1. Menopause Review on Treatment Ivan Ying Department of Medicine, Schulich School of Medicine and Dentistry University of Western Ontario University of Western Ontario Endocrinology Rounds Wednesday January 27 2010

2. Outline Introduction Introduction Definitions, hormonal changes, diagnosis Definitions, hormonal changes, diagnosis Symptoms Symptoms Treatment Treatment HRT and Cancer HRT and Cancer Cardiovascular Disease Cardiovascular Disease Osteoporosis Osteoporosis

3. Case Presentation 1 49 year old female presents because of menopausal symptoms 49 year old female presents because of menopausal symptoms PMH includes hypertension adequately treated with Avapro PMH includes hypertension adequately treated with Avapro 2 children aged 18 and 14 2 children aged 18 and 14 Non smoker, 1-2 glasses of wine a day Non smoker, 1-2 glasses of wine a day Unable to tolerate hot flashes up to 4 to 5 times a day Unable to tolerate hot flashes up to 4 to 5 times a day Poor sleep Poor sleep Random “panic attacks” associated with sweating and intense anxiety Random “panic attacks” associated with sweating and intense anxiety Sexual dysfunction (dyspareunia) causing strain on relationship with husband Sexual dysfunction (dyspareunia) causing strain on relationship with husband Still menstruating, but highly variable cycle Still menstruating, but highly variable cycle

4. Case Presentation 2 63 year old female presents because of menopausal symptoms 63 year old female presents because of menopausal symptoms PMH includes diabetes, HTN, hypercholesteremia, CAD with stent, previous hysterectomy PMH includes diabetes, HTN, hypercholesteremia, CAD with stent, previous hysterectomy Medications include metformin, glyburide Avapro, Crestor, ASA and Plavix Medications include metformin, glyburide Avapro, Crestor, ASA and Plavix Family history significant for a sister with breast cancer at age 55 Family history significant for a sister with breast cancer at age 55 Married, retired with no children Married, retired with no children Amenorrhea since age 53, no previous HRT Amenorrhea since age 53, no previous HRT Unable to tolerate intense hot flashes 4 to 5 times a day Unable to tolerate intense hot flashes 4 to 5 times a day

5. Introduction In 2009, largest demographic of “baby boomers” will reach the age of 50 In 2009, largest demographic of “baby boomers” will reach the age of 50 Increased need for an understanding and the symptoms and proper management of menopause Increased need for an understanding and the symptoms and proper management of menopause Major health issues surrounding menopause: Major health issues surrounding menopause: Cardiovascular disease Cardiovascular disease Osteoporosis Osteoporosis HRT and breast cancer risk HRT and breast cancer risk

6. Introduction What is menopause? What is menopause? The cessation of menstrual periods, occurs secondary to the genetically programmed loss of ovarian follicles The cessation of menstrual periods, occurs secondary to the genetically programmed loss of ovarian follicles Mean age of 51.4 in US Mean age of 51.4 in US Block, E, Acta Anat 1952; 14:108 and Gougeon, A, Contraception Fertile Sexual 1984; 12:527.

7. Introduction STRAW (Stages of Reproductive Aging Workshop) Staging System STRAW (Stages of Reproductive Aging Workshop) Staging System

8. Introduction During early menopausal transition, changes in the hormones levels begin to occur During early menopausal transition, changes in the hormones levels begin to occur Decrease in number of follicles causes an overall rise in FSH, a preserved to high estradiol level and low progesterone levels Decrease in number of follicles causes an overall rise in FSH, a preserved to high estradiol level and low progesterone levels Hormone levels highly variable during menopause but ultimately leads to a lack of estradiol secretion from the ovary and a high FSH level Hormone levels highly variable during menopause but ultimately leads to a lack of estradiol secretion from the ovary and a high FSH level

9. Introduction

10. Introduction Diagnosis Diagnosis Clinical diagnosis Clinical diagnosis 1 year of amenorrhea after the final menstrual period 1 year of amenorrhea after the final menstrual period Routine measurement of hormone levels (in particular FSH/estradiol) are not recommended because of the high variability during late menopausal transition Routine measurement of hormone levels (in particular FSH/estradiol) are not recommended because of the high variability during late menopausal transition

11. Symptoms Vasomotor symptoms Vasomotor symptoms Hot flashes Hot flashes Sweating Sweating Anxiety Anxiety Palpitations Palpitations Urogenital symptoms Urogenital symptoms Vaginal Dryness Vaginal Dryness Sexual Dysfunction Sexual Dysfunction Incontinence? Incontinence?

12. Symptoms Other symptoms Other symptoms Sleep disturbance Sleep disturbance Depression Depression Breast Pain Breast Pain Menstrual migraines Menstrual migraines Joint pain Joint pain Skin changes Skin changes

13. Treatment Vasomotor Symptoms Vasomotor Symptoms Lifestyle changes: regular exercise, weight management, smoking cessation and avoiding known food triggers (EtOH, hot drinks) (Grade IC) Lifestyle changes: regular exercise, weight management, smoking cessation and avoiding known food triggers (EtOH, hot drinks) (Grade IC) Non hormonal treatment (clonidine, SNRIs, gabapentin) considered when HRT is contraindicated or not wanted by patient (Grade IB ) Non hormonal treatment (clonidine, SNRIs, gabapentin) considered when HRT is contraindicated or not wanted by patient (Grade IB ) HRT is the most effective medical management of vasomotor symptoms (Grade IA) HRT is the most effective medical management of vasomotor symptoms (Grade IA)

14. Treatment Non-hormonal treatment Non-hormonal treatment Clonidine: some conflicting evidence for efficacy, poorly tolerated because of side effect profile (dry mouth, dizziness, constipation) Clonidine: some conflicting evidence for efficacy, poorly tolerated because of side effect profile (dry mouth, dizziness, constipation) SNRIs: 2 relatively small RCTs showed it was more effective than placebo, reducing vasomotor symptoms by about ~35% with 75mg/day SNRIs: 2 relatively small RCTs showed it was more effective than placebo, reducing vasomotor symptoms by about ~35% with 75mg/day Gabapentin: Some evidence from small RCTs showing more effective than placebo, especially in tamoxifen induced vasomotor symptoms Gabapentin: Some evidence from small RCTs showing more effective than placebo, especially in tamoxifen induced vasomotor symptoms

15. Treatment Natural Health Products Natural Health Products Limited evidence for natural health products for treatment of moderate to severe vasomotor symptoms Limited evidence for natural health products for treatment of moderate to severe vasomotor symptoms Several systematic reviews showed no single NHP has convincingly showed effectiveness for the treatment of vasomotor symptoms Several systematic reviews showed no single NHP has convincingly showed effectiveness for the treatment of vasomotor symptoms RCT of HT versus soy, black cohosh and multibotanicals showed only HT superior to placebo for symptom relief 1 (Herbal Alternatives for Menopause Trial, HALT) RCT of HT versus soy, black cohosh and multibotanicals showed only HT superior to placebo for symptom relief 1 (Herbal Alternatives for Menopause Trial, HALT) 1 Newton KM, Reed SD, LaCroix AZ, Grothaus LC, Ehrlich K, Guiltinan J. Treatment of vasomotor symptoms of menopause with black cohosh, multibotanicals, soy, hormone therapy, or placebo: a randomized trial. Ann Intern Med 2006;145:869–79.

16. Treatment

17. Treatment Vasomotor symptoms Vasomotor symptoms Progestin and low dose oral contraception can be used for menopausal symptoms in the menopausal transition phase (Grade IA) Progestin and low dose oral contraception can be used for menopausal symptoms in the menopausal transition phase (Grade IA)

18. Treatment Urogenital Symptoms – Vaginal Atrophy Urogenital Symptoms – Vaginal Atrophy Vaginal lubricants (Astroglide©) for dyspareunia (Grade IIIC) Vaginal lubricants (Astroglide©) for dyspareunia (Grade IIIC) Vaginal moisturizer (Replens©) for vaginal dryness and dyspareunia (Grade IA) Vaginal moisturizer (Replens©) for vaginal dryness and dyspareunia (Grade IA) Estrogen cream, estradiol ring or tablets all effective for vaginal dryness (Grade IA) Estrogen cream, estradiol ring or tablets all effective for vaginal dryness (Grade IA)

19. Treatment Urogenital Symptoms - Incontinence Urogenital Symptoms - Incontinence HRT not recommended for treatment of stress or urge incontinence (Grade IA) HRT not recommended for treatment of stress or urge incontinence (Grade IA) HERS trial showed a 12% increased risk of weekly urge incontinence and a 15% increased risk of weekly stress incontinence 1 HERS trial showed a 12% increased risk of weekly urge incontinence and a 15% increased risk of weekly stress incontinence 1 2003 Cochrane review of 15 small trials showed 50% of women treated with HRT reported symptom improvement versus 25% of placebo 2 2003 Cochrane review of 15 small trials showed 50% of women treated with HRT reported symptom improvement versus 25% of placebo 2 Data is conflicting and pathophysiology of estrogen and urinary symptoms is poorly understood Data is conflicting and pathophysiology of estrogen and urinary symptoms is poorly understood 1 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;97:116–20. 2 Moehrer B, Hextall A, Jackson S. Oestrogens for urinary incontinence in women. Cochrane Database Syst Rev 2003;2:CD001405.

20. Treatment Urogenital Symptoms – Incontinence Urogenital Symptoms – Incontinence Stress: pelvic floor exercises, weight loss, intravaginal pessaries Stress: pelvic floor exercises, weight loss, intravaginal pessaries Urge: lifestyle modification, antimuscarinic therapy Urge: lifestyle modification, antimuscarinic therapy

21. Hormone Replacement Therapy Recommendations: Recommendations: Low dose estrogen (0.3mg of conjugated estrogen or 0.5mg of estradiol), although 0.625mg conjugated estrogen used most often Low dose estrogen (0.3mg of conjugated estrogen or 0.5mg of estradiol), although 0.625mg conjugated estrogen used most often Progestin therapy recommended for any patient receiving HRT and an intact uterus (medroxyprogesterone acetate, MPA 2.5mg) Progestin therapy recommended for any patient receiving HRT and an intact uterus (medroxyprogesterone acetate, MPA 2.5mg) Consider estrogen therapy alone for patients with hysterectomy Consider estrogen therapy alone for patients with hysterectomy

22. Hormone Replacement Therapy What about breast cancer? What about breast cancer? Increased risk (RR:1.3) of EPT and breast cancer after 5 years of use Increased risk (RR:1.3) of EPT and breast cancer after 5 years of use WHI showed increased risk after 3 years in patients with previous HRT use, but no increased risk after 5 years in patients without previous HRT WHI showed increased risk after 3 years in patients with previous HRT use, but no increased risk after 5 years in patients without previous HRT Estrogen only arm showed no increased risk, and in fact a non-significant decreased risk of breast cancer Estrogen only arm showed no increased risk, and in fact a non-significant decreased risk of breast cancer

23. Hormone Replacement Therapy What about breast cancer? What about breast cancer? RR of 1.023 for each year of HRT use, comparable (RR: 1.028) increased risk for delayed menopause 1 RR of 1.023 for each year of HRT use, comparable (RR: 1.028) increased risk for delayed menopause 1 In comparison, a clinically significant epidemiologically RR is 3, positive FmHx (RR:3), BRCA gene mutation (RR: 200) In comparison, a clinically significant epidemiologically RR is 3, positive FmHx (RR:3), BRCA gene mutation (RR: 200) “Million women study” showed that there was no increased risk of breast cancer in all patients who ceased HRT regardless of duration of treatment or time since discontinuation 2 “Million women study” showed that there was no increased risk of breast cancer in all patients who ceased HRT regardless of duration of treatment or time since discontinuation 2 Most women use HRT for symptomatic relief for less than 5 years, median duration of 2 years 1 Most women use HRT for symptomatic relief for less than 5 years, median duration of 2 years 1 1 Collaborative Group on Hormonal Factors in Breast Cancer. Breast cancer and hormone replacement therapy: collaborative reanalysis of data from 51 epidemiological studies of 52,705 women with breast cancer and 108,411 women without breast cancer. Lancet 1997;350:1047–59 2 Beral V; for the Million Women Study Collaborators. Breast cancer and hormone-replacement therapy in the Million Women Study. Lancet 2003;362:419–27.

24. Hormone Replacement Therapy What about breast cancer? What about breast cancer? Original study that sparked controversy was the WHI that showed a HR of 1.24 for developing breast cancer (after 5 years) Original study that sparked controversy was the WHI that showed a HR of 1.24 for developing breast cancer (after 5 years) Comparisons of other risk factors such as late menopause, excessive EtOH consumption, first pregnancy after age 30, choosing not to breast feed carry comparable HR of about 1.3 Comparisons of other risk factors such as late menopause, excessive EtOH consumption, first pregnancy after age 30, choosing not to breast feed carry comparable HR of about 1.3

25. Hormone Replacement Therapy What about breast cancer? What about breast cancer? Family history: Patients on HRT with a family history of breast cancer are not at increased risk compared to baseline risk from family history Family history: Patients on HRT with a family history of breast cancer are not at increased risk compared to baseline risk from family history Personal history of breast cancer: HABITs trial showed a higher rate of recurrence in the HRT arm 1 (22% recurrence in the HRT arm and 8% in the control arm) Personal history of breast cancer: HABITs trial showed a higher rate of recurrence in the HRT arm 1 (22% recurrence in the HRT arm and 8% in the control arm) 1 Holmberg L, Iversen OE, Rudenstam CM, Hammar M, Kumpulainen E, Jaskiewicz J, et al; HABITS Study Group. Increased risk of recurrence after hormone replacement therapy in breast cancer survivors. J Natl Cancer Inst 2008;100:475–82.

26. Hormone Replacement Therapy What about breast cancer? What about breast cancer? SOGC recommends that “short term use of HRT for disruptive vasomotor symptoms carries little appreciable risk for the average woman entering menopause” SOGC recommends that “short term use of HRT for disruptive vasomotor symptoms carries little appreciable risk for the average woman entering menopause” Continue with regular mammography, periodic health exams including breast exams Continue with regular mammography, periodic health exams including breast exams Focus on risk factor modification such as regular excercise, decrease EtOH, smoking cessation, weight loss Focus on risk factor modification such as regular excercise, decrease EtOH, smoking cessation, weight loss

27. Cardiovascular Disease Observational studies originally pointed towards the cardioprotective effects of HRT Observational studies originally pointed towards the cardioprotective effects of HRT WHI originally reported an increased risk of MI and stroke for patients on EPT WHI originally reported an increased risk of MI and stroke for patients on EPT Follow-up analysis of the data showed no statistically significant increased risk of MI/stroke but an increased risk in the first year of initiating therapy Follow-up analysis of the data showed no statistically significant increased risk of MI/stroke but an increased risk in the first year of initiating therapy

28. Cardiovascular Disease Risk of CVD and HRT appears to be age dependent Risk of CVD and HRT appears to be age dependent WHI and HERS showed increased risk of CVD in the first year of treatment in older women (average age in WHI was 13 years after menopause) WHI and HERS showed increased risk of CVD in the first year of treatment in older women (average age in WHI was 13 years after menopause) Nurses Health Study found a decreased risk of CVD in women starting HRT under the age of 55 Nurses Health Study found a decreased risk of CVD in women starting HRT under the age of 55

29. Cardiovascular Disease Several subset analysis of these large cohorts show statistically significant cardioprotective effects of HRT when initiated early from the onset of menopause and an increased risk of CVD when initiated >10 years after menopause Several subset analysis of these large cohorts show statistically significant cardioprotective effects of HRT when initiated early from the onset of menopause and an increased risk of CVD when initiated >10 years after menopause

30. Cerebrovascular Disease Meta-analysis of large RCTs (including HERS and WHI) points towards a possible increased risk of ischemic stroke (but not TIA or hemorrhagic stroke) (RR ~1.3) Meta-analysis of large RCTs (including HERS and WHI) points towards a possible increased risk of ischemic stroke (but not TIA or hemorrhagic stroke) (RR ~1.3) Unlike cardiovascular disease, risk does not seem to be related to timing of HRT Unlike cardiovascular disease, risk does not seem to be related to timing of HRT

31. Cardiovascular Disease Mainstay of treatment is known risk factor modification: lifestyle, hypertension, diabetes, hypercholesterolemia Mainstay of treatment is known risk factor modification: lifestyle, hypertension, diabetes, hypercholesterolemia HRT should not be used for the sole purpose of prevent CVD (Grade IA) HRT should not be used for the sole purpose of prevent CVD (Grade IA) Initiating HRT in older post-menopausal women should be done with counselling and caution, low dose estrogen preferred (Grade IA) Initiating HRT in older post-menopausal women should be done with counselling and caution, low dose estrogen preferred (Grade IA)

32. Osteoporosis Mainstay treatment is adequate calcium, vitamin D and bisphosphonate therapy for those at high risk Mainstay treatment is adequate calcium, vitamin D and bisphosphonate therapy for those at high risk What about HRT? What about HRT? Estrogen is known to significantly increase osteoblast activity Estrogen is known to significantly increase osteoblast activity WHI showed a ~35% reduction in fractures in the estrogen only arm and ~24% reduction in the EPT arm WHI showed a ~35% reduction in fractures in the estrogen only arm and ~24% reduction in the EPT arm

33. Osteoporosis What about low or ultra low dose estrogen? What about low or ultra low dose estrogen? 0.3mg of conjugated estrogen of 0.5mg of estradiol considered “low dose” and 0.15mg conjugated estrogen considered ultra low dose 0.3mg of conjugated estrogen of 0.5mg of estradiol considered “low dose” and 0.15mg conjugated estrogen considered ultra low dose RCTs have shown low dose helps prevent osteoporosis, but no RCTs showing if it reduces fracture risk RCTs have shown low dose helps prevent osteoporosis, but no RCTs showing if it reduces fracture risk

34. Osteoporosis Recommendations: Recommendations: HRT should be used for menopausal symptoms and is a reasonable choice for the prevention of bone loss and fracture (Grade IA) HRT should be used for menopausal symptoms and is a reasonable choice for the prevention of bone loss and fracture (Grade IA) Low dose and UL dose estrogen can be used for menopausal symptoms, no evidence for reduction of fracture risk (Grade IA) Low dose and UL dose estrogen can be used for menopausal symptoms, no evidence for reduction of fracture risk (Grade IA)

35. Mood and Cognition Estrogen can be used to augment the effect of traditional anti-depressants in perimenopausal women may also be used alone to treat depressive symptoms (Grade IA) Estrogen can be used to augment the effect of traditional anti-depressants in perimenopausal women may also be used alone to treat depressive symptoms (Grade IA) Estrogen should not be used for the primary or secondary prevention of dementia (Grade IB) Estrogen should not be used for the primary or secondary prevention of dementia (Grade IB)

36. Back to Case 1 49 year old female presents to your office complaining of menopausal symptoms 49 year old female presents to your office complaining of menopausal symptoms PMH includes hypertension adequately treated with Avapro PMH includes hypertension adequately treated with Avapro 2 children aged 18 and 14 (born when she was 31 and 35) 2 children aged 18 and 14 (born when she was 31 and 35) Non smoker, 1-2 glasses of wine a day Non smoker, 1-2 glasses of wine a day Hot flashes on almost daily basis Hot flashes on almost daily basis Poor sleep Poor sleep Random “panic attacks” associated with sweating and intense anxiety Random “panic attacks” associated with sweating and intense anxiety Sexual dysfunction (dyspareunia) causing strain on relationship with husband Sexual dysfunction (dyspareunia) causing strain on relationship with husband Still menstruating, but highly variable cycle Still menstruating, but highly variable cycle

37. Back to the Case 1 49 in menopausal transition 49 in menopausal transition Vasomotor symptoms: Lifestyle modification; HRT or OCP both reasonable options to help control her symptoms, if HRT is chosen low dose estrogen with progestin is recommended Vasomotor symptoms: Lifestyle modification; HRT or OCP both reasonable options to help control her symptoms, if HRT is chosen low dose estrogen with progestin is recommended Urogenital symptoms: Local estrogen through a ring or cream, as well non hormonal treatment such as lubricants Urogenital symptoms: Local estrogen through a ring or cream, as well non hormonal treatment such as lubricants Breast cancer: increased risk of breast cancer is considered minimal, recommend short term use (<5 years), risk is back to baseline soon after cessation of therapy Breast cancer: increased risk of breast cancer is considered minimal, recommend short term use (<5 years), risk is back to baseline soon after cessation of therapy Cardiovascular disease: Focus on traditional risk factor modification, but HRT at this stage of menopause may be cardio protective Cardiovascular disease: Focus on traditional risk factor modification, but HRT at this stage of menopause may be cardio protective Osteoporosis: Adequate calcium and vitamin D intake, bisphosphonates if indicated; HRT considered protective but not used as primary treatment Osteoporosis: Adequate calcium and vitamin D intake, bisphosphonates if indicated; HRT considered protective but not used as primary treatment

38. Back to Case 2 63 year old female presents because of menopausal symptoms 63 year old female presents because of menopausal symptoms PMH includes diabetes, HTN, hypercholesteremia, CAD with stent, previous hysterectomy PMH includes diabetes, HTN, hypercholesteremia, CAD with stent, previous hysterectomy Medications include metformin, glyburide Avapro, Crestor, ASA and Plavix Medications include metformin, glyburide Avapro, Crestor, ASA and Plavix Family history significant for a sister with breast cancer at age 55 Family history significant for a sister with breast cancer at age 55 Married, retired with no children Married, retired with no children Amenorrhea since age 53, no previous HRT Amenorrhea since age 53, no previous HRT Unable to tolerate intense hot flashes 4 to 5 times a day Unable to tolerate intense hot flashes 4 to 5 times a day

39. Back to Case 2 63 year old female 10 years post menopause 63 year old female 10 years post menopause HRT still a viable option because of severe vasomotor symptoms HRT still a viable option because of severe vasomotor symptoms If HRT is chosen, should be given unopposed estrogen (previous hysterectomy, may not increase breast cancer risk) If HRT is chosen, should be given unopposed estrogen (previous hysterectomy, may not increase breast cancer risk) HRT should not increase baseline risk given family history HRT should not increase baseline risk given family history Risk of CVD should be a serious point of discussion, evidence clearly points to an increased risk of MI and stroke in the first year in this population Risk of CVD should be a serious point of discussion, evidence clearly points to an increased risk of MI and stroke in the first year in this population

40. Questions? Comments?