation or hysterectomy STRAW + 10. Climacteric 2012; 15: 105– 14 2016 IMS Recommendations. Climacteric 2016; 19: 109– 50

Weight gain Key points • • An absolute increase in weight at midlife is not attributable to the menopause [B] The hormonal changes that accompany menopause are associated with increases in total body fat and abdominal fat, even in lean women [B] Maintenance of a healthy diet, avoidance of caloric excess and physical activity are important components of weight management [A] Menopausal abdominal fat accumulation is ameliorated by estrogen therapy, with a reduction in overall fat mass, improved insulin sensitivity and a lower rate of development of type 2 diabetes [A] 2016 IMS Recommendations. Climacteric 2016; 19: 109– 50

Premature ovarian insufficiency Key points • • • Premature ovarian insufficiency (POI) is defined as primary hypogonadism in women younger then 40 Diagnosis is confirmed by FSH > 40 on two occasions 6 weeks apart POI should be effectively treated to prevent an increase in cardiovascular disease, osteoporosis, cognitive decline, dementia and Parkinsonism [B] Investigations should include hormone analysis, autoimmune screen, karyotyping, fragile X premutation testing and pelvic ultrasound The diagnosis should be conveyed in a sensitive and caring manner Women should be provided with adequate information and counseling The mainstay of treatment is MHT and possibly testosterone [C] Treatment should be continued at least until the age of natural menopause Oocyte or embryo donation is the only fertility treatment to have shown proven efficacy 2016 IMS Recommendations. Climacteric 2016; 19: 109– 50

Lifestyle, exercise and diet Key points • • Regular exercise is advised to reduce cardiovascular and total mortality [B] Optimal exercise is at least 150 minutes of moderate intensity per week [B] The intensity of aerobic activity should take into account the older, genderspecific, adult’s aerobic fitness Weight loss of 5– 10% is sufficient to improve many abnormalities associated with the insulin resistance syndrome [B] Smoking should be avoided [A] Lifestyle modifications include socializing and being physically and mentally active A healthy diet should include several servings of fruit and vegetables per day, whole grain fibers, fish twice weekly and low total fat. Salt and alcohol consumption should be limited 2016 IMS Recommendations. Climacteric 2016; 19: 109– 50

Urogynecology 1 Key points • • • Symptoms such as vaginal dryness, soreness, dyspareunia, urinary frequency, nocturia and urgency are extremely common in postmenopausal women There is a wide variation in the symptoms and signs of urogenital aging Urogenital symptoms respond well to estrogen [A] Long-term treatment is often required. Systemic risks have not been identified with low-dose, low-potency estrogens [B] Systemic MHT does not prevent urinary incontinence and is not preferable to topical estrogen therapy in the management of urogenital symptoms and urinary tract infections [B] 2016 IMS Recommendations. Climacteric 2016; 19: 109– 50

Urogynecology 2 Key points • • • Lifestyle changes and bladder training are recommended as first-line therapy for overactive bladder symptoms Antimuscarinic drugs plus local estrogens constitute first-line treatment in postmenopausal women with overactive bladder symptoms [A] All women with proven stress urinary incontinence will benefit from pelvic floor muscle training in the first instance Duloxetine may work synergistically with conservative therapy Some women will ultimately require surgery and retropubic and transobturator tapes are currently the most popular procedures There is currently no role for systemic estrogen therapy in women with pure stress urinary incontinence [A] 2016 IMS Recommendations. Climacteric 2016; 19: 109– 50

Postmenopausal osteoporosis 1 Key points • • • Osteoporosis is a systemic skeletal disease characterized by diminished bone strength with the risk of sustaining a fracture when falling from own body height Osteoporosis is defined as a DXA-derived T score ≤ 2. 5 or the presence of fragility fracture An individual’s 10 -year probability of fracture can be estimated using risk factor calculators such as the FRAX model [A] Intervention thresholds can be based on 10 -year fracture probability but will be country-specific Treatment may be started in patients with a fragility fracture or a T score ≤ -2. 5 or a T score of > -1 and < 2. 5 with additional risk factors [A] 2016 IMS Recommendations. Climacteric 2016; 19: 109– 50

Postmenopausal osteoporosis 2 Key points • • An appropriate assessment of prevalent fractures and secondary causes of osteoporosis should precede any therapeutic decisions Lifestyle strategies should be part of any treatment strategy [A] Choice of pharmacological therapy should be based on a balance of effectiveness, risk and cost MHT is the most appropriate therapy for fracture prevention in early menopause [A] 2016 IMS Recommendations. Climacteric 2016; 19: 109– 50

Skin, cartilage and connective tissues Key points • • Estrogen has an effect on connective tissue throughout the body [A] The marked increase in osteoarthritis in women after the menopause suggests that female sex steroids are important for cartilage homeostasis [B] Cartilage degradation and the need for joint replacement surgery are reduced among users of MHT [A] Menopause is associated with a number of changes in skin health that may be reduced with the use of MHT or topical estrogen therapy [A] 2016 IMS Recommendations. Climacteric 2016; 19: 109– 50

Cardiovascular disease Key points • • In women under age 60 and recently postmenopausal with no evidence of cardiovascular disease, the initiation of estrogen-alone therapy reduces coronary heart disease (CHD) and all-cause mortality [A] Data on daily continuous combined estrogen–progestin are less robust but other combined therapy regimens appear to be protective as shown in Danish and Finnish studies [A] Recent meta-analyses and WHI 13 -year follow-up data all show a consistent reduction in all-cause mortality for MHT users [A] It is not recommended to initiate MHT beyond age 60 years solely for primary prevention of CHD [A] 2016 IMS Recommendations. Climacteric 2016; 19: 109– 50

Venous thromboembolism Key points • • • A careful assessment of personal and family history of venous thromboembolism (VTE) is essential before prescribing MHT Oral estrogen is contraindicated in women with a personal history of VTE [A] Transdermal estrogen should be first choice in obese women with VMS [B] VTE risk increases with age and with thrombophilic disorders The risk of VTE increases with oral MHT but is rare below age 60 Observational studies and biological plausibility point to a lower risk with lowdose transdermal therapy Some progestogens may be associated with a greater VTE risk [C] The incidence of VTE is less frequent amongst Asian women [C] Population screening for thrombophilia is not indicated prior to MHT use [C] 2016 IMS Recommendations. Climacteric 2016; 19: 109– 50

Cognitive function Key points • • • MHT should not be used to enhance cognitive function [A] Healthy women considering MHT for vasomotor symptoms (VMS) should not be concerned that MHT will adversely affect cognitive function [A] Estrogen therapy may be of short-term benefit to surgically menopausal women when initiated at the time of oophorectomy [B] 2016 IMS Recommendations. Climacteric 2016; 19: 109– 50

Alzheimer’s disease and dementia Key points • • • For women with Alzheimer’s disease, MHT initiated after the onset of dementia symptoms does not benefit cognitive function or slow disease progression [A] MHT initiated within 10 years of a woman’s last menstrual period is associated with reduced risk of Alzheimer’s disease and dementia [B] MHT using estrogen plus progestin initiated at age 65+ increases risk of dementia [A] 2016 IMS Recommendations. Climacteric 2016; 19: 109– 50

Other neurological conditions Key points • • • Findings are inconsistent as to whether MHT improves or has no effect on depressive symptoms in younger postmenopausal women without depression [A] Short-term estrogen therapy may improve depressive symptoms arising during the menopause transition and increase the likelihood of remission [B] MHT may increase seizure frequency in women with epilepsy [B] MHT is not associated with Parkinson’s disease risk [B] Effects of MHT on migraine headache and multiple sclerosis are largely unknown [B] 2016 IMS Recommendations. Climacteric 2016; 19: 109– 50

Breast cancer Key points • • The risk of breast cancer associated with MHT in women over 50 is complex The increased risk is primarily associated with the addition of a synthetic progestogen to estrogen therapy and to duration of use [B] The risk may be lower with micronized progesterone or dydrogesterone [C] The MHT attributable risk is small and decreases when treatment stops [B] There is a lack of safety data supporting MHT use in breast cancer survivors Breast cancer risk should be evaluated before MHT prescription [D] Any possible increased risk associated with MHT may be decreased by selecting women with lower baseline risk including low breast density and by providing education on preventive lifestyle measures (reducing weight, reducing alcohol intake, increasing physical activity) [D] 2016 IMS Recommendations. Climacteric 2016; 19: 109– 50

Endometrial safety and bleeding Key points • • • Postmenopausal bleeding is ‘cancer until proven otherwise’. 1– 14% of women with postmenopausal bleeding will have endometrial cancer Blind endometrial sampling is an appropriate first-line investigation [B] Unopposed estrogen therapy is associated with a dose and durationrelated increased risk of endometrial cancer [A] Endometrial protection requires an adequate dose and duration of progestogen [A] For doses of estradiol of 2 mg/50 μg, an adequate dose of micronized progesterone appears to be 200 mg for 10– 14 days per month or 100 mg daily for continuous therapy [B] Higher doses of progesterone may be required for higher estradiol doses or in women with high body mass index 2016 IMS Recommendations. Climacteric 2016; 19: 109– 50

Colorectal cancer Key points • • Observational studies show a reduced risk of colorectal cancer (CRC) amongst users of oral MHT [B] Three meta-analyses have reported a reduced risk of CRC with MHT use [A] Results from WHI showed no effect for estrogen-only therapy on CRC risk [A] Results from WHI showed reduced risk of CRC with estrogen + progestin therapy [A] There are limited data on the effect of non-oral MHT on CRC risk One randomized, controlled trial in older osteoporotic women using tibolone reported a reduced risk of colorectal cancer [A] MHT should not be used solely for the prevention of CRC [D] 2016 IMS Recommendations. Climacteric 2016; 19: 109– 50

Other cancers Key points • • In WHI there was no increase in risk of cervical cancer [A] Long-term cohort studies have found no increase in cervical cancer with MHT use [B] The association between MHT and ovarian cancer remains unclear In WHI neither estrogen or estrogen + progestin demonstrated a significant increase in lung cancer incidence [A] There is no clear association between MHT use and hepatocellular carcinoma [C] MHT use may be associated with reduced risk of gastric cancer [C] There are few good studies examining links between upper GI cancers, menopause and MHT use 2016 IMS Recommendations. Climacteric 2016; 19: 109– 50

General and sexual quality of life Key points • • • When addressing quality of life and sexual well-being, age, type and time since menopause, menopausal symptoms, general health, medications, intrapersonal and interpersonal factors should be considered [A] Diagnose and routinely treat signs and symptoms of GSM/VVA [B] Always take into account the biopsychosocial model when sexual symptoms at menopause are clinically relevant in order to establish the best treatment plan [C] 2016 IMS Recommendations. Climacteric 2016; 19: 109– 50

Androgen therapy in women Key points • • Androgen levels decline with age in women with no significant change associated with the natural menopause [A] There is strong evidence that androgens influence female sexual function and that testosterone therapy may be useful for women with arousal or desire disorders [A] Women should be fully assessed for other treatable causes of sexual dysfunction before testosterone therapy can be considered Testosterone therapy should be considered as a clinical trial which should not be continued if a woman has not experienced benefit by 6 months [A] 2016 IMS Recommendations. Climacteric 2016; 19: 109– 50

Complementary and bioidentical therapies Key points • • Complementary therapies have limited evidence of efficacy and are not regulated by medicines agencies [B] Cognitive behavioral therapy, mindfulness training, acupuncture, hypnosis and stellate ganglion blockade may be useful techniques to consider when treating VMS [A] Prescribing bioidentical hormone therapy (BHT) is not recommended due to lack of evidence of efficacy, lack of quality control and lack of regulatory oversight [B] The use of serum or salivary hormone levels is not recommended to assist in the management of MHT [B] 2016 IMS Recommendations. Climacteric 2016; 19: 109– 50

Pharmacological treatments for VMS Key points • • • SSRIs and SNRIs such as venlafaxine, desvenlafaxine, paroxetine, escitalopram and citalopram are effective in reducing VMS in postmenopausal women [A] Paroxetine should be avoided in women receiving tamoxifen [A] Gabapentin is effective in reducing VMS in higher doses but has more side -effects than the SNRIs/SSRIs [B] 2016 IMS Recommendations. Climacteric 2016; 19: 109– 50

Vulvovaginal atrophy Key points • • Be proactive in order to encourage patients to disclose symptoms of vulvovaginal atrophy (VVA) and to seek treatment where appropriate [A] Treatment is best started early and needs to be continued to maintain benefits [B] The principles of treatment are restoration of urogenital physiology and alleviation of symptoms When VVA is the sole symptom, local estrogen therapy is preferred [B] Local estrogen therapy minimizes systemic absorption and serum estradiol levels are not above the normal range (< 20 pg/ml) for postmenopausal women [B] Additional progestogen is not required [B] There are limited data on the use of topical estrogens in women with hormone-dependent cancers [D] 2016 IMS Recommendations. Climacteric 2016; 19: 109– 50