The 2017 hormone therapy position statement of The North American

Copyright @ 2017 The North American Menopause Society. Unauthorized reproduction of this article is prohibited. ethinyl estradiol. Conjugated equine estrogen, used in the WHI, is isolated from the urine of pregnant mares and comprised of estrone sulfate (weaker than estradiol) and mixtures of more than 10 minor components of different active forms of estrogens (weak estrogen agonists). Conju- gated equine estrogens and estradiol are rapidly metabolized into weaker estrogens such as estrone. Thus, there may be differences in the types of concentrations of estrogens or interactions with ERs in different target tissues. Meta-analysis of FDA-approved estrogen trials found no evidence of a significant difference in effectiveness between estradiol and CEE in treating VMS. Findings with regard to adverse events (AEs) were inconsistent, 4 despite more hepatic protein production with CEE. 5 However, there were differ- ences in cognitive outcomes between types of estrogen and the brain serotonergic system, with estradiol providing more robust anxiolytic and antidepressant effects. 6,7 Progestogen indication: need for endometrial protection Chronic unopposed endometrial exposure to estrogen increases the risk for endometrial hyperplasia or cancer. 8,9 The primary menopause-related indication for progestogen use is to prevent endometrial overgrowth and the increased risk of endometrial cancer during ET use. Progestins com- monly used include MPA, norethindrone acetate, and native progesterone. Women with an intact uterus using systemic ET should receive adequate progestogen unless they are taking CEE combined with bazedoxifene. 10-12 Progestogen dose and duration of use are important in ensuring endometrial protection. When adequate progestogen is combined with estrogen, the risk of endometrial neoplasia is not higher than in untreated women. In the WHI, use of continuous oral CEE þ MPA daily was associated with a risk of endometrial cancer similar to placebo (hazard ratio [HR], 0.81; 95% confidence interval [CI], 0.48-1.36), 13 with sig- nificant reduction of risk after a median 13 years’ cumulative follow-up. 14 A higher incidence of breast cancer was seen in the WHI for CEE þ MPA compared with placebo, but a reduced incidence with CEE alone (Figure 1). 14 Observational studies have suggested that the risk of breast cancer may be less with the use of micronized progesterone (MP) compared with synthetic progestogens, 15,16 but the bioavailability of oral and transdermal progesterone is poor. Micronized progesterone needs to be adequately dosed for endometrial protection. 17-19 Improperly formulated or FIG. 1. Absolute risks of health outcomes by 10-year age groups in the Women’s Health Initiative Hormone Therapy Trials during the intervention phase. CEE, conjugated equine estrogens; MPA, medroxyprogesterone acetate. From Manson et al. 14 Reproduced with permission of the American Medical Association ß American Medical Association. All rights reserved. NAMS POSITION STATEMENT 730 Menopause, Vol. 24, No. 7, 2017 ß 2017 The North American Menopause Society

Copyright @ 2017 The North American Menopause Society. Unauthorized reproduction of this article is prohibited. Urinary tract symptoms (including pelvic floor disorders) Vaginal ET may improve incontinence by increasing the number of vessels around the periurethral and bladder neck region 73 and has been shown to reduce the frequency and amplitude of detrusor contractions to promote detrusor muscle relaxation. 74,75 Estrogen therapy, along with pelvic floor training, pessaries, or surgery, may improve synthesis of collagen and improve vaginal epithelium, but evidence for effectiveness for pelvic organ prolapse is lacking. 76 Two large trials found that users of systemic HT (CEE 0.625 mg þ MPA 2.5 mg) had an increased incidence of stress incontinence. 77,78 Increased incontinence was found in women using oral estrogen alone (RR, 1.32; 95% CI, 1.17- 1.48) and in those using combined estrogen and progestogen (RR, 1.11; 95% CI, 1.04-1.18). 79 Vaginal estrogen use showed a decreased incidence of incontinence (RR, 0.74; 95% CI, 0.64- 0.86) and overactive bladder, with one to two fewer voids in 24 hours and reduced frequency and urgency. A reduced risk of recurrent UTI with vaginal but not oral estrogen has been shown in RCTs. 80 Sexual function Systemic HT and low-dose vaginal ET provide effective treatment of VVA, improving sexual problems by increasing lubrication, blood flow, and sensation in vaginal tissues. 81 Studies have not found any significant effect of ET on sexual interest, arousal, and orgasmic response independent from its role in treating menopause symptoms. 82-84 If systemic HT is needed and women have low libido, transdermal ET formulations may be preferred to oral, given increased sex hormone-binding globulin and reduced bioa- vailability of testosterone with oral ET. 81,85,86 Conjugated equine estrogen combined with bazedoxifene relieves dyspareunia and improves VVA and some aspects of sexual function in postmenopausal women. 87-90 Key points Vasomotor symptoms ± Vasomotor symptoms may be caused by thermoregulatory dysfunction. They begin during perimenopause and may persist on average 7.4 years or longer, with ethnic differ- ences. They affect QOL and appear to be linked to CV, bone, and brain health. ± Hormone therapy remains the gold standard for relief of VMS. ± Estrogen-alone therapy can be used for symptomatic women after hysterectomy. ± For symptomatic women with a uterus requesting HT, combination therapy protects against endometrial neo- plasia, either with a progestogen or as a combination of CEE and bazedoxifene. ± For menopause symptom control, the lowest dose that offers relief should be used. Dosing and need for ongoing therapy for relief of menopause symptoms should be assessed periodically. ± Micronized progesterone 300 mg nightly significantly decreases VMS (hot flashes and night sweats) compared with placebo and improves sleep. Synthetic progestins have also shown benefit in studies. No long-term study results are available. Sleep disturbances ± During the menopause transition, women with VMS are more likely to report reduced sleep. ± Hormone therapy improves sleep in women with bothersome nighttime VMS by reducing nighttime awak- enings. The genitourinary syndrome of menopause (vaginal symptoms) ± Low-dose vaginal estrogen preparations are effective and generally safe for the treatment of VVA, with minimal systemic absorption, and preferred over systemic therapies when ET is considered only for GSM. ± For women with breast cancer, low-dose vaginal estrogen should be considered and prescribed in consultation with their oncologists. ± Progestogen therapy is not needed with low-dose vaginal ET, but randomized trial data are lacking beyond 1 year; postmenopausal bleeding in women using low-dose vag- inal ET must be thoroughly evaluated. ± Nonestrogen prescription therapies that improve VVA in postmenopausal women include ospemifene and intra- vaginal DHEA. Urinary tract symptoms (including pelvic floor disorders) ± Systemic HT does not improve urinary incontinence and may increase the incidence of stress urinary incontinence. ± Low-dose vaginal ET may provide benefit for urinary symptoms, including prevention of recurrent UTI, over- active bladder, and urge incontinence. ± Hormone therapy does not have FDA approval for any urinary health indication. Sexual function ± Both systemic HT and low-dose vaginal estrogen increase lubrication, blood flow, and sensation of vaginal tissues. ± Systemic HT generally does not improve sexual function, sexual interest, arousal, or orgasmic response in women without menopause symptoms. ± If sexual function or libido are concerns in women with menopause symptoms, transdermal ET may be preferable over oral ET because of less effect on sex hormone-binding globulin and free testosterone levels. ± Low-dose vaginal ET improves sexual function in post- menopausal women with GSM (symptomatic VVA). ± Nonestrogen alternatives approved for dyspareunia include ospemifene and intravaginal DHEA. EARLY NATURAL MENOPAUSE AND PRIMARY OVARIAN INSUFFICIENCY Women with early natural menopause and POI experience an extended period of time with loss of ovarian hormone activity compared with women experiencing normal meno- pause, with potential AEs of estradiol deficiency in all tissues. For women whose ovaries are retained at the time of hyster- ectomy, there is a two-fold increased risk of ovarian failure, 91 and 20% or more of these women may develop symptoms of diminished ovarian reserve within 1 year, with reduced anti- mu ¨llerian hormone. 92 Health risks of early natural menopause NAMS POSITION STATEMENT Menopause, Vol. 24, No. 7, 2017 733

Copyright @ 2017 The North American Menopause Society. Unauthorized reproduction of this article is prohibited. ± Observational studies report lower risk with transdermal HT than with oral and with oral estradiol compared with CEE, but neither observation is confirmed in RCTs. ± An association of HT with slower fibrosis progression in hepatitis C and with fatty liver has been observed, but randomized trials are needed to establish any potential benefits and risks of HT in postmenopausal women with liver disease. DIABETES MELLITUS, METABOLIC SYNDROME, AND BODY COMPOSITION In the WHI, women receiving continuous-combined CEE þ MPA had a statistically significant 19% reduction (HR, 0.81; 95% CI, 0.70-0.94; P ¼ 0.005) in the incidence of type 2 diabetes mellitus (DM), translating to 16 fewer cases per 10,000 person-years of therapy. 14 In the CEE-alone cohort, there was a reduction of 14% in new diagnoses of type 2 DM (HR, 0.86; 95% CI, 0.76-0.98), translating to 21 fewer cases per 10,000 person-years. Meta-analyses of published studies found that combined HT (EPT) reduced type 2 DM incidence almost 40%, with lower fasting glucose levels and levels of hemoglobin A 1c . 145,146 The benefit reverses when HT is discontinued. Metabolic syndrome and weight In general, ER a protects against fat accumulation, whereas ER b promotes fat gain. There is evidence from basic and preclinical work that disruption of estradiol signaling, either with ER deletion (genetic manipulation) or surgical oopho- rectomy, may accelerate fat accumulation, which appears to accumulate disproportionately in the abdominal area, with increased insulin resistance and dyslipidemia. 137 Estrogen-progestogen therapy either has no effect on weight or is associated with less weight gain in women who are using it than in women who are not. 147-151 In the WHI, women on combined CEE þ MPA showed small but significant decreases in body mass index and waist circum- ference during the first year. 152 Key points ± Hormone therapy significantly reduces the diagnosis of new-onset type 2 DM, but it is not US-government approved for this purpose. ± Hormone therapy may help attenuate abdominal adipose accumulation and the weight gains that are often associated with the menopause transition. MOOD, DEPRESSION, AND COGNITION For postmenopausal women without clinical depression, evidence is mixed concerning the effects of HT on mood, with small, short-term trials suggesting that HT improves mood, whereas others showed no change. 153 Postmenopausal women with a history of perimenopause-related depression respon- sive to HT may experience a recurrence of depressive symp- toms after estradiol withdrawal. 154 Small clinical trials support the use of ET for cog- nitive benefits when initiated immediately after surgical menopause. 155,156 Three large RCTs demonstrate neutral effects of HT on cognitive function when used early in the postmenopause period versus initiating treatment in women aged older than 65 years. 7,157,158 Two hypotheses — the critical window hypothesis 159,160 and the healthy cell bias hypothesis 161 — provide a framework for understanding the scientific literature on HT and cogni- tion, but neither has been definitively supported in RCTs of postmenopausal women. Later initiation of hormone therapy Several large clinical trials indicate that HT does not improve memory or other cognitive abilities and that CEE þ MPA may be harmful for memory when initiated in women aged older than 65 years. 162-164 Alzheimer disease Four observational studies provide support for the view that timing of HT initiation is a significant determinant of Alzheimer disease risk, with early initiation lowering risk and later initiation associated with increased risk. 165-168 Dementia In the WHI Memory Study, CEE þ MPA doubled the risk of all-cause dementia (23 cases per 10,000 women) when initiated in women aged older than 65 years, 164 whereas CEE alone did not significantly increase the risk of dementia. 169 The effect of HT may be modified by baseline cognitive function, with more favorable effects in women with normal cognitive function before HT initiation. 170,171 Key points ± In the absence of more definitive findings, HT cannot be recommended at any age to prevent or treat a decline in cognitive function or dementia. ± On the basis of the WHI Memory Study, caution should be taken in initiating continuous-combined daily CEE þ MPA in women aged older than 65 years, given the relatively small or infrequent increase in risk for dementia of an extra 23 cases per 10,000 person-years seen in the WHI. ± Estrogen therapy may have positive cognitive benefits when initiated immediately after early surgical menopause, but HT in the early natural postmenopause period has neutral effects on current cognitive function. ± Only limited support (observational studies) is available for a critical window hypothesis of HT in Alzheimer disease prevention. ± The effect of HT may be modified by baseline cognitive function, with more favorable effects in women with normal cognitive function before HT initiation. ± Evidence is insufficient to support HT use in the treatment of clinical depression. In small RCTs, ET was effective in improving clinical depression in perimenopausal but not postmenopausal women. ± Progestins may contribute to mood disturbance. ± Women whose depression improves with HT are likely to experience a worsening of mood after estrogen with- drawal. NAMS POSITION STATEMENT 736 Menopause, Vol. 24, No. 7, 2017 ß 2017 The North American Menopause Society

Copyright @ 2017 The North American Menopause Society. Unauthorized reproduction of this article is prohibited. 16 years’ follow-up, but this was not a primary outcome. 182 Observational studies on long duration are mixed, with some observational studies and meta-analyses reporting an elevated risk of breast cancer with estrogen-alone use for more than 5 years, 195,196 whereas others have not. 197-204 Estrogen-progestogen therapy In the WHI, daily continuous-combined CEE þ MPA resulted in increased risk of breast cancer (a rare absolute risk of breast cancer), with 9 additional breast cancer cases per 10,000 person-years of therapy (Figure 1). 14 The increase in breast cancer risk in the WHI for CEE þ MPA was found after 5.6 years, significant in nominal statistics (HR, 1.24; 95% CI, 1.01-1.53) but not significant in multiadjusted statistics 14,205 or when adjustments were made for multiple risk factors. 206 The increase appears to begin at 3 years, 207 and the HR remained elevated at 13 years in the postintervention, unblinded follow-up (HR, 1.32; nominal 95% CI, 1.08- 1.61). 14 In post hoc subgroup analysis, the increased inci- dence of breast cancer was limited to women who had prior exposure to HT (HR, 1.85; 95% CI, 1.25-2.80), whereas in women without prior exposure to HT, breast cancer incidence was not significantly affected by CEE þ MPA (HR, 1.16; 95% CI, 0.98-1.37) over 11 years’ follow-up (including mean intervention time of 5.6 y; P for interaction , 0.03). 205,206 These results should be treated with caution until confirmed elsewhere. Attributable risk of breast cancer The attributable risk of breast cancer in women (mean age, 63 y) randomized to CEE þ MPA in the WHI is less than 1 additional case of breast cancer diagnosed per 1,000 users annually, 14 a risk slightly greater than that observed with one daily glass of wine, less than with two daily glasses, and similar to the risk reported with obesity, low physical activity, and other medications. 202,208 Early hormone therapy in women at genetic risk for breast cancer One study provides some reassurance about estrogen given to younger women at higher risk. 209 The Two Sister Study of 1,419 sister-matched cases of breast cancer in women aged younger than 50 years and 1,665 controls showed no increased risk of young-onset breast cancer with use of EPT (OR, 0.80; 95% CI, 0.41-1.59), whereas unopposed estrogen use was associated with a reduced diagnosis of young-onset breast cancer (OR, 0.58; 95% CI, 0.34-0.99) Role of progestogens Some but not all observational data suggest that MP may have less effect on breast cancer risk, whereas more potent progestogens such as MPA may have a more adverse effect, 15,204 but randomized trials are needed. Mammographic breast density and estrogen Different HT regimens may be associated with increased breast density, which may obscure mammographic interpretation. 210 More mammograms and breast biopsies were required in women receiving CEE þ MPA in the WHI. 211 In trials up to 2-years’ duration, breast tenderness, breast density, and breast cancers were not increased with oral CEE plus bazedoxifene compared with placebo. 212-214 Use of hormone therapy in women with genetic risk factors for breast cancer Limited observational evidence suggests that HT use does not further increase risk of breast cancer in women with a family history of breast cancer or in women after oophorec- tomy for BRCA 1 or 2 gene mutation. 215-220 Hormone therapy after breast cancer The use of systemic HT in survivors of breast cancer is generally not advised. Observational studies and randomized trials report both neutral effects 221-230 and increased risk of breast cancer recurrence. 221,228,231 However, low-dose vagi- nal ET remains an effective treatment option for GSM, with minimal systemic absorption, and treatment may be con- sidered after an initial trial of nonhormone therapies and in consultation with an oncologist, with more concern for women on AIs. 69 Area of scientific uncertainty Breast tissue recently exposed to endogenous estrogen and progesterone may react differently to exogenous hormones than if more distantly exposed, but this theory of estrogen- induced apoptosis of occult tumors remains unproven. 232,233 Different types of estrogen may have different effects on the breast, thus limiting the generalizability of the findings of reduced breast cancer cases with CEE in the WHI. Key points ± The effect of HT on breast cancer risk may depend on the type of HT, dose, duration of use, regimen, route of administration, prior exposure, and individual character- istics. – Women’s Health Initiative results suggest a nonsigni- ficant reduced risk of breast cancer with CEE alone in women with a hysterectomy. Similar nonsignificant reductions for estradiol were observed in two smaller randomized trials (approximately 1,000 perimeno- pausal and postmenopausal participants), although not in all large observational studies. – A rare absolute risk of breast cancer ( < 1 additional case/1,000 person-years of use) was seen with daily continuous-combined CEE þ MPA in the WHI but not seen in all trials or all subanalyses of the WHI, such as in women without prior HT exposure, but it is consistent with many observational trial results. – The potential risk of breast cancer should be included in discussions about benefits and risks of HT. ± Duration of HT use may be an important factor in breast cancer risk, because in some studies, risk increased with longer durations of use. ± Different HT regimens may be associated with in- creased breast density, which may obscure mammographic NAMS POSITION STATEMENT Menopause, Vol. 24, No. 7, 2017 739

Copyright @ 2017 The North American Menopause Society. Unauthorized reproduction of this article is prohibited. older than 60 years who choose to initiate or restart HT. There are only limited nonblinded RCT data that address extended use of ET in younger, recently postmenopausal and perimeno- pausal women with or without added progestogen. 182 The WHI, the longest adequately powered blinded RCT, was limited to 5 to 7 years of therapy. However, the Beers criteria recommendation to routinely discontinue systemic HT in women aged 65 years and older is not supported by data. Vasomotor symptoms persist on average 7.4 years and for many for more than 10 years. 43,267 In a study of Swedish women aged older than 85 years, 16% reported hot flashes at least several times per week. 268 Hormone therapy can be considered for prevention of osteoporosis in women aged 65yearsandolderatelevatedriskforfracturewhenbothersome VMS persist or when HT remains the best choice for QOL reasons or because of lack of efficacy or intolerance of other osteoporosis-prevention therapies. Lower doses of transdermal estrogen may represent a preferable route of ET administration for older or menopausal women who are obese or for those with elevated triglyceridesor liverconcerns. 269 Ongoing monitoring for new health concerns, periodic trials of lower doses, trans- dermal formulations, or attempts at discontinuation may help healthcare providers and individual women aged older than 65 years clarify their decisions about continuing HT. Key points ± Considerations for long-term (or extended) use of HT include persistent VMS, QOL issues, or prevention of osteoporosis in women at elevated risk of fracture. ± The safety profile of HT is most favorable when it is initiated by women aged younger than 60 years or within 10 years of menopause onset. In general, initiation by older menopausal women aged older than 65 years requires careful consideration of all individual health benefits and risks. ± Ongoing use of systemic HT by healthy women who initiated therapy within 10 years of menopause onset and without new health risks likely has a safety profile more favorable than that for women initiating HT when aged older than 65 years, although limited long-duration data are available. ± Hormone therapy does not need to be routinely discon- tinued in women aged older than 60 or 65 years and can be considered for continuation beyond age 65 years for per- sistent VMS, QOL issues, or prevention of osteoporosis after appropriate evaluation and counseling of benefits and risks. Annual reevaluation, including reviewing comorbid- ities and periodic trials of lowering or discontinuing HT or changing to potentially safer low-dose transdermal routes, should be considered ± Vaginal estrogen (and systemic if required) or other non- estrogen therapies may be used at any age for prevention or treatment of GSM. ECONOMIC CONSIDERATIONS Greater severity of VMS is associated with lower levels of health status and work productivity and greater use of health resources. 42,270,271 The greatest benefit-risk ratio from pharmacoeconomic analyses in younger women 272 and those from the WHI 273 has been found for the use of HT for menopause-associated VMS, 274 particularly in women who have had a hysterectomy who can use ET. 275 Key points ± Potential reduced costs by treating VMS and related symptoms or preventing bone fractures should be evaluated in the context of evaluation and treatment of AEs and costs of HT medications. ± Initiation of HT closer to menopause onset increased quality-adjusted life-years and was highly cost-effective compared with initiating HT in women aged older than 65 years. ± Indirect economic costs for menopausal women include effects on QOL, work productivity, healthcare resource use, and the potential costs of women who have had a hysterectomy not receiving HT. SUMMARY In the 15 years since the publication of the first results in 2002 from the large WHI HT trials and almost 10 years since the 2007 reanalysis of the results by age and years since menopause, much has been learned, yet much controversy remains. Hormone therapy formulation, dosing, regimen, route of administration, and the timing of initiation of therapy likely produce different effects, although these have yet to be evaluated in head-to-head RCTs, and there is a significant difference in the benefits and risk of estrogen alone compared with estrogen combined with different progestogens, at least as studied in the WHI. The concept of ‘‘ lowest dose for the shortest period of time ’’ may be inadequate or even harmful for some women. A more fitting concept is ‘‘ appropriate dose, duration, regimen, and route of administration. ’’ Given the more favorable safety profile of estrogen alone, longer durations may be more appropriate. Risk stratification by age and time since menopause is recommended. Transdermal or lower doses of HT may decrease risk of VTE and stroke. Individualization with shared decision making remains key, with periodic reevaluation to determine an individual woman’s benefit-risk profile. Benefits may include relief of bothersome VMS, prevention of bone loss for women at high risk of fracture, treatment of GSM, and improved sleep, well- being, or QOL. Absolute attributable risks for women in the 50- to 59-year-old age group or within 10 years of menopause onset are low, whereas the risks of initiation of HT for women aged 60 years and older or who are further than 10 years from menopause onset appear greater, particularly for those aged 70 years and older or who are more than 20 years from menopause onset, with more research needed on potential risks of longer durations of use. Women with POI or early surgical or natural menopause have higher risks of bone loss, heart disease, and cognitive or affective disorders associated with estrogen deficiency. In NAMS POSITION STATEMENT 742 Menopause, Vol. 24, No. 7, 2017 ß 2017 The North American Menopause Society

Copyright @ 2017 The North American Menopause Society. Unauthorized reproduction of this article is prohibited. risks caused by premature loss of estrogen need to be considered. (Level II) – On the basis of limited observational studies, consider offering systemic HT until the median age of menopause (52 y). Discussions about longer use should be individualized. (Level II) V. Breast and endometrial cancer survivors — systemic or vaginal hormone therapy ± Bothersome VMS — consideration of systemic HT – Survivors of endometrial and breast cancer with bothersome VMS should be encouraged to con- sider nonhormone therapies that have been studied in RCTs in this population and found to be effec- tive. (Level III) – For survivors of endometrial cancer with prior early endometrial cancer treated with hyster- ectomy and with bothersome VMS not well con- trolled with nonhormone therapies, decisions about use of systemic HT should be made in conjunction with an oncologist. (Level III) – For survivors of breast cancer, particularly estro- gen-sensitive cancers, for which systemic HT is generally not offered, decisions about systemic HT should be made for compelling reasons after nonhormone or complementary options have been unsuccessful and after detailed counseling, with shared decision making and in conjunction with an oncologist. (Level III) ± Bothersome GSM symptoms — consideration of low- dose vaginal ET – Low-dose vaginal ET used for the GSM has min- imal systemic absorption (blood levels in the post- menopause range) and, on the basis of limited observational data, appears to hold minimal to no demonstrated risk for recurrence of endometrial or breast cancer. (Level II) – For women with early endometrial cancer who have completed successful treatment, including hysterectomy, consideration may be given for low-dose vaginal ET for relief of GSM if non- hormone options are not successful, based on limited short-term safety trials. (Level II) – For women who are survivors of breast cancer, decisions about low-dose vaginal ET should involve the woman’s oncologist, particularly for women using AIs who have lowered overall estra- diol levels. (Level III) Conclusion — overall benefit-to-risk ratio ± Hormone therapy is the most effective treatment for VMS and GSM and has been shown to prevent bone loss and fracture. ± Risks of HT differ for women, depending on type, dose, duration of use, route of administration, timing of initiation, and whether a progestogen is needed. Treat- ment should be individualized using the best available evidence to maximize benefits and minimize risks, with periodic reevaluation for the benefits and risks of continuing HT. ± For women aged younger than 60 years or who are within 10 years of menopause onset and have no contra- indications, the benefit-risk ratio appears favorable for treatment of bothersome VMS and for those at ele- vated risk of bone loss or fracture. Longer duration may be more favorable for ET than for EPT, based on the WHI RCTs. ± For women who initiate HT more than 10 or 20 years from menopause onset or when aged 60 years or older, the benefit-risk ratio appears less favorable than for younger women because of greater absolute risks of CHD, stroke, VTE, and dementia. ± For GSM symptoms not relieved with over-the-counter or other therapies, low-dose vaginal ET is recommended. ACKNOWLEDGMENTS AND DISCLOSURES NAMS appreciates the contributions of the Advisory Panel and the work of the NAMS Board of Trustees on this position statement. The authors, planners, reviewers, and staff who were in a position to control and influence the content of this activity were requiredto disclosure anyrelevantfinancialrelationship(s) of the individualor their spouse/partner that had occurred within the last 12 months with any commercial interest(s) whose products or services are related to the CME content. After reviewing disclosures from all involved in the content of this activity, NAMS has implemented mechanisms to identify and resolve any conflicts for all involved, including review of content by those who had no conflicts of interest. Acknowledgments: The NAMS 2017 Hormone Therapy Position Statement Advisory Panel: Chair , JoAnn V. Pinkerton, MD, NCMP, NAMS Executive Director; Professor of Obstetrics and Gynecology; Division Director, Midlife Health Center; University of Virginia Health System, Charlottesville, Virginia. Dr. Fernando Sa ´nchez Aguirre, Asociacio ´n Mexicana para erl Estudio del Climaterio A.C.; Mexico City, Mexico. Jennifer Blake, MD, MSc, FRCS, Chief Executive Officer, the Society of Obstetricians and Gynaecologists of Canada, Ottawa, Ontario, Canada. Felicia Cosman, MD, Professor of Medicine, Columbia University College of Physicians and Surgeons; Medical Director, Clinical Research Center; Helen Hayes Hospital, West Haverstraw, New York. Howard N. Hodis, MD, Harry J. Bauer and Dorothy Bauer Rawlins Professor of Cardiology; Professor of Medicine and Preventive Medicine; Professor of Molecular Pharmacology and Toxicology; Director of the Atherosclerosis Research Unit, Division of Cardiovascular Medicine; Kent School of Medicine; University of Southern California, Los Angeles, California. Susan Hoffstetter, PhD, WHNP-BC, FAANP, Associate Professor, St. Louis Univer- sity School of Medicine; Department of Obstetrics, Gynecol- ogy, and Women’s Health; Division of Uro-Gynecology; St. Louis, Missouri. Andrew M. Kaunitz, MD, NCMP, University of Florida Research Foundation Professor and Associate Chair, Department of Obstetrics and Gynecology, University of Florida College of Medicine, Jacksonville, Medical Director and Director, Menopause and Gynecologic Ultrasound Services, UF Southside Women’s Health, Jack- sonville, Florida. Sheryl A. Kingsberg, PhD, Chief, Division of Behavioral Medicine; University Hospitals Cleveland NAMS POSITION STATEMENT Menopause, Vol. 24, No. 7, 2017 745

Copyright @ 2017 The North American Menopause Society. Unauthorized reproduction of this article is prohibited. 30. Sullivan SD, Sarrel PM, Nelson LM. Hormone replacement therapy in young women with primary ovarian insufficiency and early menopause. Fertil Steril 2016;106:1588-1599. 31. Sarrel PM, Sullivan SD, Nelson LM. Hormone replacement therapy in young women with surgical primary ovarian insufficiency. Fertil Steril 2016;106:1580-1587. 32. Lethaby A, Ayeleke RO, Roberts H. Local oestrogen for vaginal atrophy in postmenopausal women. Cochrane Database Sys Rev 2016;8: CD001500. 33. Cirigliano M. Bioidentical hormone therapy: a review of the evidence. J Womens Health 2007;16:600-631. 34. Files JA, Ko MG, Pruthi S. Bioidentical hormone therapy. Mayo Clin Proc 2011;86:673-680. 35. Sites CK. Bioidentical hormones for menopausal therapy. Womens Health (Lond Engl) 2008;4:163-171. 36. Bhavnani BR, Stanczyk FZ. Misconception and concerns about bio- identical hormones used for custom-compounded hormone therapy. J Clin Endocrinol Metab 2012;97:756-759. 37. Boothby LA, Doering PL, Kipersztok S. Bioidentical hormone therapy: a review. Menopause 2004;11:356-367. 38. Committee on Gynecologic Practice and the American Society for Reproductive Medicine Practice Committee. Committee opinion No. 532: compounded bioidentical menopausal hormone therapy. Obstet Gynecol 2012;120:411-415. 39. FDA Consumer Health Information. US Food and Drug Administration. Bio-Identicals: Sorting Myth From Fact . www.fda.gov/ForConsumers/ ConsumerUpdates/ucm049311.htm. April 8, 2008. Accessed March 29, 2017. 40. US Food and Drug Administration. Interim Policy on Compounding Using Bulk Drug Substances Under Section 503A of the Federal Food, Drug, and Cosmetic Act: Guidance for Industry . Silver Spring, MD: US Department of Health and Human Services; 2016. www.fda.gov/ downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ UCM469120.pdf. Accessed March 28, 2017. 41. Nelson HD. Menopause. Lancet 2008;371:760-770. 42. Whiteley J, Wagner JS, Bushmakin A, Kopenhafer L, Dibonaventura M, Racketa J. Impact of the severity of vasomotor symptoms on health status, resource use, and productivity. Menopause 2013;20:518-524. 43. Avis NE, Crawford SL, Greendale G, et al; Study of Women’s Health Across the Nation. Duration of menopausal vasomotor symptoms over the menopause transition. JAMA Intern Med 2015;175: 531-539. 44. Thurston RC, Sutton-Tyrrell K, Everson-Rose SA, Hess R, Matthews KA. Hot flashes and subclinical cardiovascular disease: findings from the Study of Women’s Health Across the Nation Heart Study. Circulation 2008;118:1234-1240. 45. Thurston RC, Kuller LH, Edmundowicz D, Matthews KA. History of hot flashes and aortic calcification among postmenopausal women. Menopause 2010;17:256-261. 46. Thurston RC, Sutton-Tyrrell K, Everson-Rose SA, Hess R, Powell LH, Matthews KA. Hot flashes and carotid intima media thickness among midlife women. Menopause 2011;18:352-358. 47. Crandall CJ, Aragaki A, Cauley JA, et al. Associations of menopausal vasomotor symptoms with fracture incidence. J Clin Endocrinol Metab 2015;100:524-534. 48. Maki PM. Verbal memory and menopause. Maturitas 2015;82: 288-290. 49. Bachmann GA, Schaefers M, Uddin A, Utian WH. Lowest effective transdermal 17beta-estradiol dose for relief of hot flushes in postme- nopausal women: a randomized controlled trial. Obstet Gynecol 2007;110:771-779. 50. Canonico M, Plu-Bureau G, Lowe GD, Scarabin PY. Hormone replace- ment therapy and risk of venous thromboembolism in postmenopausal women: systematic review and meta-analysis. BMJ 2008;336: 1227-1231. 51. Archer DF, Dorin M, Lewis V, Schneider DL, Pickar JH. Effects of lower doses of conjugated equine estrogens and medroxyprogesterone acetate on endometrial bleeding. Fertil Steril 2001;75:1080-1087. 52. Ettinger B. Rationale for use of lower estrogen doses for postmenopausal hormone therapy. Maturitas 2007;57:81-84. 53. Schiff I, Tulchinsky D, Cramer D, Ryan KJ. Oral medroxyprogesterone in the treatment of postmenopausal symptoms. JAMA 1980;244: 1443-1445. 54. Hitchcock CL, Prior JC. Oral micronized progesterone for vasomotor symptoms — a placebo-controlled randomized trial in healthy postme- nopausal women. Menopause 2012;19:886-893. 55. Prior JC, Nielsen JD, Hitchcock CL, Williams LA, Vigna YM, Dean CB. Medroxyprogesterone and conjugated oestrogen are equivalent for hot flushes: a 1-year randomized double-blind trial following premeno- pausal ovariectomy. Clin Sci (Lond) 2007;112:517-525. 56. Goodwin JW, Green SJ, Moinpour CM, et al. Phase III randomized placebo-controlled trial of two doses of megestrol acetate as treatment for menopausal symptoms in women with breast cancer: Southwest Oncology Group Study 9626. J Clin Oncol 2008;26:1650-1656. 57. Ockene JK, Barad DH, Cochrane BB, et al. Symptom experience after discontinuing use of estrogen plus progestin. JAMA 2005;294:183-193. 58. Brunner RL, Aragaki A, Barnabei V, et al. Menopausal symptom experience before and after stopping estrogen therapy in the Women’s Health Initiative randomized, placebo-controlled trial. Menopause 2010;17:946-954. 59. Attarian H, Hachul H, Guttuso T, Phillips B. Treatment of chronic insomnia disorder in menopause: evaluation of literature. Menopause 2015;22:674-684. 60. Joffe H, Massler A, Sharkey KM. Evaluation and management of sleep disturbance during the menopause transition. Semin Reprod Med 2010;28:404-421. 61. Schu ¨ssler P, Kluge M, Yassouridis A, et al. Progesterone reduces wakefulness in sleep EEG and has no effect on cognition in healthy postmenopausal women. Psychoneuroendocrinology 2008;33: 1124-1131. 62. Portman DJ, Gass ML; Vulvovaginal Atrophy Terminology Consensus Conference Panel. Genitourinary syndrome of menopause: new termi- nology for vulvovaginal atrophy from the International Society for the Study of Women’s Sexual Health and the North American Menopause Society. Menopause 2014;21:1063-1068. 63. Rahn DD, Carberry C, Sanses TV, et al; Society of Gynecologic Surgeons Systematic Review Group. Vaginal estrogen for genitourinary syndrome of menopause: a systematic review. Obstet Gynecol 2014;124:1147-1156. 64. Nappi RE, Davis SR. The use of hormone therapy for the maintenance of urogynecological and sexual health post WHI. Climacteric 2012;15: 267-274. 65. Santen RJ. Vaginal administration of estradiol: effects of dose, prep- aration and timing on plasma estradiol levels. Climacteric 2015;18: 121-134. 66. Management of symptomatic vulvovaginal atrophy: 2013 position state- ment of The North American Menopause Society. Menopause 2013;20:888-902. 67. Kendall A, Dowsett M, Folkerd E, Smith I. Caution: vaginal estradiol appears to be contraindicated in postmenopausal women on adjuvant aromatase inhibitors. Ann Oncol 2006;17:584-587. 68. American College of Obstetricians and Gynecologists’ Committee on Gynecologic Practice, Farrell R. ACOG Committee Opinion No. 659 summary: the use of vaginal estrogen in women with a history of estrogen-dependent breast cancer. Obstet Gynecol 2016;127:618-619. 69. Dixon JM, Renshaw L, Young O, et al. Letrozole suppresses plasma estradiol and estrone sulphate more completely than anastrozole in postmenopausal women with breast cancer. J Clin Oncol 2008;26: 1671-1676. 70. Le Ray I, Dell 0 Aniello S, Bonnetain F, Azoulay L, Suissa S. Local estrogen therapy and risk of breast cancer recurrence among hormone- treated patients: a nested case-control study. Breast Cancer Res Treat 2012;135:603-609. 71. Constantine G, Graham S, Portman DJ, Rosen RC, Kingsberg SA. Female sexual function improved with ospemifene in postmenopausal women with vulvar and vaginal atrophy: results of a randomized, placebo-controlled trial. Climacteric 2015;18:226-232. 72. Labrie F, Archer DF, Koltun W, et al; VVA Prasterone Research Group. Efficacy of intravaginal dehydroepiandrosterone (DHEA) on moderate to severe dyspareunia and vaginal dryness, symptoms of vulvovaginal atrophy, and of the genitourinary syndrome of menopause. Menopause 2016;23:243-256. 73. Long CY, Liu CM, Hsu SC, Chen YH, Wu CH, Tsai EM. A randomized comparative study of the effects of oral and topical estrogen therapy on the lower urinary tract of hysterectomized postmenopausal women. Fertil Steril 2006;85:155-160. NAMS POSITION STATEMENT 748 Menopause, Vol. 24, No. 7, 2017 ß 2017 The North American Menopause Society

Copyright @ 2017 The North American Menopause Society. Unauthorized reproduction of this article is prohibited. 74. Robinson D, Cardozo L, Milsom I, et al. Oestrogens and overactive bladder. Neurourol Urodyn 2014;33:1086-1091. 75. Matsubara S, Okada H, Shirakawa T, Gotoh A, Kuno T, Kamidono S. Estrogen levels influence beta-3-adrenoceptor-mediated relaxation of the female rat detrusor muscle. Urology 2002;59:621-625. 76. Ismail SI, Bain C, Hagen S. Oestrogens for treatment or prevention of pelvic organ prolapse in postmenopausal women. Cochrane Database Syst Rev 2010;(9):CD007063. 77. Grady D, Brown JS, Vittinghoff E, Applegate W, Varner E, Snyder T; HERS Research Group. Postmenopausal hormones and incontinence: the Heart and Estrogen/Progestin Replacement Study. Obstet Gynecol 2001;97:116-120. 78. Hendrix SL, Cochrane BB, Nygaard IE, et al. Effects of estrogen with and without progestin on urinary incontinence. JAMA 2005;293: 935-948. 79. Cody JD, Jacobs ML, Richardson K, Moehrer B, Hextall A. Oestrogen therapy for urinary incontinence in post-menopausal women. Cochrane Database Syst Rev 2012;10:CD001405. 80. Duen ˜as-Garcia OF, Sullivan G, Hall CD, Flynn MK, O’Dell K. Pharma- cological agents to decrease new episodes of recurrent lower urinary tract infections in postmenopausal women. A systematic review. Female Pelvic Med Reconstr Surg 2016;22:63-69. 81. Long CY, Liu CM, Hsu SC, Wu CH, Wang CL, Tsai EM. A randomized comparative study of the effects of oral and topical estrogen therapy on the vaginal vascularization and sexual function in hysterectomized postmenopausal women. Menopause 2006;13:737-743. 82. Shifren JL, Monz BU, Russo PA, Segreti A, Johannes CB. Sexual problems and distress in United States women: prevalence and corre- lates. Obstet Gynecol 2008;112:970-978. 83. Santoro N, Worsley R, Miller KK, Parish SJ, Davis SR. Role of estrogens and estrogen-like compounds in female sexual function and dysfunction. J Sex Med 2016;13:305-316. 84. Wierman ME, Nappi RE, Avis N, et al. Endocrine aspects of women’s sexual function. J Sex Med 2010;7:561-585. 85. Shifren JL, Desindes S, McIlwain M, Doros G, Mazer NA. A random- ized, open-label crossover study comparing the effects of oral versus transdermal estrogen therapy on serum androgens, thyroid hormones, and adrenal hormones in naturally menopausal women. Menopause 2007;14:985-994. 86. Taylor HS, Harman SM, Pal L, et al. Effects of oral vs transdermal estrogen vs placebo on sexual function over time in the Kronos Early Estrogen Prevention Study (KEEPS). Menopause 2012;19:1373. Abstract S-9. 87. Komm BS, Mirkin S, Jenkins SN. Development of conjugated estrogens/ bazedoxifene, the first tissue selective estrogen complex (TSEC) for management of menopausal hot flashes and postmenopausal bone loss. Steroids 2014;90:71-81. 88. Kagan R, Williams RS, Pan K, Mirkin S, Pickar JH. A randomized, placebo- and active-controlled trial of bazedoxifene/conjugated estro- gens for treatment of moderate to severe vulvar/vaginal atrophy in postmenopausal women. Menopause 2010;17:281-289. 89. Bachmann G, Bobula J, Mirkin S. Effects of bazedoxifene/conjugated estrogens on quality of life in postmenopausal women with symptoms of vulvar/vaginal atrophy. Climacteric 2010;13:132-140. 90. Abraham L, Pinkerton JV, Messig M, Ryan KA, Komm BS, Mirkin S. Menopause-specific quality of life across varying menopausal popu- lations with conjugated estrogens/bazedoxifene. Maturitas 2014;78: 212-218. Erratum in: Maturitas 2014;79:488. 91. Moorman PG, Myers ER, Schildkraut JM, Iversen ES, Wang F, Warren N. Effect of hysterectomy with ovarian preservation on ovarian function. Obstet Gynecol 2011;118:1271-1279. 92. Trabuco EC, Moorman PG, Algeciras-Schimnich A, Weaver AL, Cliby WA. Association of ovary-sparing hysterectomy with ovarian reserve. Obstet Gynecol 2016;127:819-827. 93. Atsma F, Bartelink ML, Grobbee DE, van der Schouw Y. Postmeno- pausal status and early menopause as independent risk factors for cardiovascular disease: a meta-analysis. Menopause 2006;13:265-279. 94. Mondul AM, Rodriguez C, Jacobs EJ, Calle EE. Age at natural menopause and cause-specific mortality. Am J Epidemiol 2005;162: 1089-1097. 95. Muka T, Oliver-Williams C, Kunutsor S, et al. Association of age at onset of menopause and time since onset of menopause with cardio- vascular outcomes, intermediate vascular traits, and all-cause mortality: a systematic review and meta-analysis. JAMA Cardiol 2016;1:767-776. 96. Hong JS, Yi SW, Kang HC, et al. Age at menopause and cause-specific mortality in South Korean women: Kangwha Cohort Study. Maturitas 2007;56:411-419. 97. Ossewaarde ME, Bots ML, Verbeek AL, et al. Age at menopause, cause- specific mortality and total life expectancy. Epidemiology 2005;16: 556-562. 98. Biason TP, Goldberg TB, Kurokawa CS, Moretto MR, Teixeira AS, Nunes HR. Low-dose combined oral contraceptive use is associated with lower bone mineral content variation in adolescents over a 1-year period. BMC Endocr Disord 2015;15:15. 99. CibulaD,SkrenkovaJ,HillM,StepanJJ.Low-doseestrogencombinedoral contraceptives may negatively influence physiological bone mineral density acquisition during adolescence. Eur J Endocrinol 2012;166:1003-1011. 100. Castelo-Branco C, Martinez de Osaba MJ, Vanrezc JA, Fortuny A, Gonza ´lez-Merlo J. Effects of oophorectomy and hormone replacement therapy on pituitary-gonadal function. Maturitas 1993;17:101-111. 101. Kronenberg F. Menopausal hot flashes: a review of physiology and biosociocultural perspective on methods of assessment. J Nutr 2010;140:1380S-1385S. 102. Gallicchio L, Whiteman MK, Tomic D, Miller KP, Langenberg P, Flaws JA. Type of menopause, patterns of hormone therapy use, and hot flashes. Fertil Steril 2006;85:1432-1440. 103. Tucker PE, Bulsara MK, Salfinger SG, Tan JJ, Green H, Cohen PA. The effects of pre-operative menopausal status and hormone replacement therapy (HRT) on sexuality and quality of life after risk-reducing salpingo-oophorectomy. Maturitas 2016;85:42-48. 104. Graziottin A, Basson R. Sexual dysfunction in women with premature menopause. Menopause 2004;11:766-777. 105. Lindsay R. The menopause: sex steroids and osteoporosis. Clin Obstet Gynecol 1987;30:847-859. 106. Hodis HN, Mack WJ, Henderson VW, et al; ELITE Research Group. Effects of early versus late postmenopausal treatment with estradiol. N Engl J Med 2016;374:1221-1231. 107. Rocca WA, Grosshardt BR, Shuster LT. Oophorectomy, estrogen, and dementia: a 2014 update. Mol Cell Endocrinol 2014;389:7-12. 108. Emmerson E, Hardman MJ. The role of estrogen deficiency in skin ageing and wound healing. Biogerontology 2012;13:3-20. 109. Golebiowski B, Badarudin N, Eden J, et al. The effects of transdermal testosterone and oestrogen therapy on dry eye in postmenopausal women: a randomised, placebo-controlled, pilot study [published online ahead of print November 3, 2016]. Br J Ophthalmol . 110. Zetterberg M. Age-related eye disease and gender. Maturitas 2016;83: 19-26. 111. Dewundara SS, Wiggs JL, Sullivan DA, Pasquale LR. Is estrogen a therapeutic target for glaucoma? Semin Ophthalmol 2016;31:140-146. 112. Svedbrant J, Bark R, Hultcrantz M, Hederstierna C. Hearing decline in menopausal women — a 10-year follow-up. Acta Otolaryngol 2015;135: 807-813. 113. Doty RL, Tourbier I, Ng V, et al. Influences of hormone replacement therapy on olfactory and cognitive function in postmenopausal women. Neurobiol Aging 2015;36:2053-2059. 114. Coksuer H, Koplay M, Oghan F, Coksuer C, Keskin N, Ozveren O. Effects of estradiol-drospirenone hormone treatment on carotid artery intima-media thickness and vertigo/dizziness in postmenopausal women. Arch Gynecol Obstet 2011;283:1045-1051. 115. Naessen T, Lindmark B, Lagerstro ¨m C, Larsen HC, Persson I. Early postmenopausal hormone therapy improves postural balance. Meno- pause 2007;14:14-19. 116. Utian WH, Woods NF. Impact of hormone therapy on quality of life after menopause. Menopause 2013;20:1098-1105. 117. Effects of hormone therapy on bone mineral density: results from the postmenopausal estrogen/progestin interventions (PEPI) trial. The Writ- ing Group for the PEPI. JAMA 1996;276:1389-1396. 118. Ravn P, Bidstrup M, Wasnich RD, et al. Alendronate and estrogen- progestin in the long-term prevention of bone loss: four-year results from the early postmenopausal intervention cohort study. A randomized, controlled trial. Ann Intern Med 1999;131:935-942. 119. Christiansen C, Riis BJ. 17 Beta-estradiol and continuous norethister- one: a unique treatment for established osteoporosis in elderly women. J Clin Endocrinol Metab 1990;71:836-841. 120. Greenwald MW, Gluck OS, Lang E, Rakov V. Oral hormone therapy with 17beta-estradiol and 17beta-estradiol in combination with NAMS POSITION STATEMENT Menopause, Vol. 24, No. 7, 2017 749

Copyright @ 2017 The North American Menopause Society. Unauthorized reproduction of this article is prohibited. norethindrone acetate in the prevention of bone loss in early postme- nopausal women: dose-dependent effects. Menopause 2005;12:741-748. 121. Grodstein F, Stampfer MJ, Falkeborn M, Naessen T, Persson I. Post- menopausal hormone therapy and risk of cardiovascular disease and hip fracture in a cohort of Swedish women. Epidemiology 1999;10:476-480. 122. Kiel DP, Felson DT, Anderson JJ, Wilson PW, Moskowitz MA. Hip fracture and the use of estrogens in postmenopausal women. The Framingham Study. N Engl J Med 1987;317:1169-1174. 123. Cauley JA, Seeley DG, Ensrud K, Ettinger B, Black D, Cummings SR. Estrogen replacement therapy and fractures in older women. Study of Osteoporotic Fractures Research Group. Ann Intern Med 1995; 122:9-16. 124. Anderson GL, Limacher M, Assaf AR, et al; Women’s Health Initiative Steering Committee. Effects of conjugated equine estrogen in postme- nopausal women with hysterectomy: the Women’s Health Initiative randomized controlled trial. JAMA 2004;291:1701-1712. 125. Wasnich RD, Bagger YZ, Hosking DJ, et al; Early Postmenopausal Intervention Cohort Study Group. Changes in bone density and turnover after alendronate or estrogen withdrawal. Menopause 2004;11:622-630. 126. Heiss G, Wallace R, Anderson GL, et al; WHI Investigators. Health risks and benefits 3 years after stopping randomized treatment with estrogen and progestin. JAMA 2008;299:1036-1045. 127. LaCroix AZ, Chlebowski RT, Manson JE, et al; WHI Investigators. Health outcomes after stopping conjugated equine estrogens among postmenopausal women with prior hysterectomy: a randomized con- trolled trial. JAMA 2011;305:1305-1314. 128. Karim R, Dell RM, Greene DF, Mack WJ, Gallagher JC, Hodis HN. Hip fracture in postmenopausal women after cessation of hormone therapy: results from a prospective study in a large health management organ- ization. Menopause 2011;18:1172-1177. 129. Watts NB, Cauley JA, Jackson RD, et al; Women’s Health Initiative Investigators. No increase in fractures after stopping hormone therapy: results from the women’s health initiative. J Clin Endocrinol Metab 2017;102:302-308. 130. Xiao YP, Tian FM, Dai MW, Wang WY, Shao LT, Zhang L. Are estrogen-related drugs new alternatives for the management of osteo- arthritis? Arthritis Res Ther 2016;18:151. 131. de Klerk BM, Schiphof D, Groeneveld FP, et al. Limited evidence for a protective effect of unopposed oestrogen therapy for osteoarthritis of the hip: a systematic review. Rheumatology (Oxford) 2009;48: 104-112. 132. Watt FE. Hand osteoarthritis, menopause and menopausal hormone therapy. Maturitas 2016;83:13-18. 133. Tanamas SK, Wijethilake P, Wluka AE, et al. Sex hormones and structural changes in osteoarthritis: a systematic review. Maturitas 2011;69:141-156. 134. Barnabei VM, Cochrane BB, Aragaki AK, et al; Women’s Health Initiative Investigators. Menopausal symptoms and treatment-related effects of estrogen and progestin in the Women’s Health Initiative. Obstet Gynecol 2005;105:1063-1073. 135. Chlebowski RT, Cirillo DJ, Eaton CB, et al. Estrogen alone and joint symptoms in the Women’s Health Initiative randomized trial. Meno- pause 2013;20:600-608. 136. Ahmed N, Mandel R, Fain MJ. Frailty: an emerging geriatric syndrome. Am J Med 2007;120:748-753. 137. Van Pelt RE, Gavin KM, Kohrt WM. Regulation of body composition and bioenergetics by estrogens. Endocrinol Metab Clin North Am 2015;44:663-676. 138. Nedergaard A, Henriksen K, Karsdal MA, Christiansen C. Menopause, estrogens and frailty. Gynecol Endocrinol 2013;29:418-423. 139. Lightfoot AP, Cooper RG. The role of myokines in muscle health and disease. Curr Opin Rheumatol 2016;28:661-666. 140. Tiidus PM, Lowe DA, Brown M. Estrogen replacement and skeletal muscle: mechanisms and population health. J Appl Physiol (1985) 2013;115:569-578. 141. Everson GT, McKinley C, Kern F Jr. Mechanisms of gallstone formation in women. Effects of exogenous estrogen (Premarin) and dietary cho- lesterol on hepatic lipid metabolism. J Clin Invest 1991;87:237-246. 142. Cirillo DJ, Wallace RB, Rodabough RJ, et al. Effect of estrogen therapy on gallbladder disease. JAMA 2005;293:330-339. 143. Marjoribanks J, Farquhar C, Roberts H, Lethaby A, Lee J. Long-term hormone therapy for perimenopausal and postmenopausal women. Cochrane Database Syst Rev 2017;1:CD004143. 144. Brady CW. Liver disease in menopause. World J Gastroenterol 2015; 21:7613-7620. 145. Salpeter SR, Walsh JM, Ormiston TM, Greybar E, Buckley NS, Salpeter EE. Meta-analysis: effect of hormone-replacement therapy on components of the metabolic syndrome in postmenopausal women. Diabetes Obes Metab 2006;8:538-554. 146. Xu Y, Lin J, Wang S, Xiong J, Zhu Q. Combined estrogen replacement therapy on metabolic control in postmenopausal women with diabetes mellitus. Kaohsiung J Med Soc 2014;30:350-361. 147. Norman RJ, Flight IH, Rees MC. Oestrogen and progestogen hormone replacement therapy for peri-menopausal and post-menopausal women: weight and body fat distribution. Cochrane Database Syst Rev 2000;CD001018. 148. Jensen LB, Vestergaard P, Hermann AP, et al. Hormone replacement therapy dissociates fat mass and bone mass, and tends to reduce weight gain in early postmenopausal women: a randomized controlled 5-year clinical trial of the Danish Osteoporosis Prevention Study. J Bone Miner Res 2003;18:333-342. 149. Guthrie JR, Dennerstein L, Dudley EC. Weight gain and the menopause: a 5-year prospective study. Climacteric 1999;2:205-211. 150. Chen Z, Bassford T, Green SB, et al. Postmenopausal hormone therapy and body composition — a substudy of the estrogen plus progestin trial of the Women’s Health Initiative. Am J Clin Nutr 2005;82:651-656. 151. Espeland MA, Stefanick ML, Kritz-Silverstein D, et al. Effect of postmenopausal hormone therapy on body weight and waist and hip girths. Postmenopausal Estrogen-Progestin Investigations Study Inves- tigators. J Clin Endocrinol Metab 1997;82:1549-1556. 152. Margolis KL, Bonds DE, Rodabough RJ, et al; Women’s Health Initiative Investigators. Effect of estrogen plus progestin on the inci- dence of diabetes in postmenopausal women: results from the Women’s Health Initiative Hormone Trial. Diabetologia 2004;47:1175-1187. 153. Rubinow DR, Johnson SL, Schmidt PJ, Girdler S, Gaynes B. Efficacy of estradiol in perimenopausal depression: so much promise and so few answers. Depress Anxiety 2015;32:539-549. 154. Schmidt PJ, Ben Dor R, Martinez PE, et al. Effects of estradiol with- drawal on mood in women with past perimenopausal depression: a randomized clinical trial. JAMA Psychiatry 2015;72:714-726. 155. Phillips SM, Sherwin BB. Effects of estrogen on memory function in surgi- cally menopausal women. Psychoneuroendocrinology 1992;17: 485-495. 156. Sherwin BB. Estrogen and/or androgen replacement therapy and cognitive functioning in surgically menopausal women. Psychoneuroendocrinology 1988;13:345-357. 157. Espeland MA, Shumaker SA, Leng I, et al; WHIMSY Study Group. Long-term effects on cognitive function of postmenopausal hormone therapy prescribed to women aged 50 to 55 years. JAMA Intern Med 2013;1429-1436. 158. Henderson VW, St John JA, Hodis HN, et al. Cognitive effects of estradiol after menopause: a randomized trial of the timing hypothesis. Neurology 2016;87:699-708. 159. Marder K, Sano M. Estrogen to treat Alzheimer’s disease: too little, too late? So what’s a woman to do? Neurology 2000;54:2035-2037. 160. Resnick SM, Henderson VW. Hormone therapy and risk of Alzheimer disease: a critical time. JAMA 2002;288:2170-2172. 161. Brinton LA, Richesson D, Leitzmann MF, et al. Menopausal hormone therapy and breast cancer risk in the NIH-AARP Diet and Health Study Cohort. Cancer Epidemiol Biomarkers Prev 2008;17:3150-3160. 162. Grady D, Yaffe K, Kristof M, Lin F, Richards C, Barrett-Connor E. Effect of postmenopausal hormone therapy on cognitive function: the Heart and Estrogen/progestin Replacement Study. Am J Med 2002;113: 543-548. 163. Resnick SM, Maki PM, Rapp SR, et al; Women’s Health Initiative Study of Cognitive Aging Investigators. Effects of combination estrogen plus progestin hormone treatment on cognition and affect. J Clin Endocrinol Metab 2006;91:1802-1810. 164. Shumaker S, Legault C, Rapp S, et al; WHIMS Investigators. Estrogen plus progestin and the incidence of dementia and mild cognitive impair- ment in postmenopausal women: the Women’s Health Initiative Mem- ory Study: a randomized controlled trial. JAMA 2003;289:2651-2662. 165. Whitmer RA, Quesenberry CP, Zhou J, Yaffe K. Timing of hormone therapy and dementia: the critical window theory revisited. Ann Neurol 2011;69:163-169. 166. Shao H, Breitner JC, Whitmer RA, et al; Cache County Investigators. Hormone therapy and Alzheimer disease dementia: new findings from the Cache County Study. Neurology 2012;79:1846-1852. 167. Henderson VW, Benke KS, Green RC, Cupples LA, Farrer LA; MIRAGE Study Group. Postmenopausal hormone therapy and NAMS POSITION STATEMENT 750 Menopause, Vol. 24, No. 7, 2017 ß 2017 The North American Menopause Society

Copyright @ 2017 The North American Menopause Society. Unauthorized reproduction of this article is prohibited. Alzheimer’s disease risk: interaction with age. J Neurol Neurosurg Psychiatry 2005;76:103-105. 168. Imtiaz B, Tuppurainen M, Rikkonen T, et al. Postmenopausal hormone therapy and Alzheimer disease: a prospective cohort study. Neurology 2017;88:1062-1068. 169. Shumaker S, Legault C, Kuller L, et al; Women’s Health Initiative Memory Study. Conjugated equine estrogens and incidence of probable dementia and mild cognitive impairment in postmenopausal women: Women’s Health Initiative Memory Study. JAMA 2004;291: 2947-2958. 170. Resnick SM, Espeland MA, Jaramillo SA, et al. Postmenopausal hormone therapy and regional brain volumes: the WHIMS-MRI Study. Neurology 2009;72:135-142. 171. Coker LH, Espeland MA, Hogan PE, et al; WHIMS-MRI Study Group. Change in brain and lesion volumes after CEE therapies: the WHIMS- MRI studies. Neurology 2014;82:427-434. 172. Mikkola TS, Tuomikoski P, Lyytinen H, et al. Estradiol-based post- menopausal hormone therapy and risk of cardiovascular and all-cause mortality. Menopause 2015;22:976-983. 173. Savolainen-Peltonen H, Tuomikoski P, Korhonen P, et al. Cardiac death risk in relation to the age at initiation or the progestin component of hormone therapies. J Clin Endocrinol Metab 2016;101:2794-2801. 174. Tuomikoski P, Lyytinen H, Korhonen P, et al. the risk of fatal stroke in Finnish postmenopausal hormone therapy users before and after the Women’s Health Initiative: a cohort study. Maturitas 2015;81:384-388. 175. Carrasquilla GD, Berglund A, Gigante B, et al. Does menopausal hormone therapy reduce myocardial infarction risk if initiated early after menopause? A population-based case-control study. Menopause 2015;22:598-606. 176. Shufelt CL, Johnson BD, Berga SL, et al; Women’s Ischemia Syndrome Evaluation Study Group. Timing of hormone therapy, type of meno- pause, and coronary disease in women: data from the National Heart, Lung, and Blood Institute-sponsored Women’s Ischemia Syndrome Evaluation. Menopause 2011;18:943-950. 177. Boardman HM, Hartley L, Eisinga A, et al. Hormone therapy for preventing cardiovascular disease in post-menopausal women. Cochrane Database Syst Rev 2015;(3):CD002229. 178. Salpeter SR, Walsh JM, Greybar E, Salpeter EE. Brief report: coronary heart disease events associated with hormone therapy in younger and older women. A meta-analysis. J Gen Intern Med 2006;21:363-366. 179. Salpeter SR, Walsh JM, Greybar E, Ormiston TM, Salpeter EE. Mortality associated with hormone replacement therapy in younger and older women: a meta-analysis. J Gen Intern Med 2004;19:791-804. 180. Salpeter SR, Cheng J, Thabane L, Buckley NS, Salpeter EE. Bayesian meta-analysis of hormone therapy and mortality in younger postmeno- pausal women. Am J Med 2009;12:1016-1022. 181. Rossouw JE, Prentice RL, Manson JE, et al. Postmenopausal hormone therapy and risk of cardiovascular disease by age and years since menopause. JAMA 2007;297:1465-1477. 182. Schierbeck LL, Rejnmark L, Tofteng CL, et al. Effect of hormone replacement therapy on cardiovascular events in recently postmeno- pausal women: randomized trial. BMJ 2012;345:e6409. 183. Akhrass F, Evans AT, Wang Y, et al. Hormone replacement therapy is associated with less coronary atherosclerosis in postmenopausal women. J Clin Endocrinol Metab 2003;88:5611-5614. 184. Barrett-Connor E, Laughlin GA. Hormone therapy and coronary artery calcification in asymptomatic postmenopausal women: the Rancho Bernardo Study. Menopause 2005;12:40-48. 185. Manson JE, Allison MA, Rossouw JE, et al; WHI and WHI-CACS Investigators. Estrogen therapy and coronary-artery calcification. N Engl J Med 2007;356:2591-2602. 186. Harman SM, Black DM, Naftolin F, et al. Arterial imaging outcomes and cardiovascular risk factors in recently menopausal women: a random- ized trial. Ann Intern Med 2014;161:249-260. 187. Canonico M, Carcaillon L, Plu-Bureau G, Oger E, et al. Post- menopausal hormone therapy and risk of stroke: impact of the route of estrogen administration and type of progestogen. Stroke 2016;47: 1734-1741. 188. Renoux C, Dell 0 Aniello S, Garbe E, Suissa S. Transdermal and oral hormone replacement therapy and the risk of stroke: a nested case- control study. BMJ 2010;340:c2519. 189. Speroff L. Transdermal hormone therapy and the risk of stroke and venous thrombosis. Climacteric 2010;13:429-432. 190. Canonico M, Alhenc-Gelas M, Plu-Bureau G, Olie ´ V, Scarabin PY. Activated protein C resistance among postmenopausal women using transdermal estrogens: importance of progestogen. Menopause 2010;17: 1122-1127. 191. Canonico M, Oger E, Plu-Bureau G, et al; Estrogen and Thromboemb- olism Risk (ESTHER) Study Group. Hormone therapy and venous thromboembolism among postmenopausal women: impact of the route of estrogen administration and progestogens: the ESTHER study. Cir- culation 2007;115:840-845. 192. Stefanick ML, Anderson GL, Margolis KL, et al; WHI Investigators. Effects of conjugated equine estrogens on breast cancer and mammog- raphy screening in postmenopausal women with hysterectomy. JAMA 2006;295:1647-1657. 193. Cherry N, McNamee R, Heagerty A, Kitchner H, Hannaford P. Long- term safety of unopposed estrogen used by women surviving myocardial infarction: 14-year follow-up of the ESPRIT randomised controlled trial. BJOG 2014;121:700-705. 194. Santen RJ, Allred DC, Ardoin SP, et al; Endocrine Society. Postmeno- pausal hormone therapy: an Endocrine Society scientific statement. J Clin Endocrinol Metab 2010;95:s1-s66. 195. Beral V; Million Women Study Collaborators. Breast cancer and hormone-replacement therapy in the Million Women Study. Lancet 2003;362:419-427Erratum in: Lancet 2003;362:1160. 196. Brinton RD. Investigative models for determining hormone therapy- induced outcomes in brain: evidence in support of a healthy cell bias of estrogen action. Ann N Y Acad Sci 2005;1052:57-74. 197. Prentice RL, Manson JE, Langer RD, et al. Benefits and risks of postmenopausal hormone therapy when it is initiated soon after men- opause. Am J Epidemiol 2009;170:12-23. 198. Lyytinen H, Pukkala E, Ylikorkala O. Breast cancer risk in postmeno- pausal women using estrogen-only therapy. Obstet Gynecol 2006;108: 1354-1360. 199. Bakken K, Fournier A, Lund E, et al. Menopausal hormone therapy and breast cancer risk: impact of different treatments. The European Pro- spective Investigation into Cancer and Nutrition. Int J Cancer 2011;128:144-156. 200. Kerlikowske K, Miglioretti DL, Ballard-Barbash R, et al. Prognostic characteristics of breast cancer among postmenopausal hormone users in a screened population. J Clin Oncol 2003;21:4314-4321. 201. Schairer C, Lubin J, Troisi R, Sturgeon S, Brinton L, Hoover R. Meno- pausal estrogen and estrogen-progestin replacement therapy and breast cancer risk. JAMA ;283:485-491Erratum in: JAMA 2000;284: 2597. 202. Chen WY, Manson JE, Hankinson SE, et al. Unopposed estrogen therapy and the risk of invasive breast cancer. Arch Intern Med 2006;166:1027-1032. 203. Jones ME, Schoemaker MJ, Wright L, et al. Menopausal hormone therapy and breast cancer: what is the true size of the increased risk? Br J Cancer 2016;115:607-615. 204. Mikkola TS, Savolainen-Peltonen H, Tuomikoski P, et al. Reduced risk of breast cancer mortality in women using postmenopausal hormone therapy: a Finnish nationwide comparative study. Menopause 2016;23:1199-1203. 205. Chlebowski RT, Anderson GL, Gass M, et al; WHI Investigators. Estrogen plus progestin and breast cancer incidence and mortality in postmenopausal women. JAMA 2010;304:1684-1692. 206. Anderson GL, Chlebowski RT, Rossouw JE, et al. Prior hormone therapy and breast cancer risk in the Women’s Health Initiative randomized trial of estrogen plus progestin. Maturitas 2006;55: 103-115. 207. Chlebowski RT, Hendrix SL, Langer RD, et al; WHI Investigators. Influence of estrogen plus progestin on breast cancer and mammography in healthy postmenopausal women: the Women’s Health Initiative randomized trial. JAMA 2003;289:3243-3253. 208. Li CI, Daling JR, Tang MT, Haugen KL, Porter PL, Malone KE. Use of antihypertensive medications and breast cancer risk among women aged 55 to 74 years. JAMA Intern Med 2013;173:1629-1637. 209. O’Brien KM, Fei C, Sandler DP, Nichols HB, DeRoo LA, Weinberg CR. Hormone therapy and young-onset breast cancer. Am J Epidemiol 2015;181:799-807. 210. Pettersson A, Graff RE, Ursin G, et al. Mammographic density pheno- types and risk of breast cancer: a meta-analysis. J Natl Cancer Inst 2014;106; doi: 10. 1093/jnci/dju078. 211. Chlebowski RT, Anderson G, Pettinger M, et al; Women’s Health Initiative Investigators. Estrogen plus progestin and breast cancer detection by means of mammography and breast biopsy. Arch Intern Med 2008;168:370-377. NAMS POSITION STATEMENT Menopause, Vol. 24, No. 7, 2017 751

Copyright @ 2017 The North American Menopause Society. Unauthorized reproduction of this article is prohibited. 212. Harvey JA, Pinkerton JV, Baracat EC, Shi H, Chines AA, Mirkin S. Breast density changes in a randomized controlled trial evaluating bazedoxifene/conjugated estrogens. Menopause 2013;20:138-145. 213. Pinkerton JV, Harvey JA, Pan K, et al. Breast effects of bazedoxifene- conjugated estrogens: a randomized controlled trial. Obstet Gynecol 2013;121:959-968. 214. Pinkerton JV, Pickar JH, Racketa J, Mirkin S. Bazedoxifene/conjugated estrogens for menopausal symptom treatment and osteoporosis preven- tion. Climacteric 2012;15:411-418. 215. Rebbeck TR, Friebel T, Wagner T, et al; PROSE Study Group. Effect of short-term hormone replacement therapy on breast cancer risk reduction after bilateral prophylactic oophorectomy in BRCA1 and BRCA2 mutation carriers: the PROSE Study Group. J Clin Oncol 2005;23: 7804-7810. 216. Eisen A, Lubinski J, Gronwald J, et al; Hereditary Breast Cancer Clinical Study Group. Hormone therapy and the risk of breast cancer in BRCA1 mutation carriers. J Natl Cancer Inst 2008;100: 1361-1367. 217. Domchek SM, Mitchell G, Lindeman GJ, et al. Challenges to the development of new agents for molecularly defined patient subsets: lessons from BRCA1/2-associated breast cancer. J Clin Oncol 2011; 29:4224-4226. 218. Chai X, Domchek S, Kauff N, Rebbeck T, Chen J. RE: breast cancer risk after salpingo-oophorectomy in healthy BRCA1/2 mutation carriers: revisiting the evidence for risk reduction. J Natl Cancer Inst 2015;107; doi: 10. 1093/jnci/djv217. 219. Gabriel CA, Tigges-Cardwell J, Stopfer J, Erlichman J, Nathanson K, Domchek SM. Use oftotal abdominal hysterectomy and hormonereplace- ment therapy in BRCA1 and BRCA2 mutation carriers undergoing risk- reducing salpingo-oophorectomy. Fam Cancer 2009;8:23-28. 220. Heemskerk-Gerritsen BA, Seynaeve C, van Asperen CJ, et al; Heredi- tary Breast and Ovarian Cancer Research Group Netherlands. Breast cancer risk after salpingo-oophorectomy in healthy BRCA1/2 mutation carriers: revisiting the evidence for risk reduction. J Natl Cancer Inst 2015;107; doi: 10. 1093/jnci/djv033. 221. Col NF, Kim JA, Chlebowski RT. Menopausal hormone therapy after breast cancer: a meta-analysis and critical appraisal of the evidence. Breast Cancer Res 2005;7:R535-R540. 222. Durna EM, Wren BG, Heller GZ, Leader LR, Sjoblom P, Eden JA. Hormone replacement therapy after a diagnosis of breast cancer: cancer recurrence and mortality. Med J Aust 2002;177:347-351. 223. Decker DA, Pettinga JE, VanderVelde N, Huang RR, Kestin L, Burdakin JH. Estrogen replacement therapy in breast cancer survivors: a matched-controlled series. Menopause 2003;10:277-285. 224. Beckmann MW, Jap D, Djahansouzi S, et al. Hormone replacement therapy after treatment of breast cancer: effects on postmenopausal symptoms, bone mineral density and recurrence rates. Oncology 2001;60:199-206. 225. Marttunen MB, Hietanen P, Pyrhonen S, Tiitinen A, Ylikorkala O. A prospective study on women with a history of breast cancer and with or without estrogen replacement therapy. Maturitas 2001;39:217-225. 226. DiSaia PJ, Brewster WR, Ziogas A, Anton-Culver H. Breast cancer survival and hormone replacement therapy: a cohort analysis. Am J Clin Oncol 2000;23:541-545. 227. Ursic-Vrscaj M, Bebar S. A case-control study of hormone replacement therapy after primary surgical breast cancer treatment. Eur J Surg Oncol 1999;25:146-151. 228. Holmberg L, Iversen OE, Rudenstam CM, et al; HABITS Study Group. Increased risk of recurrence after hormone replacement therapy in breast cancer survivors. J Natl Cancer Inst 2008;100:475-482. 229. von Schoultz E, Rutqvist LE, Stockholm Breast Cancer Study G. Menopausal hormone therapy after breast cancer: the Stockholm randomized trial. J Natl Cancer Inst 2005;97:533-535. 230. Fahle ´n M, Fornander T, Johansson H, et al. Hormone replacement therapy after breast cancer: 10 year follow up of the Stockholm randomised trial. Eur J Cancer 2013;49:52-59. 231. Breast cancer and hormone replacement therapy: collaborative reanal- ysis of data from 51 epidemiological studies of 52,705 women with breast cancer and 108,411 without breast cancer. Collaborative Group on Hormonal Factors in Breast Cancer. Lancet 1997;350:1047-1059. Erra- tum in: Lancet 1997;350:1484. 232. Jordan VC. The new biology of estrogen-induced apoptosis applied to treat and prevent breast cancer. Endocr Relat Cancer 2015;22: R1-R31. 233. Chlebowski RT, Rohan TE, Manson JE, et al. Breast cancer after use of estrogen plus progestin and estrogen alone; analyses of data from 2 Women’s Health Initiative randomized clinical trials. JAMA Oncol 2015;1:296-305. 234. O’Donnell RL, Clement KM, Edmondson RJ. Hormone replacement therapy after treatment for a gynaecological malignancy. Curr Opin Obstet Gynecol 2016;28:32-41. 235. Shim SH, Lee SJ, Kim SN. Effects of hormone replacement therapy on the rate of recurrence in endometrial cancer survivors: a meta-analysis. Eur J Cancer 2014;50:1628-1637. 236. Barakat RR, Bundy BN, Spirtos NM, Bell J, Mannel RS; Gynecologic Oncology GroupStudy. Randomizeddouble-blind trialof estrogenreplace- ment therapy versus placebo in stage I or II endometrial cancer: a Gyneco- logic Oncology Group Study. J Clin Oncol 2006;24:587-592. 237. Hinds L, Price J. Menopause, hormone replacement and gynaecological cancers. Menopause Int 2010;16:89-93. 238. Ayhan A, Taskiran C, Simsek S, Sever A. Does immediate hormone replacement therapy affect the oncologic outcome in endometrial cancer survivors? Int J Gynecol Cancer 2006;16:805-808. 239. Singh P, Oehler MK. Hormone replacement after gynaecological cancer. Maturitas 2010;65:190-197. 240. Guidozzi F. Estrogen therapy in gynecological cancer survivors. Climacteric 2013;16:611-617. 241. Biliatis I, Thomakos N, Rodolakis A, Akrivos N, Zacharakis D, Antsaklis A. Safety of hormone replacement therapy in gynaecological cancer survivors. J Obstet Gynaecol 2012;32:321-325. 242. Dunton CJ, Kelsten ML, Brooks SE, Viglione MJ, Carlson JA, Mikuta JJ. Low-grade stromal sarcoma: DNA flow cytometric analysis and estrogen progesterone receptor data. Gynecol Oncol 1990;37:268-275. 243. Ursic-Vrscaj M. Hormone replacement therapy after uterine leiomyosar- coma treatment. Case reports. Eur J Gynaecol Oncol 1999;20:379-382. 244. Ryu H, Choi YS, Song IC, et al. Long-term treatment of residual or recurrent low-grade endometrial stromal sarcoma with aromatase inhibi- tors: a report of two cases and a review of the literature. Oncol Lett 2015;10:3310-3314. 245. Weiss NS, Lyon JL, Krishnamurthy S, Dietert SE, Liff JM, Daling JR. Noncontraceptive estrogen use and the occurrence of ovarian cancer. J Natl Cancer Inst 1982;68:95-98. 246. Mørch LS, Løkkegaard E, Andreasen AH, Kru ¨ger-Kjaer S, Lidegaard O. Hormone therapy and ovarian cancer. JAMA 2009;302:298-305. 247. Lacey JV Jr, Brinton LA, Leitzmann. et al. Menopausal hormone therapy and ovariancancer riskin the National Institutes ofHealth-AARPDietand Health Study Cohort. J Natl Cancer Inst 2006;98:1397-1405. 248. Greiser CM, Greiser EM, Do ¨ren M. Menopausal hormone therapy and risk of ovarian cancer: systematic review and meta-analysis. Hum Reprod Update 2007;13:453-463. 249. Zhou B, Sun Q, Cong R, et al. Hormone replacement therapy and ovarian cancer risk: a meta-analysis. Gynecol Oncol 2008;108:641-651. 250. Beral V; Million Women Study Collaborators, Bull D, Green J, Reeves G. Ovarian cancer and hormone replacement therapy in the Million Women Study. Lancet 2007;369:1703-1710. 251. Danforth KN, Tworoger SS, Hecht JL, Rosner BA, Colditz GA, Hankinson SE. A prospective study of postmenopausal hormone use and ovarian cancer risk. Br J Cancer 2007;96:151-156. 252. Trabert B, Wentzensen N, Yang HP, et al. Ovarian cancer and meno- pausal hormone therapy in the NIH-AARP diet and health study. Br J Cancer 2012;107:1181-1187. 253. Li D, Ding CY, Qiu LH. Postoperative hormone replacement therapy for epithelial ovarian cancer patients: a systematic review and meta- analysis. Gynecol Oncol 2015;139:355-362. 254. Mørch LS, Lidegaard Ø, Keiding N, Løkkegaard E, Kjær SK. The influence of hormone therapies on colon and rectal cancer. Eur J Epidemiol 2016;31:481-489. 255. Simon MS, Chlebowski RT, Wactawski-Wende J, et al. Estrogen plus progestin and colorectal cancer incidence and mortality. J Clin Oncol 2012;30:3983-3990. 256. Chlebowski RT, Wakelee H, Pettinger M, et al. Estrogen plus progestin and lung cancer: follow-up of the Women’s Health Initiative random- ized trial. Clin Lung Cancer 2016;17:10-17. 257. Chlebowski RT, Schwartz AG, Wakelee H, et al; Women’s Health Initiative Investigators. Oestrogen plus progestin and lung cancer in postmenopausal women (Women’s Health Initiative trial): a post-hoc analysis of a randomized trial. Lancet 2009;374: 1243-1251. NAMS POSITION STATEMENT 752 Menopause, Vol. 24, No. 7, 2017 ß 2017 The North American Menopause Society

Copyright @ 2017 The North American Menopause Society. Unauthorized reproduction of this article is prohibited. 258. Yao Y, Gu X, Zhu J, Yuan D, Song Y. Hormone replacement therapy in females can decrease the risk of lung cancer: a meta-analysis. PLoS One 2013;8:e71236. 259. Bae JM, Kim EH. Hormonal replacement therapy and the risk of lung cancer in women: an adaptive meta-analysis of cohort studies. J Prev Med Public Health 2015;48:280-286. 260. Oh SW, Myung SK, Park JY, Lym YL, Ju W. Hormone therapy and risk of lung cancer: a meta-analysis. J Womens Health (Larchmt) 2010; 19:279-288. 261. Pesatori AC, Carugno M, Consonni D, et al. Hormone use and risk for lung cancer: a pooled analysis from the International Lung Cancer Consortium (ILCCO). Br J Cancer 2013;109:1954-1964. 262. Chen X, Cai L. Meta-analysis of the effects of hormone replacement therapy and oral contraceptives associated with female lung cancer risk. [Article in Chinese]. Wei Sheng Yan Jiu 2009;38:672-676. 263. Banks E, Beral V, Reeves G, Balkwill A, Barnes I; Million Women Study Collaborators. Fracture incidence in relation to the pattern of use of hormone therapy in postmenopausal women. JAMA 2004;291: 2212-2220. 264. Haentjens P, Magaziner J, Colo ´n-Emeric CS, et al. Meta-analysis: excess mortality after hip fracture among older women and men. Ann Intern Med 2010;152:380-390. 265. Bassuk SS, Manson JE. Oral contraceptives and menopausal hormone therapy: relative and attributable risks of cardiovascular disease, cancer, and other health outcomes. Ann Epidemiol 2015;25:193-200. 266. Mikkola TS, Tuomikoski P, Lyytinen H, et al. Increased cardiovascular mortality risk in women discontinuing postmenopausal hormone therapy. J Clin Endocrinol Metab 2015;100:4588-4594. 267. Gartoulla P, Worsley R, Bell RJ, Davis SR. Moderate to severe vaso- motor and sexual symptoms remain problematic for women aged 60 to 65 years. Menopause 2015;22:694-701. 268. Vikstrom J, Spetz Holm A, Sydsjo G, Marcusson J, Wressle E, Hammar M. Hot flashes still occur in a population of 85-year-old Swedish women. Climacteric 2013;16:453-459. 269. Bergendal A, Kieler H, Sundstro ¨m A, Hirschberg AL, Kocoska-Maras L. Risk of venous thromboembolism associated with local and systemic use of hormone therapy in peri- and postmenopausal women and in relation to type and route of administration. Menopause 2016;23: 593-599. 270. Sarrel P, Portman D, Lefebvre P, et al. Incremental direct and indirect costs of untreated vasomotor symptoms. Menopause 2015;22:260-266. 271. Geukes M, van Aalst MP, Nauta MC, Oosterhof H. The impact of menopausal symptoms on work ability. Menopause 2012;19: 278-282. 272. Salpeter SR, Buckley NS, Liu H. Salpeter EE The cost-effectiveness of hormone therapy in younger and older postmenopausal women. Am J Med 2009;122:42-52e2. 273. Roth JA, Etzioni R, Waters TM, et al. Economic return from the Women’s Health Initiative estrogen plus progestin clinical trial: a modeling study. Ann Intern Med 2014;160:594-602. 274. Utian WH. Psychosocial and socioeconomic burden of vasomotor symptoms in menopause: a comprehensive review. Health Qual Life Outcomes 2005;3:47-58. 275. Sarrel PM, Njike VY, Vinante V, Katz DL. The mortality toll of estrogen avoidance: an analysis of excess deaths among hysterectomized women aged 50 to 59 years. Am J Public Health 2013;103:1583-1588. NAMS POSITION STATEMENT Menopause, Vol. 24, No. 7, 2017 753